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WO2007018272A1 - Sugar-modified liposome and composition for drug delivery containing the liposome - Google Patents

Sugar-modified liposome and composition for drug delivery containing the liposome Download PDF

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Publication number
WO2007018272A1
WO2007018272A1 PCT/JP2006/315882 JP2006315882W WO2007018272A1 WO 2007018272 A1 WO2007018272 A1 WO 2007018272A1 JP 2006315882 W JP2006315882 W JP 2006315882W WO 2007018272 A1 WO2007018272 A1 WO 2007018272A1
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WIPO (PCT)
Prior art keywords
bond
sugar chain
ribosome
item
modified
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Ceased
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PCT/JP2006/315882
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French (fr)
Japanese (ja)
Inventor
Noboru Yamazaki
Shuuji Kojima
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National Institute of Advanced Industrial Science and Technology AIST
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National Institute of Advanced Industrial Science and Technology AIST
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Priority to JP2007529625A priority Critical patent/JPWO2007018272A1/en
Publication of WO2007018272A1 publication Critical patent/WO2007018272A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a drug delivery system for treatment for recognizing a target cell / tissue such as cancer and locally delivering a drug or gene to an affected area, which can be applied in the medical and pharmaceutical fields including pharmaceuticals and cosmetics.
  • the present invention relates to a sugar chain-modified ribosome excellent in intestinal absorbability and a drug delivery composition encapsulating a substance to be delivered into the body, which can be used as a diagnostic cell 'tissue sensing probe.
  • DDS drug and gene delivery system
  • the nanotechnology / materials promotion strategy of the Council for Science and Technology in Japan also includes “Nanobiology that uses and controls the mechanisms of materials and organisms” as an important area, and is one of the five years of research and development goals.
  • NNI National Nanotechnology Strategy
  • DDS drug and gene delivery system
  • the nanotechnology / materials promotion strategy of the Council for Science and Technology in Japan also includes “Nanobiology that uses and controls the mechanisms of materials and organisms” as an important area, and is one of the five years of research and development goals.
  • One example is “Establishment of basic seeds for biofunctional materials and pinpoint treatment technologies for extending health and life expectancy”.
  • the incidence and mortality of cancer has been increasing year by year as it becomes an aging society, and the development of target-oriented DDS, which is a novel therapeutic material, is awaited.
  • the importance of targeted DDS nanomaterials with no side effects in other diseases is drawing attention, and the scale of the field is expected to exceed 10 trillion yen in the near future.
  • an active targeting method is also attempted.
  • This is an ideal targeting method, also called “missile drug”, but it has not been completed in Japan and overseas, and future development is greatly expected.
  • a ligand is bound on the ribosome membrane surface, and it is allowed to actively target by allowing the receptor present on the cell membrane surface of the target tissue to specifically recognize.
  • Receptor ligands present on the cell membrane surface targeted by this active targeting method may include antigens, antibodies, peptides, glycolipids and glycoproteins.
  • glycolipids and glycoprotein sugar chains are involved in various cell-to-cell communications such as the generation and morphogenesis of biological tissues, cell proliferation and differentiation, biological defense and fertilization mechanisms, canceration and metastasis mechanisms. It is becoming clear that it plays an important role as an information molecule!
  • Non-Patent Document 5 Non-Patent Document 6, Non-Patent Document 7, and Non-Patent Document 8
  • DDS material As a new type of DDS material research, the development of DDS materials that can be used by oral administration, which is the easiest and cheapest to administer, is also an important issue.
  • peptidic drugs are generally water-soluble and have a high molecular weight, and the gastrointestinal tract has a low permeability to the small intestinal mucosa. Therefore, research on ligand-bound ribosomes is attracting attention as a DDS material for delivering these high molecular weight drugs and genes from the intestinal tract into the blood (see Non-Patent Document 9).
  • Patent Document 1 discloses a pharmaceutical composition having a pharmaceutically acceptable carrier and a compound containing a component that selectively binds to a selectin receptor.
  • a sugar chain intended for oral administration is used as a pharmaceutical agent itself for inhibiting inflammatory diseases and other diseases mediated by cell adhesion. Is different.
  • the present inventors have developed a sugar chain-modified liposome in which a sugar chain is bound to a ribosome via a linker protein (Patent Document 2). Furthermore, it was found that the type of sugar chain and the amount of sugar chain binding seem to be related to the directivity to each target cell or target tissue (Patent Documents 3 to 5 and Non-Patent Document 10). However, to date, no glycosylated ribosome optimal for delivery to the small intestine has been developed. In addition, there has been no systematic study on sugar chains useful in small intestine delivery, and it has remained unclear what kind of sugar chains should be used.
  • Patent Literature 1 Japanese Patent Publication No. 5-507519
  • Patent Document 2 Japanese Patent Laid-Open No. 2003-226638
  • Patent Document 3 Japanese Patent Laid-Open No. 2003-226647
  • Patent Document 4 WO 2005/011632
  • Patent Document 5 WO 2005/011633
  • Non-patent literature l Yamazaki, N., Kojima, S., Bovin, ⁇ . V., Andre, S., Gabius, S. and Gabius, H. —J. (2000) Adv. Drug Delivery Rev. 43 , 225— 24
  • Non-Patent Document 2 Yamazaki, N., Jigami, ⁇ ., Gabius, ⁇ . —J., Kojima, S (200 1) Trends in Glycoscience and Glycotechnology 13, 319— 329. http: / / www. Gak. Co .jp / TIGG / 71PDF / yamazaki.pdf
  • Non-Patent Document 3 Forssen, E. and Willis, M. (1998) Adv. Drug Delivery Rev. 29, 249-271.
  • Non-Patent Document 4 Toshio Takahashi 'Hashida Mitsuru (1999), Today's DDS ⁇ Drug Delivery System, 159, 167, Pharmaceutical Jana Nano, Osaka)
  • Non-Patent Document 5 DeFrees, S. A., Phillips, L., Guo, L. and Zalipsky, S. (19 96) J. Am. Chem. Soc. 118, 6101— 6104.
  • Non-Patent Document 6 Spevak, W., Foxall, C., Charych, D.H., Dasqupta, F. and
  • Non-Patent Document 7 Stahn, R., Schafer, H., Kernchen, F. and Schreiber, J. (1 998) Glycobiology 8, 311—319.
  • Non-Patent Document 8 Yamazaki, N., Jigami, Y., Gabius, H. —J., Kojima, S (200
  • Non-patent document 9 Lehr, C. — M. (2000) J. Controlled Release 65, 19—29
  • Non-patent document 10 Noboru Yamayose (2005), Development of active 'targeting DDS nanoparticles, 3, 97- 102
  • an object of the present invention is to provide a sugar chain-modified ribosome useful for in-vivo delivery such as oral administration, and a drug delivery composition in which a drug or gene is encapsulated in the sugar chain-modified ribosome.
  • Manal, 6 Manal, 3 (Manal, 3) Manal, 6Manbl, 4GlcNAcbl, 4GlcNAc,
  • Manal, 6 Manal, 3 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,
  • Galb l 3GalNAcb 1, 4 (Neu5Aca2, 3) Galb 1, 4Glcb 1, 1 Cer,
  • Manal, 6 Manal, 3) Manal, 6 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,
  • a sugar chain-modified ribosome to which at least one sugar chain selected from is bound.
  • (Four) The sugar chain-modified liposome according to (3), wherein the linker is a biological protein.
  • the sugar chain-modified ribosome force is made hydrophilic by binding a hydrophilic compound to at least one of a liposome membrane or a linker, and is characterized in that (1) to ( The sugar chain-modified ribosome according to 5).
  • Strand-modified ribosome is made hydrophilic by binding a hydrophilic compound to at least one of a liposome membrane or a linker, and is characterized in that (1) to ( The sugar chain-modified ribosome according to 5).
  • the hydrophilic compound is a low molecular weight hydrophilic compound, preferably a low molecular weight hydrophilic compound having at least one OH group, more preferably a low molecular weight hydrophilic compound having at least two OH groups.
  • the sugar chain-modified ribosome according to (1) which is a compound or a tris (hydroxyalkyl) aminoalkane.
  • a drug delivery composition comprising the sugar chain-modified ribosome according to any one of (1) to (9) and a drug.
  • the drug delivery composition according to (10), wherein the drug is a substance selected from pharmaceuticals, research reagents, cosmetics, and functional foods.
  • the drug delivery composition according to (10) or (11), wherein the drug is an anticancer drug, an anti-inflammatory drug, a biopharmaceutical or a vitamin drug.
  • the present invention provides a sugar chain-modified ribosome useful for oral administration, a method for producing the same, and a method for using the same.
  • the sugar chain-modified ribosome of the present invention greatly expands the scope of development of a DDS preparation capable of providing a desired drug at a target delivery site. According to the present invention, it is possible to develop and put into practical use a delivery system necessary for realizing new treatments in various fields such as cancer treatment, gene therapy, and regenerative medicine.
  • Various sugar chain-modified ribosomes useful for such oral administration are provided for the first time by the present invention. Brief Description of Drawings
  • FIG. 1 is a schematic diagram of production of a sugar chain-modified ribosome that can be used in the present invention.
  • FIG. 2 is a graph showing the antitumor effect in tumor-bearing mice after intravenous injection of doxorubicin-encapsulated ribosome # 155.
  • FIG. 3 is a fluorescence micrograph showing the effect of doxorubicin accumulation in tumor tissues in tumor-bearing mice after intravenous injection of doxorubicin-encapsulated ribosome # 155 in tumor-bearing mice.
  • the left and right images are green and red fluorescence micrographs of the same tumor tissue, respectively.
  • FIG. 4 is a graph showing the antitumor effect in tumor-bearing mice after oral administration of doxorubicin-encapsulated ribosome No. 237.
  • FIG. 5 is a fluorescence micrograph showing the effect of doxorubicin accumulation on tumor tissues in tumor-bearing mice after oral administration of doxorubicin-encapsulated ribosome No. 237.
  • the left and right images are green and red fluorescence micrographs of the same tumor tissue, respectively.
  • FIG. 6 is a graph when calculating IC50.
  • the X axis shows the concentration of the drug of interest, and the Y axis shows the amount of ligand bound.
  • sugar chain refers to a compound comprising one or more unit sugars (monosaccharide and Z or a derivative thereof). When two or more unit sugars are connected, each unit sugar is linked by dehydration condensation using a glycosidic bond.
  • sugar chains examples include polysaccharides contained in the living body (glucose, galactose, mannose, fucose, xylose, N-acetylethyldarcosamine, N-acetylethylgalatosamine, sialic acid and In addition to their conjugates and derivatives), there are a wide range of sugar chains that are degraded or derived from complex biomolecules such as degraded polysaccharides, glycoproteins, proteoglycans, glycosaminodarlicans, glycolipids, etc. It is not limited to. Therefore, in the present specification, the sugar chain can be used interchangeably with “polysaccharide”, “sugar”, and “carbohydrate”.
  • the “sugar chain” in the present specification may include both sugar chains and sugar chain-containing substances.
  • monosaccharides such as glucose, galatose, mannose, fucose, xylose, N-acetylethyldarcosamine, N-acetylgalatatosamine, sialic acid, and complexes and derivatives thereof
  • It is a strong substance that is attached to proteins and lipids inside and outside the body of cells. The functions differ depending on the sequence of monosaccharides, and they are usually branched in a complex manner.
  • the human body is expected to have several hundreds of sugar chains with various structures, and there are tens of thousands of useful structures in the human body.
  • sugar or “monosaccharide” refers to a polyhydroxyaldehyde or polyhydroxyketone containing at least one hydroxyl group and at least one aldehyde group or ketone group, and represents the basic unit of a sugar chain. Constitute.
  • sugar is also referred to as carbohydrate, and both are used interchangeably.
  • sugar A chain refers to a chain or sequence in which one or more sugars are linked
  • a sugar or monosaccharide refers to one unit that constitutes a sugar chain.
  • aldose aldose
  • ketose ketose
  • the V misalignment type can also be used.
  • Gal N acetylenore a-D galactosamine
  • galactose refers to any isomer, but is typically j8-D-galactose, and is used to refer to j8-D galactose unless otherwise specified.
  • acetylylgalatatosamine refers to any isomer, but is typically N-acetinole a D galactosamine, and unless otherwise specified, N-acetyl-a-D galactosamine Used to refer to
  • mannose refers to any isomer, but is typically a-D-mannose, and is used to refer to ex D-mannose unless otherwise specified.
  • glucose refers to any isomer, but is typically j8-D-glucose, and is used to refer to 13D-glucose unless otherwise specified.
  • acetylyldarcosamine refers to any isomer, but is typically N-acetylenic ⁇ D darcosamine, and unless otherwise specified, refers to ⁇ acetylene ⁇ -D-darcosamine. Used as a thing.
  • fucose refers to any isomer, but is typically a L-fucose, and is used to refer to a-L fucose unless otherwise specified.
  • acetylylneuraminic acid refers to any isomer, but is typically a-N acetylneuraminic acid, and unless otherwise specified, refers to aN acetylneuraminic acid. Used as a thing.
  • serine refers to any isomer, typically L-serine. Unless otherwise stated, it is used to refer to L-serine.
  • sugar symbols, designations, abbreviations (Glc, etc.) and the like are different when they represent a monosaccharide and when used in a sugar chain.
  • the unit sugar exists in a form excluding hydrogen or hydroxyl group due to dehydration condensation with another unit sugar to which it is bonded. Therefore, these sugar abbreviations, when used to represent monosaccharides, have all hydroxyl groups present, but when used in sugar chains, the hydroxyl groups of the sugar to which the hydroxyl group is attached are dehydrated. It can be seen that only oxygen remains after condensation.
  • sugar power When covalently bonded to albumin, the reducing end of the sugar is aminated, and is capable of binding to other components such as albumin via its amine group.
  • the hydroxyl group at the reducing end Note that it refers to those substituted with an amine group.
  • Monosaccharides are generally joined by glycosidic bonds to form disaccharides and polysaccharides.
  • the direction of the bond relative to the plane of the ring is indicated by ⁇ and j8.
  • the specific carbon atom that forms the bond between the two carbons is also described.
  • the ⁇ -glycoside bond between galactose C-1 and glucose C-4 is represented by Gal
  • Branches of sugar chains are represented by parentheses, and are arranged and placed immediately to the left of the unit sugar to be bound. For example,
  • the gap between C-1 in galactose and C-4 in glucose When the glycoside is linked and C-3 of this glucose is ⁇ -glycosidically linked to fucose C-1, it is expressed as Gal jS 1, 4 (Fucal, 3) Glc.
  • Monosaccharides are represented on the basis of the lowest possible number of (latent) carbo groups. According to the general standard of organic chemical nomenclature, even when a group superior to a (latent) carbo group is introduced into a molecule, it is usually represented by the above numbering.
  • sugar chain used in the present specification examples include a sugar chain having at least one unit sugar selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc, Fuc, Neu5Ac and Ser. Be mentioned.
  • a sugar chain for example,
  • Galb l 3GalNAcb 1, 4 (Neu5Aca2, 8Neu5Aca2,3) Galb l, 4Glcb 1, 1 Cer,
  • Manal, 2Manal, 6 Manal, 3) Manal, 6 (Manal, 2Manal, 2Manal, 3) Manbl, 4GlcNAcbl, 4 GlcNAc,
  • Manal, 6 Manal, 3) Manal, 6 (Manal, 2Manal, 2Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,
  • Galbl 3 (Fucal, 4) GlcNAcbl, 3Galbl, 4Glc,
  • Manal, 6 Manal, 3) Manal, 6 (Manal, 2Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,
  • Manal, 6 Manal, 3 (Manal, 3) Manal, 6Manbl, 4GlcNAcbl, 4GlcNAc,
  • Manal, 6 Manal, 3 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,
  • Galb l 3GalNAcb 1, 4 (Neu5Aca2, 3) Galb 1, 4Glcb 1, 1 Cer,
  • Manal, 6 Manal, 3) Manal, 6 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,
  • a sugar chain selected from the group consisting of two or more combinations of these forces, but is not limited to these.
  • the reason why two or more combinations can be used is not limited by theory, but each of the sugar chains has specificity for a lectin localized in the tissue or cell of the intended delivery site, Even if they are mixed, they are considered to exhibit their uniqueness.
  • a combination of sugar chains is represented by inserting "+" between the sugar chains contained.
  • ribosome usually means a closed vesicle composed of a lipid layer assembled in a membrane and an aqueous layer inside.
  • phospholipids typically used cholesterol, glycolipids, and the like can also be incorporated. Since ribosomes are closed vesicles that contain water inside, it is possible to retain water-soluble drugs in the vesicles. Therefore, these ribosomes are used to deliver drugs and genes that cannot pass through the cell membrane into the cell. Also, because of its good biocompatibility, D There is great expectation as a nanoparticulate carrier material for DS.
  • Ribosomes can be prepared by any technique known in the art. For example, among them, a method using a cholic acid dialysis method is exemplified. In the cholic acid dialysis method, production is carried out by a) preparation of mixed micelles of lipid and surfactant, and b) dialysis of mixed micelles. Next, in a preferred embodiment of the sugar chain ribosome of the present invention, coupling of a glycoprotein having a sugar chain bound to a protein that preferably uses a protein as a linker to the ribosome is performed by the following two-step reaction. Can be done by.
  • FIG. 1 shows an example of the reaction flow.
  • a glycoprotein containing a desired! / Sucrose chain can be bound to liposomes, and a wide variety of glycoproteins' ribosome conjugates having the desired sugar chain can be obtained. It is very important to examine the particle size distribution to see the purity and stability of the ribosome.
  • gel filtration chromatography GPC
  • SEM scanning electron microscope
  • DLS dynamic light scattering
  • a ribosome of the molar ratio 35: 45: 5: 15 of dipalmitoylphosphatidylcholine (DPPC), cholesterol, dicetyl phosphate (DCP), ganglioside can be produced.
  • DPPC dipalmitoylphosphatidylcholine
  • DCP dicetyl phosphate
  • ganglioside can be produced.
  • This ribosome is stable even when stored at 4 ° C for several months.
  • the stability of ribosomes in vivo can be examined using mice. The ribosome is intravenously injected into the mouse, and after 3 hours, blood is collected to prepare serum, and the ribosome is purified and collected by ultrafiltration using a membrane with a pore size of 0.03 m. As a result of SEM observation, it can be confirmed that the ribosome morphology does not change even before and after recovery for 3 hours in vivo.
  • Lipids constituting the sugar chain-modified ribosome of the present invention include, for example, phosphatidylcholines, phosphatidylethanolamines, phosphatidic acids, long-chain alkyl phosphates, glycolipids (gandariosides, etc.), phosphatidylglycerols, and the like. , Sphingomyelins, cholesterols and the like.
  • phosphatidylcholines include dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, and the like.
  • phosphatidylethanolamines include dimyristoyl phosphatidylethanolamine. Min, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine and the like.
  • Examples of the phosphatidic acids include dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, and distearoyl phosphatidic acid.
  • Examples of long chain alkyl phosphates include dicetyl phosphate.
  • glycolipids examples include galactosylceramide, dalcosylceramide, latatosylceramide, phosphatide, globoside, and contosides.
  • Gandriosides include ganglioside GMl (Gal j8 1, 3GalNA C j 8 1, 4 (NeuA a 2, 3) Gal j8 1, 4Gl C j 8 1, 1, Cer), gandarioside GDla, gandarioside GTlb, etc. It is done.
  • phosphatidylglycerols dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycose mouth, distearoyl phosphatidylglycerol and the like are preferable.
  • phosphatidic acids, long-chain alkyl phosphates, glycolipids, and cholesterol have the effect of increasing the stability of ribosomes, so it is desirable to add them as constituent lipids.
  • the lipids constituting the ribosome of the present invention include phosphatidylcholines (molar ratio 0 to 70%), phosphatidylethanolamines (molar ratio 0 to 30%), phosphatidic acids, and long-chain alkyl phosphate groups.
  • lipids selected (molar ratio 0-30%), glycolipids, phosphatidylglycerols and sphingomyelins also selected group power One or more lipids (molar ratio 0-40%) And those containing cholesterol (molar ratio 0 to 70%). It is preferable to include glycolipids such as gandarioside. This is because the binding of a linker such as albumin becomes easy.
  • the ribosome according to the present invention can contain a redesignoside, to which a linker such as a peptide is bound, and to which a sugar chain is bound.
  • the sugar chain-modified ribosome of the present invention containing the sugar chain contained in the glycolipid as a constituent component can be produced.
  • the present invention provides a sugar chain modified ribosome.
  • Traditionally it is well targeted to the desired target cell or tissue in vivo. It was a great strength that was offered.
  • the present invention has an effect that targeting that has been impossible with conventional DDS materials becomes possible by providing a sugar chain-modified ribosome directed to a desired target cell or tissue in a living body.
  • such a sugar chain-modified ribosome is bound with a sugar chain having at least one structure selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc, Fuc, Neu5Ac and Ser. Yes.
  • sugar chain-modified ribosome refers to a substance containing a sugar chain and a ribosome, preferably a ribosome modified by direct or indirect binding of a sugar chain.
  • S sugar chain
  • M linker (may or may not be present)
  • L ribosome
  • covalent bond Or a cross-linking agent such as 3,3,1 dithiobis (sulfosuccinimidyl propionate) (DT SSP))).
  • the sugar chain-modified ribosome of the present invention contains S—M
  • the ribosome proximal end of a sugar chain of a sugar chain-modified ribosome refers to the terminal portion of the sugar chain that is most proximal to the ribosome.
  • the sugar at the ribosome proximal end of the sugar chain is preferably Gal, GalNAc, Man, Glc, GlcNAc, Ser or Cer, and in a particularly preferred embodiment, Ser or Cer.
  • the ribosomal proximal end of a sugar chain refers to the sugar (monosaccharide) that is most proximal to the ribosome. Therefore, in the present specification, when “the ribosome proximal end of the sugar chain includes a sugar chain that has more than two sugars”, the proximal ribosome end of the sugar chain is located at the proximal end of the ribosome of the sugar chain.
  • sugars monosaccharides
  • other sugars contained in sugar chains that are more powerful than the above disaccharides (monosaccharides; this may be the same as or different from the most proximal sugar) Is also included.
  • distal end of the ribosome of the sugar chain refers to the terminal portion of the sugar chain that is most distal to the liposome.
  • the sugar at the ribosome distal end of the sugar chain is preferably Gal, 3 '-(O-SO H) Gal, GalNAc, Man and Fuc or Neu5Ac
  • 3 ′-(O—SO 2 H) Gal In certain preferred embodiments, 3 ′-(O—SO 2 H) Gal.
  • the most distal end of the ribosome of a sugar chain refers to a sugar (monosaccharide) that is most distal to the ribosome. Therefore, in the present specification, when “the sugar chain having a disaccharide or more force is included at the distal end of the ribosome of the sugar chain”, the distal end of the sugar chain is the distal end of the ribosome of the sugar chain. In addition to a certain sugar (monosaccharide), other sugars (monosaccharide; this may be the same as or different from the sugar at the most distal end). .) Is also included.
  • the sugar chain-modified ribosome of the present invention may have a specific sugar chain pattern regardless of location.
  • “Sugar chain pattern” refers to a pattern determined by the type, bond, and anomer of a specific sugar chain. This sugar chain pattern is a preferable sugar chain pattern for passing through the intestinal mucosa. Without being bound by theory, it is considered that the sugar chain of a specific “good” pattern is included somewhere, making it easier to get on the absorption path by the pump present in the intestinal mucosa. In the present invention, systematic investigations revealed that the following sugar chain patterns included “oral absorption”.
  • sugar chain patterns that may have a specific sugar chain pattern regardless of location include, but are not limited to, the following:
  • the sugar chain of a sugar chain-modified ribosome has the following structure: R 1 — X 1 — X 2 — R 2 , wherein R 1 and R 2 are independently hydrogen or any sugar chain, and X 1 is Fuc, GalNAc , Gal, 3,-(O— SO H) Gal
  • the sugar chain of the glycosylated ribosome is Having the following structure: R 1 — X 1 — X 2 — X 3 — R 2 , wherein R 1 and R 2 are independently hydrogen or any sugar chain And X 1 is selected from the group consisting of Fuc, Gal, GalNAc, GlcNAc, Man and Neu5Ac, and X 2 is selected from the group consisting of Gal, GlcNAc, GalNAc and Man, and the X 3 Is selected from the group consisting of Glc, GlcNAc, Gal, GalNAc, Ser, Cer and Man; the sugar chain of the glycosylated ribosome has the following structure: RLX 1 — X 2 — X 3 — X 4 — Have R 2 Wherein
  • the sugar chain-modified ribosome of the present invention may have a specific sugar chain pattern on the distal end side of the ribosome. Without being bound by theory, it is considered that the sugar chain structure on the distal end side of the ribosome is characterized by being easily recognized by the intestinal mucosa because it exists outside the sugar chain-modified ribosome. In the present invention, a systematic investigation revealed that the following sugar chain pattern was recognized by the intestinal mucosa and was immediately suitable for oral administration.
  • Examples of the sugar chain pattern that can have a specific sugar chain pattern on the distal end side of the ribosome include, but are not limited to, the following: Liposome distal end of the sugar chain of the sugar chain-modified ribosome From the distal end side has the following structure: Fuc 1 — A 2 — R z , where A 2 is selected from the group consisting of Gal, Glc and GlcNAc, and the R z is Hydrogen or any sugar chain, pattern; ribosome distal end of sugar chain of sugar chain modified ribosome 1S From the distal end side, the following structure: Fuc 1 — A 2 — A 3 — or have R z, wherein said a 2 are, Ga ho was is GlcNAc, the a 3 is Glc, is selected from the group consisting of Gal and GlcNAc, the R z and its is hydrogen Or a pattern that is an arbitrary sugar chain;
  • the ribosome distal end of the sugar chain has the following structure:
  • the ribosome distal end of the sugar chain of the sugar chain-modified ribosome has the following structure from the distal end side: Fuc 1 — A 2 — A 3 — A 4 — A 5 — R z
  • the A 2 is Gal
  • the A 3 is GlcNA
  • the A 4 is Gal
  • the A 5 is Glc
  • the R z is hydrogen, or Any sugar chain, pattern
  • the distal end has the following structure from the distal end side: Gal 1 — B 2 — B
  • the B 2 is GalNAc or GlcNAc
  • the B 3 is Gal
  • the R Z is hydrogen or any sugar pattern; sugar chain modification of the ribosomal sugar chain Ribosome distal end force From the distal end side, it has the following structure: Gal 1 — B 2 — B 3 — B 4 — R Z , where Gal 1 is sulfated even though it is sulfated.
  • the sugar chain-modified ribosome of the present invention may have a specific sugar chain pattern on the proximal end side of the ribosome.
  • this sugar chain pattern is on the ribosome side and is not bound by theory, it is thought that the sugar chain pattern itself is fixed and the absorption by the intestinal mucosa is stabilized, so that the absorbability is improved. Furthermore, by having these structural patterns, the stability of ribosome is also considered to contribute to the improvement of oral absorption.
  • Examples of the sugar chain pattern that may have a specific sugar chain pattern on the proximal end side of the ribosome include, but are not limited to, the following: Liposome proximal end of the sugar chain of the sugar chain-modified ribosome Force has the following structure: R 1 — F 2 — GlcNAc 3 where R
  • the F 2 is selected from the group consisting of Gal, Fuc, GlcN Ac and 3, one (O—SO H) Gal,
  • the GlcNAc 3 is
  • R 1 - F 2 - F 3 - GlcNAc 4 has, wherein said R 1 Is independently hydrogen or any sugar chain, F 2 is a sugar selected from Man, Fuc and Neu5Ac, and F 3 is Ga or GlcNAc.
  • GlcNAc 4 is present in the proximal-most end of the ribosome, the pattern; carbohydrate in glycosylation ribosome ribosome proximal end forces the following structure: R 1 - F 2 - F 3 - F 4 - a GlcNAc 5 Wherein F 1 is independently hydrogen or any sugar chain, F 2 is Man, F 3 is Man, and F 4 is , GlcNAc, where GlcNAc 5 is present at the proximal end of the ribosome; the ribosome proximal end of the sugar chain of the sugar chain modified ribosome has the following structure: R 1 — F 2 — F 3 — F 4 — F 5 — GlcNAc 6 , wherein R 1 is independently hydrogen or any sugar chain, F 2 is Man, F 3 is Man, the F 4 is Man, and the F 5 is GlcNAc, where the GlcNAc 6 is present at the proximal end of the rib
  • the ribosome proximal end of the sugar chain of the glycosylated ribosome has the following structure: R 1 --J 3 — J 4 J 5 — Glc 6
  • R 1 is independently hydrogen or any sugar chain
  • good 2 is Fuc
  • good 3 is Gal
  • good 4 is GlcN Ac Or GalN Ac
  • Xie 5 is Gal
  • the ribosome proximal end force of the sugar chain of the sugar chain-modified ribosome has the following structure: R 1 — K 2 — Man 3 where R 1 is independently hydrogen or any sugar chain And the K 2 is Man, where Man 3 is present at the proximal end of the ribosome, the pattern; sugar chain modified ribosome sugar end force of the sugar chain of the modified ribosome
  • R 1 — L 2— has Cer 3
  • the sugar chain-modified ribosome of the present invention may have a specific sugar at both ends.
  • having a specific sugar increases the affinity of the sugar chain for the intestinal mucosa and improves the stability of the ribosome, which also contributes to the improvement of oral absorption. Conceivable.
  • Examples of patterns that may have specific sugars at both ends include, but are not limited to, the following:
  • the sugar power of the most proximal ribosome of the sugar chain is Glc or GlcNAc, and the sugar chain
  • the sugar force at the distal end of the ribosome SGa is Fuc, pattern; ,. VN. IOS'I O
  • Manal, 6 Manal, 3 (Manal, 3) Manal, 6Manbl, 4GlcNAcbl, 4GlcNAc,
  • Manal, 6 Manal, 3 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,
  • Galb l 3GalNAcb 1, 4 (Neu5Aca2, 3) Galb 1, 4Glcb 1, 1 Cer,
  • Manal, 6 Manal, 3) Manal, 6 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,
  • a ribosome modified with a sugar chain selected from the group consisting of a combination of two or more in any ratio.
  • ribosome number refers to the following Table 1, Table 2, and Table 3. The number refers to the sugar chain-modified ribosome to which the sugar chain is bound.
  • the sugar chain-modified ribosome used in the present specification may contain, for example, the sugar chains shown in Table 1 at a density suitable for transferring from the intestinal tract into the blood.
  • modified bond density is the amount of sugar chains used in preparing sugar chain-modified ribosomes, and the density of sugar chains bound per mg of lipid in the ribosome. It is expressed as (mg sugar chain Zmg lipid).
  • the binding density of the sugar chain-modified ribosome of the present invention is not desired to be bound by theory, empirically, the amount of sugar chain used in the preparation is almost proportional to the density of sugar chains bound to the ribosome. What you are doing is divided. Therefore, in this specification, unless otherwise stated, the bond density is determined by the amount used during preparation. In the in vitro mouth, for example, it can be determined indirectly using E-selectin.
  • the sugar chain-modified ribosome of the present invention can control the directivity with respect to the intended delivery site by selecting the type of sugar chain to be bound to the ribosome and the binding density.
  • Table 1 below shows the ribosome number, sugar chain structure, modified bond density, and oral administration (enteral) directivity.
  • the average value of liposomes absorbed by the intestinal tract 10 minutes after administration is 4 to 6 times the average value of reference ribosome.
  • “+” indicates the average value of the liposome absorbed by the intestinal tract 10 minutes after administration when ribosome (reference ribosome) conjugated with tris (hydroxymethyl) aminomethane instead of sugar chain was orally administered. Represents 3-4 times the average value of the reference ribosome.
  • the sugar chain-modified ribosome suitable for oral administration of the present invention is prepared using the sugar chain of the type shown in Table 1 above and the modified bond density and combinations thereof. obtain.
  • the target directivity is + or ++, it is the power that can be expected to have the same effect even if two or more sugar chains are combined. This is because sugar chains that are recognized as preferred by lectins of target tissues or target cells are recognized as preferred when combined.
  • the sugar chain-modified ribosome suitable for oral administration used in the present invention is preferably liposomal numbers 27, 29, 40, 45, 50, 53, 56, 67, 68, 69, 70, 71, 87. , 105, 117, 120, 125, 139, 142, 150, 152, 153, 154, 175, 184, 186, 197, 204, 22 4, 225, 230, 236, 237, 240, 273, 285, 288 or It can be 290.
  • the sugar chain-modified ribosome used in the present specification may contain, for example, the sugar chains shown in Table 2 at a density suitable for delivery to a tumor.
  • delivery to a tumor includes fibrosarcoma, sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, lymphangiosarcoma, periosteum, medium Skin tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, rectal cancer, spleen cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, brain cancer, squamous cell carcinoma , Sebaceous carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, primary bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, cervical cancer , Testicular cancer, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma
  • modified bond density is the amount of sugar chain used in producing a sugar chain-modified ribosome, and is the number of sugar chains bound per mg of lipid in the ribosome. Expressed as density (mg sugar chain Zmg lipid).
  • density mg sugar chain Zmg lipid.
  • the binding density of the sugar chain-modified ribosome of the present invention is not desired to be bound by theory, empirically, the amount of sugar chain used in the preparation is almost equal to the density of sugar chains bound to the ribosome. Proportionalness is a component. Therefore, in the present specification, unless otherwise stated, the binding density is determined by the amount used at the time of preparation. In the in vitro mouth, for example, it can be determined indirectly using E-selectin.
  • the sugar chain-modified ribosome of the present invention is a kind of sugar chain that is bound to the ribosome. By selecting the type and binding density, the directivity to the intended delivery site can be controlled. Table 2 below shows the ribosome number, sugar chain structure, modified bond density, and tumor directionality.
  • “+ +” Means that when a ribosome (reference ribosome) conjugated with Gal ⁇ 1, 3GalNAc ⁇ ⁇ , 4 (Neu5Ac a 2, 3) Galj81, G1 CJ 81, lCer is injected intravenously instead of a sugar chain, It represents that the mean value of ribosome delivered to the tumor 5 minutes after injection is 2 to 4 times the mean value of the reference ribosome.
  • the reference ribosome is a ribosome bound to tris (hydroxymethyl) aminomethane
  • “+” means that the average value of the ribosome delivered to the tumor 5 minutes after intravenous injection is the average value of the reference liposome. 1. 1 to 1.4 means that it will be 4 times.
  • Gal j8 1, 3GalNA C j 8 1, 4 (Neu5Ac a 2, 3) G al j8 1, 4G1 CJ 8 1, ICer was used.
  • a sugar chain-modified ribosome suitable for delivery to a tumor of the present invention can be prepared using a sugar chain of the type shown in Table 2 above and a modified bond density, and combinations thereof.
  • a sugar chain of the type shown in Table 2 above can be prepared using a sugar chain of the type shown in Table 2 above and a modified bond density, and combinations thereof.
  • the sugar chain-modified ribosome suitable for delivery to the tumor used in the present invention is preferably ribosome number 22, 27, 29, 38, 40, 41, 45, 53, 60, 68, 69, 71, 87, 91, 93, 96, 105, 106, 111, 116, 117, 120, 125, 139, 150, 151, 152, 153, 1 54, 155, 184, 186, 189, 191, 195, 197, 204 , 209, 213, 218, 220, 224, 225, 229, 230, 233, 234, 235, 236, 237, 240, 263, 285, 288, 290, 292, or 295.
  • the sugar chain-modified ribosome used in the present specification has, for example, the sugar chains shown in Table 3. It may be included at an appropriate density for delivery to the site of inflammation.
  • delivery to a site of inflammation refers to cytology that occurs in blood vessels and adjacent tissues affected by physical or chemical or biological agent damage or abnormal stimulation. This refers to the delivery to the area where the basic pathological process occurs, which is the dynamic complex force of histological reaction. Whether it is an inflammatory site can be confirmed by detecting an inflammatory substance (prostaglandins, leukotrienes, etc.).
  • modified bond density is the amount of sugar chains used in preparing sugar chain-modified ribosomes, and the density of sugar chains bound per mg of lipid in the ribosome. It is expressed as (mg sugar chain Zmg lipid).
  • the binding density of the sugar chain-modified ribosome of the present invention is not desired to be bound by theory, but empirically, the amount of sugar chain used for preparation is almost proportional to the density of sugar chains bound to the ribosome. What you are doing is divided. Therefore, in this specification, unless otherwise stated, the bond density is determined by the amount used at the time of preparation. In the in vitro mouth, for example, it can be determined indirectly using E-selectin.
  • the sugar chain-modified ribosome of the present invention can control the directivity with respect to the intended delivery site by selecting the type of sugar chain to be bound to the ribosome and the binding density.
  • Table 3 shows the ribosome number, sugar chain structure, modified bond density, and directivity to the inflammatory site.
  • reference ribosome is a ribosome coupled with tris (hydroxymethyl) aminomethane
  • ++ is the average value of the reference ribosome delivered to the inflammatory site 5 minutes after intravenous injection. 1. Indicates 5 to 4.9 times.
  • sugar chain-modified ribosomes suitable for delivery to the inflammatory site of the present invention can be prepared using the types of sugar chains and modified bond densities shown in Table 3 above and combinations thereof.
  • the target directivity is found to be + or ++, the same effect can be expected by combining two or more sugar chains. This is because it is recognized that a sugar chain that recognizes a lectin of a target tissue or a target cell is preferable even if it is combined.
  • the sugar chain-modified ribosome suitable for delivery to the inflammatory site used in the present invention is preferably ribosome number 22, 27, 38, 40, 41, 50, 53, 56, 60, 68, 69. , 70, 71, 76, 87, 91, 93, 96, 105, 106, 111, 116, 1 17, 120, 125, 137, 139, 146, 150, 151, 152, 153, 154, 155, 183, 184, 186, 189, 191, 195, 197, 199, 204, 209, 213, 218, 220, 224, 229, 230, 233, 234, 235, 237, 240, 26
  • the preferred sugar chain-modified ribosome of the present invention as described in the above table is obtained by the following method.
  • this method comprises (a) a step of providing a ribosome; (b) a step of hydrophilizing the ribosome; (c) a linker on the hydrophilized liposome as necessary. And (d) binding a sugar chain described in Table 3 above to produce a sugar chain-modified ribosome.
  • the step of treating the ribosome in step (b) with hydrophilic property directly or indirectly on the lipid membrane or linker of the liposome is performed directly or indirectly.
  • the linker used in step (c) is a human-derived protein, and a sugar chain is directly or indirectly bound to the ribosome in step (d). Under conditions, sugar chains are bound to produce sugar chain-modified ribosomes.
  • the ribosome and the linker, and the linker and the sugar chain are preferably bound using a bifunctional crosslinking agent (for example, DTSSP).
  • a bifunctional crosslinking agent for example, DTSSP
  • the sugar chain-modified ribosome of the present invention is, for example, a biopharmaceutical or a biotherapeutic substance (for example, siRNA, shRNA, siRNA derivative, shRNA derivative, RNA, RNA derivative, DNA, DNA derivative, monoclonal antibody, vaccine, interferon, hormone, prostaglandin, transcription factor, recombinant protein, antibody drug, nucleic acid> drug, gene therapy drug), alkylated anticancer drug, metabolic antagonist Agents, plant-derived anticancer agents, anticancer antibiotics, biological response modifiers (BRM) 'site force ins, platinum complex anticancer agents, immunotherapeutic agents, hormone anticancer agents, monoclonal antibodies, etc.
  • a biopharmaceutical or a biotherapeutic substance for example, siRNA, shRNA, siRNA derivative, shRNA derivative, RNA, RNA derivative, DNA, DNA derivative, monoclonal antibody, vaccine, interferon, hormone, prostaglandin, transcription factor, recombinant protein, antibody drug, nucle
  • Oncology drugs central nervous system drugs, peripheral nervous system-sensory organ drugs, respiratory disease drugs, cardiovascular drugs, gastrointestinal drugs, hormone drugs Drugs, urological 'genital agents, vitamins' nourishing tonics, metabolic drugs, antibiotics, chemotherapeutic drugs, test drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, self-immune drugs, circulation Systemic drugs, lifestyle-related diseases such as diabetes and hyperlipidemia, corticosteroids, immunosuppressive agents, antibacterial agents, antiviral agents, angiogenesis inhibitors, cytoforce-in, chemokines, anti-site-forced in Antibodies, anti-chemokine antibodies, anti-site force-in chemokine receptor antibodies, siRNA, shRNA, miRNA, smRNA, antisense RNA or gene therapy-related nucleic acid preparations such as ODN or DN A, neuroprotective factors, antibody drugs, molecules Target drug, bone Examples include, but are not limited to, osteoporosis, bone metabolism-improving drugs, neuropeptides, bio
  • linker is a molecule that mediates the binding between a sugar chain and the ribosome surface.
  • the sugar chain may be bound to the ribosome surface via a linker.
  • the linker can be appropriately selected by those skilled in the art, but those that are biocompatible are preferred, and are preferably pharmaceutically acceptable.
  • the linker used in the present specification is, for example, a biological protein, preferably a human-derived protein, more preferably a human-derived serum protein, and still more preferably human serum albumin or ushi serum albumin. obtain. In particular, when human serum albumin is used, it has been confirmed by experiments on mice that the uptake into each tissue is large.
  • the “crosslinking agent” means that a chemical bond is formed between molecules of a chain polymer so as to form a bridge. Typically, it acts between high molecules such as lipids, proteins, peptides, and sugar chains and other molecules (for example, lipids, proteins, peptides, and sugar chains), and is covalently bound within or between molecules.
  • a ribosome and a sugar chain may be covalently formed by this cross-linking agent, or through a linker, between the linker and the sugar chain, and the linker.
  • One and the ribosome may be bound by a cross-linking agent.
  • the cross-linking agent varies depending on the target for crosslinking, and examples thereof include, but are not limited to, aldehydes (for example, dartal aldehyde), carpositimides, imide esters and the like.
  • aldehydes for example, dartal aldehyde
  • carpositimides for example, carpositimides
  • imide esters and the like.
  • an aldehyde-containing group such as dartaldehyde can be used.
  • Bivalent reagents such as ethylene glycol bisbissuccinimidinoresuccinate and ethylene glycol bissunorefostasinimidyl succinate can be used.
  • the terms "protein”, “polypeptide”, “oligopeptide” and “peptide” are used interchangeably in this specification, and are amino acid residues of any length.
  • a remer. This polymer may be linear, branched or cyclic.
  • the amino acid may be a modified amino acid, which may be natural or non-natural.
  • the term can also encompass one assembled into a complex of multiple polypeptide chains.
  • the term also encompasses amino acid polymers that are naturally or artificially modified. Such modifications include, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphate, or any other manipulation or modification (eg, conjugation with a labeling component).
  • This definition also includes, for example, polypeptides containing one or more analogs of amino acids (eg, including unnatural amino acids, etc.), peptidomimetics (eg, peptoids), and known in the art. Other modifications are included.
  • protein refers to a polymer of amino acid having a relatively large molecular weight or a modification thereof
  • peptide refers to a relatively small molecular weight. It should be understood that it may refer to a polymer of amino acids having or modifications thereof. Examples of such molecular weight include, but are not limited to, about 30 kDa, preferably about 20 kDa, more preferably about 10 kDa.
  • biological protein refers to a protein derived from an organism, including any organism (eg, any type of multicellular organism (eg, animal (eg, vertebrate)). , Invertebrates), plants (eg monocotyledonous plants, dicotyledonous plants, etc.))).
  • the protein is derived from a vertebrate (e.g., metaraunagi, shark eels, teleosts, teleosts, amphibians, reptiles, birds, mammals, etc.), more preferably a mammal (e.g.
  • Pouches, rodents, crustaceans, wings, carnivores, carnivores, long noses, odd-hoofed animals, cloven-hoofed animals, rodents, scales, sea cattle, cetaceans, primates, Proteins from rodents, maggots, etc. are used. More preferably, a protein derived from a primate (for example, chimpanzee, second monkey, human) is used. Most preferably, a biological protein intended for administration is used.
  • human serum protein refers to a protein contained in a liquid portion that remains when human blood naturally coagulates.
  • human serum albumin refers to albumin contained in human serum
  • ushi serum albumin refers to albumin contained in serum of ushi.
  • at least one of the ribosome membrane and the linker may be made hydrophilic by binding a hydrophilic compound, preferably a tris (hydroxyalkyl) aminoalkane. ,.
  • hydrophilization refers to binding of a hydrophilic compound to the ribosome surface.
  • the compound used for the hydrophilic property is a low molecular weight hydrophilic compound, preferably a low molecular weight hydrophilic compound having at least one OH group, and more preferably a low molecular weight hydrophilic compound having at least two OH groups.
  • a low molecular weight hydrophilic compound having at least one amino group that is, a hydrophilic compound having at least one OH group and at least one amino group in the molecule can be mentioned.
  • the hydrophilic compound Since the hydrophilic compound is a small molecule, it does not hinder the progress of the sugar chain molecule recognition reaction by the lectin on the surface of the target cell membrane due to steric hindrance to the sugar chain.
  • the hydrophilic compound does not include a sugar chain to which a lectin used for directing a specific target such as a lectin can be bound in the sugar chain-modified ribosome of the present invention.
  • examples of such hydrophilic compounds include amino alcohols such as tris (hydroxyalkyl) aminoalkane including tris (hydroxymethyl) aminomethane, and more specifically, tris (hydroxymethylol).
  • the compound is not limited, and examples thereof include compounds in which an amino group is introduced into a sugar chain to which a lectin such as cellobiose does not bind.
  • the ribosome surface is rendered hydrophilic using a divalent reagent for crosslinking and tris (hydroxymethyl) aminomethane on the lipid phosphatidylethanolamine of the ribosome membrane.
  • the general formula of the hydrophilic compound is represented by the following formula (1), formula (2), formula (3) and the like.
  • R 2 and R 4 are absent or C C, preferably C-force C, more preferably C-force C linear or branched carbonization
  • X represents a reactive functional group that binds to the ribosomal lipid directly or to a divalent reagent for crosslinking, such as COOH, NH, NH
  • n a natural number.
  • the surface of the ribosome that has been rendered hydrophilic with such a hydrophilic compound is thinly covered with a hydrophilic compound. However, since the thickness of the cover of the hydrophilic compound is small, even when sugar chains are bound to ribosomes, the reactivity of sugar chains and the like cannot be suppressed.
  • the hydrophilicity of the ribosome can be determined by a conventionally known method, for example, a method for producing a ribosome using a phospholipid obtained by covalently binding polyethylene glycol, polyvinyl alcohol, maleic anhydride copolymer, etc. — 302685 (eg, CNDAC-containing ribosomal formulations dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine; dipalmitoylphosphatidylglycerol, distearoyl phosphatidylglycerol; sphingomyelin; cholesterol
  • N monomethoxypolyethylene glycol succinyl distearoyl phosphatidylethanolamine (hereinafter referred to as PEG2000-DSPE) with a molecular weight of polyethylene glycol moiety of about 2000; CNDAC hydrochloride, glucose aqueous solution and trehalose aqueous solution are used.
  • PEG2000-DSPE N monomethoxypolyethylene glycol succinyl distearoyl phosphatidylethanolamine
  • tris (hydroxymethyl) aminomethane of the present invention is preferable in several respects as compared with the conventional hydrophilization method using polyethylene glycol or the like.
  • tris (hydroxymethyl) aminomethane is a low molecular weight substance, so that it has a high molecular weight such as conventional polyethylene glycol.
  • it is less likely to cause steric hindrance to sugar chains, and does not interfere with the progress of sugar chain molecule recognition reactions by lectins (sugar chain recognition proteins) on the surface of target cells. Is particularly preferable.
  • the ribosome according to the present invention has good particle size distribution, component composition, and dispersion characteristics even after the hydrophilization treatment, and has excellent long-term storage and in vivo stability. It is preferable for use as a pharmaceutical preparation.
  • lipids such as dimyristoyl phosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, etc.
  • Bissulfosuccimidyl subtilate, disucci-midyl glutarate, dithiobissuccinimidyl propionate, disuccinimidyl subionate, 3,3,1 dithiopis (sulfosucci-midyl propionate), ethylene glyconorebissucci Dipalmitoyl phosphatidyl ethanol on the liposomal membrane is prepared by reacting with a bivalent reagent such as midinoresuccinate or ethylene glycol bissulfosucci-midyl succinate.
  • a trivalent (hydroxymethyl) aminomethane is bound to the surface of the ribosome by binding a divalent reagent to a lipid such as glucose, and then reacting tris (hydroxymethyl) aminomethane with the other side of the divalent reagent.
  • a ribosome obtained by hydrophilizing a ribosome is extremely stable in vivo, and has a half-life in vivo without binding a target-directed sugar chain as described later. Since it is long, it can be suitably used as a drug carrier in a drug delivery system.
  • the present invention also includes a ribosome whose surface is made hydrophilic with a low molecular weight compound.
  • delivery vehicle refers to a carrier (vehicle) that mediates delivery of a desired substance. If the substance to be delivered is a drug, it is referred to as a “drug delivery vehicle”.
  • the drug delivery system is also called a drug delivery system, and is sometimes classified into an absorption-controlled DDS, a controlled-release DDS, and a target-oriented DDS.
  • the ideal DDS is a system that delivers a drug “to the necessary part of the body”, “a necessary amount”, and “for the required time”.
  • Targeting DDS (written as Targeting DDS, translated into target-oriented DDS) is categorized as noisy 'targeting (passive / target-oriented) DDS and active' targeting (active 'target-oriented) DDS. Is done.
  • the former controls the behavior in the body using physicochemical properties such as carrier particle size and hydrophilicity.
  • the latter is a method in which a special mechanism is added to these to actively control the direction to the target tissue.For example, it has a specific molecular recognition function for the target molecules of specific cells that constitute the target tissue.
  • drug delivery vehicle refers to a vehicle for delivering a desired drug.
  • the present invention relates to a drug delivery vehicle for oral administration.
  • the drug delivery vehicle for oral administration can further comprise a pharmaceutically acceptable carrier and the like.
  • Pharmaceutically acceptable carriers include, for example, antioxidants, preservatives, colorants, flavors, and diluents, emulsifiers, suspending agents, solvents, fillers, extenders, buffers, delivery vehicles, dilutions Agents, excipients and Z or pharmaceutical adjuvants, including but not limited to.
  • the drug delivery vehicle for oral administration of the present invention is administered in the form of a composition comprising a glycosylated ribosome together with one or more physiologically acceptable carriers, excipients or diluents.
  • a suitable vehicle can be water for injection, physiological solution, or artificial cerebrospinal fluid.
  • Acceptable carriers, excipients or stabilizers used herein are non-toxic to the recipient and are preferably inert at the dosages and concentrations used.
  • Such non-toxic and inert carriers include, for example, phosphate, citrate, or other organic acids; ascorbic acid, ⁇ -tocopherol; low molecular weight polypeptides; proteins (eg, serum albumin Hydrophilic polymers (eg polyvinylpyrrolidone); amino acids (eg glycine, glutamine, asparagine, arginine or lysine); monosaccharides, disaccharides and other carbohydrates (glucose, mannose or dextrin); Chelating agents (eg, EDTA); sugar alcohols (eg, mantol or sorbitol); salt-forming counterions (eg, sodium); and moth or non-ionic surfactants (eg, Tween, pulluric or polyethylene glycol (PEG)), but is not limited thereto.
  • Exemplary suitable carriers include neutral buffered saline or serum albumin. Combined saline is mentioned.
  • the product is formulated as a lyophilizer using a suitable excipient (eg, sucrose).
  • suitable excipient eg, sucrose
  • Other standard carriers, diluents and excipients may be included as desired.
  • Other exemplary compositions include Tris buffer at pH 7.0-8.5 or acetate buffer at pH 4.0-5.5, which are sardine, sorbitol or suitable substitutes thereof. Can be included.
  • the present invention provides a drug delivery vehicle for oral administration containing a sugar chain-modified ribosome.
  • the drug delivery vehicle of the present invention comprises a sugar chain having at least one structure selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc, Fuc and Neu5Ac, preferably the sugar chains shown in Table 1 above.
  • Including a sugar chain-modified ribosome linked with The sugar chain-modified ribosome may encapsulate or bind a drug or gene.
  • Examples of the drug encapsulated or bound to the sugar chain-modified ribosome of the present invention include, but are not limited to, the following: biopharmaceuticals or biotherapeutic substances (eg, siRNA, shRNA, siRNA) Derivatives, shRNA derivatives, RNA, RNA derivatives, DNA, DNA derivatives, monoclonal antibodies, vaccines, interferons, hormones, prostaglandins, transcription factors, recombinant proteins, antibody drugs, nucleic acids>
  • the drug delivery vehicle for oral administration of the present invention is used for oral administration of a biological agent to a subject in need of the biological agent, and for the respiratory system, circulatory system, digestive system, urinary ' It can also be used to treat mammals with genital, central or peripheral nervous system disorders.
  • the drug delivery vehicle for oral administration of the present invention can also enhance the absorption controllability in the intestinal tract by adjusting the type of sugar chain and the binding density of the sugar chain-modified ribosome.
  • the liposome By binding to the liposome both sugar chains that enhance intestinal absorption control and sugar chains that have directivity to specific tissues or organs, both directivity to specific tissues or organs and intestinal absorption control are achieved. It is also possible to produce ribosomes with the above characteristics.
  • the drug delivery vehicle for oral administration of the present invention can be easily prepared by those skilled in the art by considering pH, isotonicity, stability, and the like.
  • the drug delivery vehicle for oral administration of the present invention is mixed with a pharmaceutically acceptable carrier, and is a liquid such as a solid preparation such as a tablet, capsule, granule, powder or powder, syrup, suspension or solution. It can be administered orally as a formulation.
  • the drug delivery vehicle for oral administration of the present invention comprises a physiologically acceptable carrier, excipient or stabilizer as necessary (Japanese Pharmacopoeia 14th edition or the latest edition, Remington's Pharmaceutical sciences, 18th Edition, AR Gennaro, ed., Mack Publishing Company, 1990, etc.) and a glycan composition having the desired degree of purity, by mixing it in the form of a lyophilized cake or aqueous solution Can be prepared and stored.
  • the amount of the drug delivery vehicle for oral administration used in the treatment method of the present invention depends on the purpose of use, target disease (type, severity, etc.), patient age, weight, sex, medical history, cell morphology. Or it can be easily determined by those skilled in the art in consideration of the type and the like.
  • the frequency with which the treatment method of the present invention is applied to a subject (or patient) also depends on the purpose of use, target disease (type, severity, etc.), patient age, weight, gender, medical history, treatment course, etc. Can be easily determined by those skilled in the art.
  • the frequency may be, for example, administered daily—once every several months (eg once a week, once a month). It is preferable to administer once a week, once a month, while monitoring the course.
  • Drug delivery vehicles for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosage forms suitable for administration. Such carriers allow drug delivery vehicles to be formulated into liquids, gels, syrups, slurries, suspensions, etc. suitable for consumption by the patient.
  • the drug delivery vehicle of the present invention comprises a composition contained in a sugar chain-modified ribosome in an amount effective to achieve the intended purpose of the drug or biological agent.
  • An “effective amount to treat” is a term well recognized by those skilled in the art and is an amount of a drug effective to produce the intended pharmacological result (eg, prevention, treatment, prevention of recurrence, etc.). Say. Thus, a treatment effective amount is an amount sufficient to reduce symptoms of the disease to be treated.
  • One useful approach to ascertaining an effective amount (eg, a therapeutically effective amount) for a given application is to measure the extent of recovery of the target disease. The amount actually administered will depend on the individual to whom the treatment is to be applied, and is preferably an amount optimized to achieve the desired effect without significant side effects. The determination of an effective dose is well within the ability of those skilled in the art.
  • Therapeutically effective doses, prophylactically effective doses, and the like and toxicity are standard pharmaceutical procedures in cell cultures or laboratory animals (e.g. ED, doses therapeutically effective in 50% of the population; and
  • the dose ratio between fruit and toxic effects is the therapeutic index, which is the ratio ED ZLD
  • 50 can be expressed as 50.
  • Drug delivery vehicles that exhibit large therapeutic indices are preferred.
  • Cell culture and animal experimentation power obtained Data used to formulate a range of quantities for human use.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED with little or no toxicity. This dosage is the dosage form used,
  • the dose is appropriately selected depending on age and other patient conditions, the type of disease, the type of cells used, and the like.
  • the drug delivery vehicle of the present invention can be manufactured in a manner similar to that known in the art (eg, mixing, dissolving, etc.).
  • the “instruction” refers to a method for administering the sugar chain-modified ribosome of the present invention or a drug delivery vehicle for oral administration, etc.
  • This instruction manual includes a word indicating a procedure for administering the sugar chain-modified liposome of the present invention or a drug delivery vehicle for oral administration.
  • This instruction is prepared according to a format prescribed by the national supervisory authority in which the present invention is implemented (for example, the Ministry of Health, Labor and Welfare in Japan and the Food and Drug Administration (FDA) in the United States). It is clearly stated that it has been approved by the supervisory authority. Instructions are so-called package inserts, usually provided in paper form, but not limited to it, for example, electronic media (eg homepage (website) provided by the Internet, e-mail) It can also be provided in such a form.
  • electronic media eg homepage (website) provided by the Internet, e-mail
  • subject refers to an organism to which the treatment of the present invention is applied, and is also referred to as “patient”.
  • patient refers to an organism to which the treatment of the present invention is applied, and is also referred to as “patient”.
  • patient or subject may preferably be a human.
  • the present invention relates to a disorder of the respiratory system, circulatory system, digestive system, urinary system, genital system, central nervous system, or peripheral nervous system.
  • a sugar chain-modified ribosome for the manufacture of a medicament for treating harm is provided.
  • any form described in the above can be used as the sugar chain-modified ribosome.
  • the present invention treats a subject having a disorder of the respiratory system, circulatory system, digestive system, urinary 'genital system, central nervous system, or peripheral nervous system.
  • This method comprises the step of administering to a subject an orally administered drug delivery vehicle for treating a disorder, wherein the orally administered drug delivery vehicle comprises a glycosylated liposome and a pharmaceutically acceptable carrier. And the glycosylated ribosome contains an amount of the drug effective to treat the disorder.
  • the sugar chain-modified ribosome any form described in the above (Sugar-modified ribosome) can be used.
  • the present invention provides a method for delivering a biological agent to a target site in a subject in need of the biological agent.
  • This method includes the step of orally administering the sugar chain-modified ribosome of the present invention, wherein the sugar chain-modified ribosome contains an effective amount of the biological factor.
  • the sugar chain-modified ribosome any form described in the above (Sugar chain-modified ribosome) can be used.
  • the present invention provides a method for producing a sugar chain-modified ribosome.
  • This method comprises the steps of: (a) providing a ribosome; (b) treating the ribosome with a hydrophilic treatment; (c) binding a linker to the hydrophilic ribosome, if necessary. A linker-linked ribosome; and (d) a step of binding a sugar chain to the ribosome to generate a sugar chain-modified ribosome.
  • the step of treating the ribosome in step (b) with a hydrophilic property is carried out directly or indirectly on the lipid membrane or linker of the ribosome.
  • the linker used in step (c) is performed by binding a compound (for example, tris (hydroxyalkyl) aminoalkane) and the like, and a human-derived protein (for example, human serum albumin) is used.
  • a sugar chain is bound to the ribosome directly or indirectly under the condition for binding the sugar chain to produce a sugar chain-modified ribosome.
  • the present invention provides a method for producing a sugar chain-modified ribosome for delivering a drug to a target delivery site.
  • This method comprises the steps of: (a) providing a sugar chain-modified ribosome having various sugar chain densities to achieve delivery to the intended delivery site; (b) adjusting the sugar chain density on the sugar chain-modified ribosome. Thus determining the density to achieve optimal delivery to the delivery site; and (c) incorporating the drug into the determined optimal glycosylated ribosome to produce a drug-containing ribosome.
  • the ribosome itself can be produced according to a well-known method. Examples thereof include a thin film method, a reverse layer evaporation method, an ethanol injection method, and a dehydration-one rehydration method. .
  • the particle size of ribosome can be adjusted by using an ultrasonic irradiation method, an etrusion method, a French press method, a homogenization method, or the like.
  • the production method of the ribosome itself of the present invention will be specifically described. For example, first, a lipid containing phosphatidylcholines, cholesterol, phosphatidylethanolamines, phosphatidic acids, gangliosides, glycolipids or phosphatidylglycerols as a component.
  • a lipid containing phosphatidylcholines, cholesterol, phosphatidylethanolamines, phosphatidic acids, gangliosides, glycolipids or phosphatidylglycerols as a component.
  • a lipid containing phosphatidylcholines, cholesterol, phosphatidylethanolamines, phosphatidic acids, gangliosides, glycolipids or phosphatidylglycerols as
  • the combination of phosphatidic acids or long-chain alkyl phosphates such as dicetyl phosphate is essential to negatively charge the ribosome, and the combination of phosphatidylethanolamines is a hydrophilic reaction site.
  • Gandariosides or glycolipids or phosphatidylglycerol The combination of the kinds is essential as a binding site of the linker.
  • Group power consisting of redesignosides, glycolipids, phosphatidylglycerols, sphingomyelins, and cholesterols At least one selected lipid assembles in the ribosome and functions as a scaffold (raft) that binds the linker.
  • the ribosome of the present invention is further stabilized by the formation of rafts that can bind such proteins. That is, the liposome of the present invention has at least one kind of lipid selected from the group forces of gandarioside, glycolipid, phosphatidylglycerol, sphingomyelins and cholesterol for binding the linker. It contains ribosomes with rafts. Then, ribosomes are produced by ultrafiltration of the mixed micelles obtained in this way.
  • the ribosome used in the present invention is a force that can be used even if it is a normal one.
  • the surface is desired to be hydrophilic. After preparing the ribosome as described above, the surface of the ribosome is made hydrophilic.
  • the present invention also includes liposomes that are not bound to sugar chains that are hydrophilic using the above-mentioned hydrophilic compounds.
  • Such hydrophilic ribosomes have increased stability of the ribosome itself, and are linked to sugar chains.
  • liposomal lipids are phosphatidylcholines (molar ratio 0 to 70%), phosphatidylethanolamines (molar ratio 0 to 30%), phosphatidic acids, and long-chain alkyl phosphates.
  • lipids molar ratio 0-30%), gandariosides, glycolipids, phosphatidylglycerols and sphingomyelins are selected. It is a ribosome containing the above lipids (molar ratio 0 to 40%) and cholesterols (molar ratio 0 to 70%).
  • the present invention further includes a method of hydrophilizing the ribosome by binding the above-described hydrophilic compound to the ribosome. It also includes hydrophilic ribosomes with no sugar chains attached.
  • the target-directed ribosome or intestinal absorbable ribosome of the present invention can be produced by binding a sugar chain to a ribosome to which no sugar chain is bound.
  • the sugar chain that can be used in the sugar chain-modified ribosome of the present invention can be synthesized by a general sugar chain synthesis method. These methods include (1) chemical synthesis, (2) fermentation using genetically modified cells or microorganisms, and (3) sugar hydrolase (glycosylation). (4) a synthesis method using a glycosyltransferase (glycosyltransferase).
  • the sugar chain used in the sugar chain-modified ribosome of the present invention may be a sugar chain synthesized by the above method or a commercially available sugar chain.
  • any of the above sugar chains may be directly bound to the liposome prepared as described above.
  • a sugar chain may be bonded via one.
  • the type of sugar chain to be bound to the ribosome is not limited to one, and a plurality of sugar chains may be bound.
  • the plurality of sugar chains may be a plurality of sugar chains having binding activity to different lectins that are commonly present on the cell surface of the same tissue or organ, or may be present on the cell surface of different tissues or organs. It may be a sugar chain that has binding activity to different lectins.
  • a ribosome is produced by mixing a sugar chain as a glycolipid, or a sugar chain is bound to a phospholipid of the ribosome after production and the sugar chain density is controlled.
  • a biological protein particularly a human-derived protein, as the linker.
  • Proteins derived from living organisms are not limited, but proteins that exist in blood such as albumin And other physiologically active substances present in the living body. For example, human serum albumin
  • the ribosome of the present invention is very stable, and can be post-treated by binding a protein, binding a linker, or binding a sugar chain after the ribosome is formed. Therefore, after producing a large amount of ribosomes, it is possible to produce various ribosomes according to the purpose by binding different proteins or binding linkers or sugar chains depending on the purpose.
  • a sugar chain is directly bonded to a lipid constituting the ribosome via a linker.
  • the ribosome of the present invention is a ribosome having a complex carbohydrate type ligand such as glycolipid and glycoprotein and hydrophilized with a low molecular weight compound.
  • the liposome needs to contain a compound having a pharmaceutical effect.
  • the compound having a medicinal effect may be encapsulated in a ribosome, or may be bound to the ribosome surface.
  • a protein having a medicinal effect may be used as a force linker.
  • the protein may also serve as a linker for binding the liposome and the sugar chain and a protein having a medicinal effect. Examples of proteins having medicinal effects include physiologically active proteins.
  • a cross-linking agent can be used when binding the ribosome and the linker.
  • the sugar chain can be bound to the ribosome via the linker by the method described below.
  • Treatment with an oxidizing agent such as NaBi03 oxidizes the gandarioside present on the ribosome membrane surface, and then using a test drive such as NaBH CN, NaBH, etc.
  • Ngurioside is coupled by a reductive amination reaction.
  • This linker is also preferably hydrophilized.
  • a compound having a hydroxy group is bound to Ringer protein.
  • Propionate, disuccimidinosberate, 3, 3, monodithiobis The above-mentioned hydrophilic properties such as tris (hydroxymethyl) aminomethane using a bivalent reagent such as ethylene glycol bissuccinimidolesuccinate and ethylene glycol bissulfosuccinimidyl succinate.
  • the compound used for sex should be bound to the linker on the liposome.
  • a divalent reagent for crosslinking is bonded to all the amino groups of the linker. Then, a glycosylamine compound obtained by glycosylation of the reducing ends of various sugar chains is prepared, and the above-mentioned cross-linked divalent reagent on the ribosome and the amino group of this sugar chain is prepared. To other unreacted ends.
  • the covalent bond between the sugar chain and Z or hydrophilic compound and the ribosome, or the covalent bond between the sugar chain and Z or hydrophilic compound and the linker is cleaved when the ribosome is taken into the cell. It is also possible to do this.
  • the sugar chain when a linker and a sugar chain are covalently bonded via a disulfide bond, the sugar chain is cleaved by reduction in the cell.
  • the sugar chain is cleaved, the ribosome surface becomes hydrophobic, binds to the biological membrane, disturbs the membrane stability, and releases the drug contained in the ribosome.
  • the sugar chain is bound to a linker on the ribosome.
  • the reducing end of the sugar constituting the sugar chain is glycosylated using ammonia salts such as NH HCO and NH COONH.
  • the particle size of the ribosome or sugar chain-bound ribosome of the present invention is 30 to 500 nm, preferably 50 to 350 nm. Moreover, it is desirable that the ribosome of the present invention is negatively charged. By being negatively charged, interaction with negatively charged cells in the living body can be prevented.
  • the zeta potential on the surface of the ribosome of the present invention is 50 to: LOmV, preferably 1 to 40 to 0 mV, more preferably 1 to 30 to 10 mV at 37 ° C. in physiological saline.
  • the drug contained in the sugar chain-modified ribosome of the present invention includes biopharmaceuticals or biotherapeutic substances (eg, siRNA, shRNA, siRNA derivatives, shRNA derivatives, RNA, RNA derivatives, DNA, DNA derivatives, monoclonal antibodies) , Vaccine, interferon, hormone, prostaglandin, transcription factor, recombinant protein, antibody drug, nucleic acid>
  • biopharmaceuticals or biotherapeutic substances eg, siRNA, shRNA, siRNA derivatives, shRNA derivatives, RNA, RNA derivatives, DNA, DNA derivatives, monoclonal antibodies
  • Vaccine interferon, hormone, prostaglandin, transcription factor, recombinant protein, antibody drug, nucleic acid>
  • Drugs gene therapy drugs
  • alkylated anticancer agents antimetabolites
  • plant-derived anticancer agents anticancer antibiotics
  • BRM 'site force-ins platinum complex anticancer agents
  • immunotherapeutic agents hormonal anticancer agents
  • monoclonal antibodies etc.
  • Drugs for oncology drugs for central nervous system, drugs for peripheral nervous system 'sensory organs, drugs for respiratory diseases, drugs for cardiovascular system, drugs for digestive organs, drugs for hormonal system, drugs for urinary organs, drugs for genital organs, vitamins' nutrient tonic, Metabolic drugs, antibiotics' chemotherapy drugs, test drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, autoimmune drugs, cardiovascular drugs, lifestyle diseases such as diabetes and hyperlipidemia Drug, Adrenocortical hormone, Immunosuppressant, Antibacterial agent, Antiviral agent, Anti-angiogenic agent, Cyto-force-in, Chemokine, Anti-site-force-in antibody, Anti-chemokine antibody, Anti-site force-in 'chemokine receptor anti , SiRNA, shRNA, miRNA, smRNA, antisense RNA or gene therapy-related nucleic acid products such as ODN or DNA, neuroprotective factor, antibody drug, molecular targeting drug, osteoporosis / bone metabolism improving drug, neuropeptide And
  • oncology drugs such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, prusphan, hydrochloric acid-mustine, mitoblonitol, melphalan, dacarbazine, ramustine, estramustine phosphate, etc.
  • Antimetabolites such as mercaptopurine, thioinosine (mercaptopurine riboside), methotrexate, enocitabine, cytarabine, ancitabine hydrochloride (cyclocytidine hydrochloride), fluorouracil, 5-FU, tegafur, doxyfluridine, carmofur, etoposide, binplastin sulfate, sulfuric acid
  • Plant-derived anticancer agents such as pinklistin, vindesine sulfate, paclitaxel, taquinol, alkaloids such as irinotecan hydrochloride and nogitecan hydrochloride, actinomycin D, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride , Doxorubicin hydrochloride, aclarubicin hydrochloride (acla
  • the ribosome of the present invention can be used for the treatment of diseases such as cancer and inflammation.
  • cancer includes all neoplastic diseases such as tumors and leukemias.
  • these drugs are included in the sugar chain-modified ribosome of the present invention and administered, the drugs accumulate at sites of cancer and inflammation compared to when the drug is administered alone. Compared to the case of single administration, it can be accumulated 2 times or more, preferably 5 times or more, more preferably 10 times or more, particularly preferably 50 times or more.
  • it can accumulate 3 to 4 times, preferably 4 to 6 times.
  • the sugar chain-modified ribosome of the present invention can be used for treatment of various diseases by encapsulating a drug as described above.
  • the drug-encapsulated sugar chain-modified ribosome can be administered by intravenous injection or oral administration. Even if the sugar chain-modified ribosome of the present invention is delivered to an organ when orally administered, the medium transferred into the blood by oral administration shows the same tendency as intravenous injection. May be encapsulated in the ribosome or bound to the ribosome surface.
  • a protein can be bound to the surface in the same manner as the above linker binding method, and other compounds can be bound to the surface. By using the functional group of the compound, it can be bonded by a known method.
  • Encapsulation inside the ribosome is performed by the following method.
  • phosphatidylethanolamines, phosphatidic acids or long-chain alkyl phosphates, contosides, glycolipids or phosphatidylglycerols and cholesterols can be used.
  • lipids drugs and the like are enclosed in ribosomes.
  • the ribosome preparation obtained by encapsulating a drug or gene that can be used for treatment or diagnosis in the ribosome of the present invention selectively controls the migration to cancer tissue, inflammatory tissue, and various tissues. It is intended to increase the efficacy by concentrating therapeutic drugs or diagnostic agents on target cells and tissues, or to reduce side effects by reducing the uptake of drugs to other cells and tissues. .
  • a labeling compound such as a fluorescent dye or a radioactive compound is encapsulated or bound to the ribosome.
  • the labeled compound binding ribosome binds to the affected area, the labeled compound is taken up by the affected cell, and a disease can be detected and diagnosed using the presence of the labeled compound as an index.
  • a DNA probe diagnostic agent for example, a DNA probe diagnostic agent, an X-ray contrast agent, a radioactive reagent, a radioactive contrast agent, a radioactive diagnostic agent, a fluorescent reagent, a fluorescent contrast agent, a fluorescent diagnostic agent, for CT Contrast agent, PET contrast agent, SPECT contrast agent, MRI contrast agent, AIDS diagnostic agent, hematology test reagent, functional test reagent, microbial test reagent, molecular imaging, in vivo imaging, fluorescence imaging, It can be used for luminescence imaging, cell sorter, PET and S PECT.
  • Research reagents include reagents used in recombinant DNA technology, immunoassay, immunology, hybridization methods, and enzyme assays.
  • this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand, and can be used to treat diseased parts and various organs. It shows that drugs, fluorescent substances, radiolabeled substances, etc. are accumulated and delivered with high efficiency by active targeting. Therefore, the sugar chain-modified ribosome of the present invention can visualize the accumulation in a target tissue such as a tumor. It also provides a delivery vehicle for use as a reagent or diagnostic agent.
  • the present invention can also be used in the field of health' food. In such a case, the points to be noted when using it as an oral medicine should be considered as necessary.
  • a functional food such as a specific health food, such as a “health food”
  • a food composition in which a functional food, nutritional supplement or health supplement is encapsulated or bound to the sugar chain-modified ribosome of the present invention can be used.
  • Functional foods, nutritional supplements, or health supplements that can be used in the present invention are not limited to foods that are designed and processed and converted to effectively express food functions. .
  • ribosomes can be included in ribosomes as they are, or processed products such as extracts may be included.
  • Food compositions containing ribosomes are taken orally.
  • the ribosome to be used may not be bound to a sugar chain, or may be bound to a sugar chain that enhances intestinal absorption or a sugar chain that targets a specific tissue or organ.
  • the ribosome of the present invention When the ribosome of the present invention is administered as a food composition, it may be processed into a food such as a liquid beverage, a gel food, or a solid food. It may also be processed into tablets, granules, etc.
  • the food composition of the present invention can be used as a functional food, a nutritional supplement or a health supplement according to the type of food contained in the ribosome.
  • a ribosome containing DHA can be used as a functional food, nutritional supplement, or health supplement effective for mild senile dementia and memory improvement.
  • Examples of preferred embodiments for achieving the object of the present invention include the following items.
  • (Item 1) Galactose (Gal), N-acetyl galatatosamine (GalNAc), Mannose (Man), Glucose (Glc), N-acetyl dalcosamine (GlcNAc), Fucose (Fuc), N-acetyl neuraminic acid ( Neu5Ac), Galatatose 3-sulfuric acid (3- (O—SO H) Gal),
  • a sugar chain-modified ribosome comprising a sugar chain containing at least one sugar selected from the group consisting of ramid (Cer) and serine (Ser), and a ribosome.
  • the sugar chain has the following structure: R 1 —X 1 —X 2 —R 2 , wherein R 1 and R 2 are independently hydrogen, or Any sugar chain, and X 1 is Fuc ⁇ GalNAc ⁇ Gal, 3, (O—SOH) Gal, GlcNAc
  • the sugar chain-modified ribosome according to item 1 wherein the sugar chain-modified ribosome is selected from the group consisting of Man and Neu5Ac, and the X2 is selected from the group consisting of Gal, Glc, GlcNAc, Ser, GalNAc, Cer and Man force.
  • the sugar chain-modified ribosome according to item 2 wherein the sugar chain directly binds to the ribosome like a force or hydrophobic interaction directly on the R 2 side.
  • the bond between X 1 and X 2 is ⁇ , 2 bond, ⁇ , 3 bond, ⁇ 1, 4 bond, ⁇ 1, 6 bond, ⁇ - ⁇ bond, «2, 3 bond, «2, 6 bond, ⁇ ⁇ , 1 bond, ⁇ ⁇ , 3 bond, ⁇ ⁇ , 4 bond and j81, 6 bond force, where al-O bond is when X 2 is Ser Item 3.
  • X 1 — X 2 force 3 ′-(O— SO H) Gal- GlcNAc, Fuc -Gal, Fuc -Glc, Fuc- GlcNAc ⁇ Gal- Gal,
  • X 1 — X 2 is Fuc ⁇ 1, 2Gal, Fucal, 3 Glc, Fucal, 3GlcNAc, Fucal, 4GlcNAc, 3′— (O— SO H) Galj81, 3Glc
  • NAc Gala 1, 3Gal, GaljS 1, 3GalNAc, GaljS 1, 3GlcNAc, GaljS 1, 4Glc, GaljS 1, 4GlcNAc ⁇ GaljS 1, 6GlcNAc ⁇ GalNAc a 1, 3Gal, GalNAc a lO: L Ser ⁇ GalNAc ⁇ 1, 4Gal , GlcNAc ⁇ 1, 3Gal, GlcNAc ⁇ 1, 4GlcNAc, G lcj81,! CerNeu5Ac 2, 3Gal, Neu5Ac 2, 6GalNAcMan 1, 2Man Man Item 6.
  • the sugar chain-modified ribosome according to Item 5 having a structure selected from the group consisting of 1,3ManMana 1,4ManMana 1,6Man and ManjS 1,4GlcNAc.
  • the aforementioned sugar chain has the following structure: R 1 — X 1 — X 2 — X 3 — R 2 , wherein R 1 and R 2 are independently hydrogen.
  • X 1 is selected from the group consisting of Fuc, Gal, GalNAc, GlcNAc, Man and Neu5Ac
  • the X 2 consists of Gal, GlcN Ac, GalNAc and Man
  • the sugar chain-modified ribosome according to Item 1 wherein the sugar chain is selected from the group, and the X 3 is selected from the group consisting of Glc, GlcN Ac, Gal, GalNAc, Ser, Cer and Man.
  • Item 8 The sugar chain-modified ribosome according to item 7, wherein the sugar chain binds to the ribosome directly on the R 2 side or indirectly like a hydrophobic interaction.
  • X ⁇ all glycosylation selected from coupling force becomes the group are defined between X bond and X 2 and X 3 between, wherein the said X 1 and X 2 Bond between ⁇ , 2 bond, ⁇ 1, 3 bond, ⁇ 1, 4 bond, ⁇ 1, 3 bond, ⁇ 1, 4 bond, a 2, 3 bond, a 2, 6 bond, ⁇ , 6 bond And ⁇ , 3 bond strength, and the bond between X 2 and X 3 is ⁇ 1,1 bond, ⁇ 1,3 bond, j81,4 bond, ⁇ , 2 bond, ⁇ — Oc bond, ⁇ , 6 bond, ⁇ , 3 bond and j81, 4 bond force, where oc
  • X 3 is present in the Ser, glycosylation ribosome of claim 7.
  • Said X 1 -X 2 -X 3 is Fuc-Gal-Glc, Fuc-Gal-GlcN Ac ⁇ Fuc-GlcNAc-Gal, Gal -GalNAc -Gal, Gal -GlcNAc -Gal, Gal -GlcNAc- Gal, Gal— G lc Cer, GlcNAc— Gal— Glc, Neu5 Ac-Gal-GalNAc, Neu5Ac— Gal— Glc, Neu5 Ac— Gal— GlcNAc, Neu5Ac— GalNAc— Ser, Man— Man— Man— Man, Man-Man -GlcNAc, and Man— GlcNAc-selected from the group consisting of GlcNAc Item 9.
  • X 1 — X 2 — X 3 is Fuca 1, 2Galj81, 3GlcNAc, Fuca 1, 2Galj81, 4Glc, Fuc ⁇ 1, 2Galj81, 4GlcNAc, Fuca 1, 4GlcNA C j 81, 3Gal, GaljS 1, 3GalNA C j 81, 4Gal, GaljS 1, 4GalNA C j 81, ICer ⁇ GaljS 1, 3GlcNA C j 81, 3Gal, GalNA C j 81, 4Gal ⁇ 1, 4Glc, GlcNAc ⁇ 1, 3Galj81, 4Glc, Neu5Ac a 2, 3Galj81, 3GalNAc, Neu 5Ac a 2, 3Gal ⁇ 1, 3GlcNAc, Neu5Ac a 2, 3Gal ⁇ 1, 3GlcNAc, Neu5Ac a 2, 3Gal ⁇ 1, 3GlcNAc, Neu
  • the sugar chain has the following structure: R 1 — X 1 — X 2 — X 3 — X 4 — R 2 , wherein R 1 and R 2 are independently Is hydrogen or any sugar chain, the X 1 is selected from the group consisting of Fuc, Gal, Neu5Ac and Man, and the X 2 is a group consisting of Gal, GalNAc, GlcNAc and Man
  • the X 3 is selected from the group consisting of GlcNAc, GalNAc, Gal and Man, and the X 4 is selected from the group also consisting of Gal, Glc, Man, Cer and GlcNAc force.
  • Sugar chain-modified ribosome (Item 14) The sugar chain-modified ribosome according to item 12, wherein the sugar chain binds to the ribosome directly by force on the R 2 side or indirectly like a hydrophobic interaction. (Item 15) At least one sugar chain bond selected from the group consisting of a bond between X 1 and X 2 , a bond between X 2 and X 3 and a binding force between X 3 and X 4 Where the bond between X 1 and X 2 is ⁇ , 2 bond, ⁇ 1, 3 bond, ⁇ 2, 3 bond, 131, 3 bond and ⁇ 1, 6 bond force The bond between X 2 and X 3 is selected from the group consisting of ⁇ 1,3 bond, ⁇ 1,4 bond, a 1,2 bond, a 1,3 bond, and ⁇ 1,6 binding force.
  • the bond between X 3 and X 4 is selected from the group consisting of ⁇ 1, 1 bond, ⁇ 1, 3 bond, ⁇ 1, 4 bond, a 1, 3 bond and a 1, 6 bond force.
  • the binding force between X 1 and X 2 is al, 2 bonds, ⁇ 1, 3 bonds, ⁇ 2, 3 Bond, ⁇ ⁇ , 3 bond and a 1, 6 bond strength
  • the bond between X 2 and X 3 is ⁇ 1, 3 bond, ⁇ 1, 4 bond, a 1, 2 Selected from the group consisting of a bond, a 1, 3 bond, and a 1, 6 bond
  • the bond between X 3 and X 4 is ⁇ 1, 1 bond, ⁇ 1, 3 bond, ⁇ 1, 4
  • the bond between X 1 and X 2 is al, 2 bond, al, 3 bond, a 2, 3 bond, ⁇ 1, 3 bond and ⁇ 1, 6 bond strength
  • the bond between X 2 and X 3 is selected from the group consisting of ⁇ ⁇ , 3 bond, / 31, 4 bond, a 1, 2 bond, a 1, 3 bond, and a 1, 6 bond force
  • a group selected from the group consisting of: a bond strength between X 3 and X 4 ⁇ 1, 1 bond, ⁇ 1, 3 bond, ⁇ 1, 4 bond, a 1, 3 bond and a 1, 6 bond force 14.
  • the sugar chain-modified ribosome according to item 13, which is selected from the above.
  • X 1 — X 2 — X 3 — X 4 are Fuc—Gal—GlcNAc—Gal, Fuc—GlcNAc—Gal—Glc ⁇ GalNAc—Gal—Glc—Cer ⁇ Gal—GalNAc—Gal—Glc ⁇ Gal -GlcNAc-Gal- Glc, Neu5Ac- Gal- GalNAc- Gal, Neu5Ac- Gal- Glc- Cer, Man- Man- Man- Man- Man, Man- Man- Man- GlcNAc, and Man- Man- Glc NAc- GlcNAc 14.
  • X 1 — X 2 — X 3 — X 4 is Fucal, 2Galj81, 3GlcNAc ⁇ 1, 3Gal, Fucal, 4GlcNA C j 81, 3Galj81, 4Glc, GalNAc j81, 4Galj81, 4Glc ⁇ 1, lCer, GaljS 1, 3GalNA C j 81, 4Galj81, 4Glc, GaljS 1, 3GlcNA C j 81, 3 GaljS 1, 4Glc, Neu5Ac a 2, 3Galj81, 3GalNAc ⁇ 1, 4Gal, Neu5Ac a 2, 3G alj81, 4Glcj81, 4Cer, Man a 1, 2Mana 1, 2Mana 1, 3Man, Man a 1, 2M ana 1, 3Mana 1, 6Man, Mana 1,
  • the sugar chain-modified ribosome according to 18. (Item 20)
  • the above-mentioned glycan force has the following structure: R 1 — X 1 — X 2 — X 3 — X 4 — X 5 — R 2 where R 1 and R 2 are independently Is hydrogen or any sugar chain, and the X 1 is Fuc, Neu5Ac or Is selected from the group consisting of and Man, the X 2 is, Ga Fireflys is Man, the X 3 is selected from the group consisting of GlcNAc c, GalNAc and Man, the X 4 is Gal, GlcNAc and Man
  • the bond between items 23 and X 2 , the bond between X 2 and X 3 , the bond between X 3 and X 4 and the bond force between X 4 and X 5 And at least two sugar chain bonds are defined, wherein the bond between X 1 and X 2 is ⁇ ⁇ , 3 bond, al, 2 bond, a 2, 3 bond, al, 3 bond
  • the binding force between X 2 and X 3 is selected from the group of ⁇ ⁇ , 3 bond, al, 2 bond, ⁇ 1, 3 bond and a 1, 6 bond force is selected, the bond between the X 3 and X 4 are, beta 1, 3 bond, beta 1, 4 bonds, selected from a 1, 3 bond and a 1, 6 bond strength becomes the group, with the X 4 21.
  • a bond between X 1 and X 2 , X 2 and X 3 bond between, is selected from the group becomes binding force between the coupling and X 4 and X 5 between X 3 and X 4
  • At least three glycosylation is defined, wherein the bonding force beta 1, 3 bond between the X 1 and X 2, al, 2 bond, a 2, 3 coupled, al, 3 bonds and a Selected from the group consisting of 1, 6 bonds, and the bond between X 2 and X 3 is selected from the group consisting of ⁇ ⁇ , 3 bonds, al, 2 bonds, al, 3 bonds and a 1, 6 bonds
  • the bond strength between X 3 and X 4 is selected from the group j81, 3 bond, / 31, 4 bond, al, 3 bond and a 1, 6 bond force, and the bond between X 4 and X 5
  • a 1, 6 bond strength is also a group, with the X 3 Binding force between X 4 ⁇ 1, 3 bond, 131, 4 bond, ⁇ 1, 3 bond and a 1, 6 bond selected from the group consisting of a bond between X 4 and X 5 ⁇ , 1 bond or
  • X 1 — X 2 — X 3 — X 4 — X 5 is Fuc- Gal- GlcNAc- Gal- G1 c— Gal- GalNAc- Gal- Glc- Cer ⁇ Neu5Ac- Gal- GalNAc- Gal- Item 21.
  • X 1 -X 2 -X 3 -X 4 -X 5 is Fuc a 1, 2Galj81, 3GlcNAc ⁇ 1, 3Gal ⁇ 1, 4Glc, GaljS 1, 3GalNAc ⁇ 1, 4Galj81, 4Glc ⁇ 1, lCer, Neu5Ac a 2, 3 GaljS 1, 3GalNAcj81, 4Galj81, 4Glc j8, Man a 1, 2Mana 1, 2Mana 1, 3 ManjS 1, 4GlcNAc, Man a 1, 2Mana 1, 3 ManjS 1, 4GlcNAc, Man a 1, 2Mana 1, 3Mana 1, 6Manj81, 4GlcNAc, Mana 1, 2Mana 1, 3Manj81, 4GlcNAc j81, 4GlcNAc, Mana 1, 2Mana 1, 6Mana 1, 6Manj81, 4GlcNAc, Mana 1, 3Mana 1, 6Manj81, 4GlcNAc, Man
  • the sugar chain-modified ribosome according to Item 26 which has a structure selected from the group consisting of force, 4GlcNAc ⁇ 1, 4GlcNAc and force.
  • the sugar chain has the following structure: R 1 — X 1 — X 2 — X 3 — X 4 — X 5 — X 6 — R 2 , where R 1 and R 2 is independently hydrogen or any sugar chain, the X 1 is Man or Neu5Ac, the X 2 is Man or Gal, and the X 3 is Man or GalNAc
  • Item 3D Bond between X 1 and X 2 , Bond between X 2 and X 3 , Bond between X 3 and X 4 , Bond between X 4 and X 5 and X 5 and At least two sugar chain bonds selected from the group that also has a binding force between X 6 are defined, wherein the bond between X 1 and X 2 is ⁇ 1, 2 bond or ⁇ 2 , 3 bond, and the bond between X 2 and X 3 is a 1, 2 bond, ⁇ 1, 3 bond, ⁇ 1, 6 bond or ⁇ 1, 3 bond, and X 3 and X 4 Is a ⁇ 1,3 bond or ⁇ 1,6 bond, and the bond between X 4 and X 5 is a ⁇ 1,4 bond, and the bond between X 5 and X 6 is The sugar chain-modified ribosome according to Item 28, wherein the bond is
  • the glycosylated liposome according to Item 28. (Item 33) A bond between X 1 and X 2 , a bond between X 2 and X 3 , a bond between X 3 and X 4 , At least four sugar chain bonds selected from the group consisting of a bond between X 4 and X 5 and a binding force between X 5 and X 6 , wherein X 1 and X 2 Is a 1, 2 bond or ex 2, 3 bond, and the bond between X 2 and X 3 is ex 1, 2 bond, ex 1, 3 bond, a 1, 6 bond Together Other are beta 1, 3 bond, the bond between the X 3 and X 4 is a 1, 3 bond or a 1, 6 bond, bond j8 1 between the X 4 and X 5
  • the bond between X 1 and X 2 is an a 1, 2 bond or an a 2, 3 bond
  • the bond between X 2 and X 3 is an ⁇ , 2 bond, ⁇ , 3 bond, ⁇ 1, 6 bond or j81, 3 bond
  • the bond between X 3 and X 4 is a 1, 3 bond or a 1, 6 bond
  • X 4 and X bond The sugar chain modification according to Item 28, wherein the bond between 5 is a ⁇ 1,4 bond, and the bond between X 5 and X 6 is a ⁇ 1,1 bond or a ⁇ 1,4 bond. Ribosome.
  • X 1 — X 2 — X 3 — X 4 — X 5 — X 6 is Man- Man- Man- Man- GlcNAc-GlcNAc or Neu5 Ac- Gal-GalNAc- Gal-Glc- Cer The sugar chain-modified ribosome according to Item 28.
  • X 1 — X 2 — X 3 — X 4 — X 5 — X 6 are Manal, 2Manal, 2Manal, 3Man ⁇ 1, 4GlcNAcj81, 4GlcNAc81, Mana 1, 2Mana 1, 3Mana 1, 6Manj81, 4 GlcNAc j81, 4GlcNAc ⁇ Man a 1, 2Mana 1, 6Mana 1, 6Manj81, 4GlcNA C j 81, 4GlcNAc and Neu5Ac a 2, 3Galj81, 3GalNAc ⁇ 1, 4Galj81, 4Glc ⁇ 1, ICer 36.
  • the sugar chain-modified liposome according to item 35 wherein (Item 37) The sugar chain-modified ribosome according to item 1, which is selected from the group consisting of the sugar powers Gal, GalNAc, Man, Glc, GlcNAc and Ser of the ribosome proximal end of the sugar chain and a combination force thereof. (Item 38) The sugar at the most distal end of the ribosome of the sugar chain is Ga 1, 3, 1 (O—SO 2 H) Gal, GalNAc, Man, Fuc and Neu5Ac and their
  • sugar chain-modified ribosome according to item 1, wherein the sugar chain-modified ribosome is selected from the group consisting of a combination force.
  • the sugar force at the proximal end of the ribosome of the sugar chain is selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc and Ser, and their combination power, and the most distal end of the liposome in the sugar chain Sugar powers Gal, GalNAc, 3, (O—SOH) Gal, Man, Fuc and
  • Item 2 The sugar chain-modified ribosome according to Item 1, which is selected from the group consisting of Neu5Ac and a combination force thereof.
  • the sugar chain-modified ribosome according to item 37 which is a sugar power Ser or Cer at the most proximal end of the ribosome of the sugar chain.
  • the sugar chain-modified ribosome according to item 38 wherein the sugar at the most distal end of the ribosome of the sugar chain is 3, — (O—SO 2 H) Gal.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Fuc 1 — A 2 — R Z , where A 2 consists of Gal, Glc and GlcNAc Item 2.
  • the bond between Fuc 1 and A 2 is ⁇ , 2 bond, ⁇ , 3 bond and ⁇ , 4 bond. 43.
  • the sugar chain-modified ribosome according to item 42 which is selected from the group consisting of resultant forces.
  • the sugar chain modification according to item 42 having a structure selected from the group consisting of Fuc-Gal, Fuc-Glc and Fuc-Glc NAc force from the distal end side of the ribosome distal end force of the sugar chain Ribosome.
  • Ribosome distal end force of the sugar chain A structure selected from the group consisting of Fuc a 1, 2Gal, Fuc a 1, 3Glc, Fuc a 1, 3GlcNAc and Fuc a 1, 4GlcNAc from the distal end side 45.
  • the sugar chain-modified ribosome according to item 44 having a structure.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Fuc 1 — A 2 — A 3 — R z , where A 2 is Ga is GlcNAc, the a 3 is Glc, is selected from the group consisting of Gal and GlcNAc, and the R z is hydrogen or is any sugar, sugar chain modification ribosome of claim 1 .
  • At least one sugar chain bond selected from the group consisting of a bond between Fuc 1 and A 2 and a binding force between A 2 and A 3 is defined, where Fuc 1 And A 2 are ⁇ 1, 2 bonds or a 1, 4 bonds, and the bonds between ⁇ 2 and ⁇ 3 are ⁇ 1, 3 bonds or
  • All glycosylation selected from coupling force becomes the group are defined between the coupling and A 2 and A 3 between the F uc 1 and A 2, wherein said Fuc 1
  • the bond between A 2 and A 2 is a ⁇ 1, 2 bond or a 1, 4 bond
  • the bond between A 2 and A 3 is a ⁇ 1, 3 bond or
  • the sugar chain-modified ribosome according to item 46. (Item 49) The item wherein the ribosome distal end of the sugar chain has a structure selected from the group consisting of Fuc-Gal-Glc, Fuc-Gal-GlcNAc and Fuc-GlcNAc-Gal from the distal end side 46.
  • the sugar chain-modified ribosome according to 46. (Item 50) The ribosome distal end of the sugar chain is F from the distal end side.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Fuc ⁇ -A 2 — A 3 — A 4 — R z , where A 2 is Gal or GlcNA, the A 3 is Ga or GlcNA, the A 4 is Ga or Glc, and the R z is hydrogen or any sugar.
  • the sugar chain-modified ribosome according to Item 1.
  • At least one sugar chain bond selected from the group consisting of a bond between Fuc 1 and A 2 , a bond between A 2 and A 3, and a bond force between A 3 and A 4 Is defined,
  • the bond between the Fuc 1 and A 2 is a ⁇ 1 , 2 bond or ⁇ 1, 4 bond
  • the bond between the A 2 and A 3 is a ⁇ 1,3 bond.
  • the bond between the Fuc 1 and A 2 is a ⁇ 1 , 2 bond or ⁇ 1, 4 bond
  • the bond between the A 2 and A 3 is ⁇ 1, 52.
  • the sugar chain-modified ribosome according to Item 51 which is a 3-bond and has a binding force ⁇ 1,3 bond or j81,4-bond between ⁇ 3 and ⁇ 4 .
  • the ribosome distal end of the sugar chain is Fuc a 1 from the distal end side.
  • the ribosome distal end of the sugar chain is on the distal end side
  • it has the following structure: Gal 1 —B 2 —R z , where Gal 1 may be sulfated or unsulfated, and B 2 may be Gal, GalNAc Item 2.
  • the sugar chain-modified liposome according to Item 1 which is selected from the group consisting of GlcNAc and Glc, and wherein R Z is hydrogen or any sugar.
  • the bond between Gal 1 and B 2 is selected from the group consisting of ⁇ 1,3 bond, ⁇ 1,3 bond, ⁇ 1,4 bond and j8 1,6 bond force.
  • Ribosome distal end force of the sugar chain having a structure selected from the group consisting of Gal-Gal, Gal-GaIN Ac, Gal-Glc and Gal-GlcNAc from the distal end side Item 66.
  • the ribosome distal end of the sugar chain is Gala 1, 3Gal, GaljS 1, 3GalNAc, GaljS 1, 3GlcNAc, GaljS 1, 4G1 c, GaljS 1, 4GlcNAc and GaljS 1, 6GlcNAc from the distal end side.
  • the sugar chain-modified ribosome according to item 65 which has a structure selected from the group consisting of: (Item 69)
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Gal 1 — B 2 — B 3 — R z , where Gal 1 is sulfated.
  • the B 2 which may or may not be sulfated, is GalNAc or GlcNAc, the B 3 is Gal, and the R Z is hydrogen or any sugar.
  • All of the sugar chain binding of selected from the binding force becomes a group are defined between the coupling and B 2 and B 3 between the Gal 1 and B 2, wherein the said Gal 1 a bond is 1, 3 bond between B 2, avidity beta 1, 4 bond or between the B 2 and B 3
  • the ribosome distal end of the sugar chain has a Gal
  • the sugar chain-modified ribosome according to Item 72 which has a structure selected from the group consisting of: (Item 74)
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Gal 1 — B 2 — B 3 — B 4 — R z , where Gal 1 is The B 2, which may or may not be sulfated, is GalNAc or GlcNAc, the B 3 is Gal, the B 4 is Glc, and the R 2.
  • At least one sugar chain bond selected from the group consisting of a bond between Gal 1 and B 2 , a bond between B 2 and B 3, and a bond between B 3 is defined.
  • the bond between Gal 1 and B 2 is a
  • the bond between B 2 and B 3 is a 1,4 bond or a j81,3 bond
  • bond between the B 3 and B 4 are / 31, 4 bonds, glycosylation ribosome of claim 74.
  • at least two sugar chain bonds selected from the group consisting of binding forces between B 3 and B 4 are defined, wherein the bond between Gal 1 and B 2 is ⁇
  • the sugar chain-modified ribosome according to item 74 which has a structure of Gal-GalNAc Gal-Glc or Gal-GlcNAc-Gal-Glc from the distal end side of the ribosome distal end force of the sugar chain.
  • the ribosome distal end of the sugar chain is Gal ⁇ 1, 3GalNA C j 8 1, 4Gal j8 1, 4Glc or Gal j8 1, 3GlcNA C j 8 1, 3Gal j8 1, from the distal end side. 80.
  • the sugar chain-modified ribosome according to item 79 which has a structure of 4 Glc.
  • the B 2 is GalN Ac
  • the B 3 is Gal
  • the B 4 is Glc.
  • At least three sugar chain bonds are defined, wherein the bond between Gal 1 and B 2 is a ⁇ 1,3 bond, and the bond between ⁇ 2 and ⁇ 3 is 1, 4 a bond, a binding is beta 1, 4 bonds between the beta 3 and beta 4, coupling between the beta 4 and beta 5 is beta 1, 1 binding, as described in item 80 Sugar chain-modified ribosome.
  • the sugar chain-modified ribosome according to item 80 which has a structure of Gal-GalNAc-Gal-Glc-Cer from the distal end side of the ribosome distal end force of the sugar chain.
  • Ribosome distal end force of the sugar chain The sugar chain according to item 85 having a structure of Gal j8 1, 3GalNA C j 8 1, 4Gal j8 1, 4Glc j8 1, ICer from the distal end side Modified ribosome.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: GalNAc 1 — C 2 — R Z , where C 2 is Ga or Ser.
  • the sugar chain-modified ribosome according to Item 1 wherein R Z is hydrogen or any sugar.
  • the bond between GalNAc 1 and C 2 is an ⁇ ⁇ , 3 bond or l—O— bond, where ⁇ ⁇ — ⁇ — bond is present when C 2 is Ser. 81.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Man 1 — D 2 — R z , where D 2 is Man, and Item 2.
  • the bond between Man 1 and D 2 is selected from the group consisting of ⁇ ⁇ , 2 bond, ⁇ ⁇ , 3 bond, ⁇ ⁇ , 4 bond and ⁇ 1, 6 bond force.
  • the described sugar chain-modified liposome (Item 93) The sugar chain-modified ribosome according to item 91, wherein the ribosome distal end of the sugar chain has a Man-Man structure from the distal end side. (Item 94) The ribosome distal end of the sugar chain is located on the side of the distal end of Man ⁇ 1, 2Man, Man al, 3Man, Man a 1, 4Man. 94.
  • the sugar chain-modified ribosome according to Item 93 which has a structure selected from the group consisting of Man a 1, 6Man.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Man 1 — D 2 — D 3 — R z , where D 2 is Man , wherein D 3 is GlcNAc or is Man, and said R z is hydrogen or is any sugar, sugar chain modification ribosomes placing serial to item 1.
  • Man 1 and has at least one glycosylation is defined is selected from the binding force becomes the group between the bond and D 2 and D 3 between D 2, wherein the said Man 1
  • the bond between D 2 is selected from the group consisting of ⁇ ⁇ , 2 bond, ⁇ ⁇ , 3 bond and ⁇ ⁇ , 6 bond force, and the bond force between D 2 and D 3 ⁇ ⁇ , 2 96.
  • a sugar chain-modified ribosome according to item 95 which is selected from the group consisting of a bond, a 1,3 bond, a 1,6 bond, and a ⁇ , 4 binding force.
  • Man 1 and all binding force glycosylation also be selected from the group consisting are defined between the coupling and the D 2 and D 3 between D 2, wherein the said Man 1
  • the bond between D 2 and the bond between D 2 and D 3 is selected from the group consisting of 1, 2 bond, ⁇ 1, 3 bond, and ⁇ 1, 6 bond force, ⁇ ⁇ , 96.
  • the sugar chain-modified ribosome according to Item 95 which is selected from the group consisting of 2-bond, ⁇ 1,3 bond, ⁇ 1,6 bond and
  • the ribosome distal end of the sugar chain is connected to Man a 1, 2Man a 1, 2Man, Man a 1, 2Man a 1, 3Man, Man 1, 2Man a 1, 6Man, Man from the distal end side. a 1, 3Man a 1, 6Man, Man a 1, 3Man j8 1, 4G1 cNAc, Man a 1, 6Man a 1, 6Man and Man a 1, 6Man j8 1, 4GlcNAc 99.
  • the sugar chain-modified ribosome according to Item 98.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Mar ⁇ -D 2 — D 3 — D 4 — R Z , where D 2 is a Man, the D 3 is a Man or GlcNAc, the D 4 is a Man or GlcNAc, and the R z is hydrogen or Ru any sugar der, of claim 1 Sugar chain-modified ribosome.
  • At least one sugar chain bond selected from the group consisting of a bond between Man 1 and D 2 , a bond between D 2 and D 3, and a bond force between D 3 and D 4
  • the bond between Man 1 and D 2 is selected from the group of ⁇ 1, 2 bond, ⁇ 1, 3 bond and a 1, 6 bond force, and D 2 and D 2
  • the bond strength between 3 and 1 is selected from the group consisting of 1, 2 bond, ⁇ 1, 3 bond, ⁇ 1, 6 bond and
  • the bond between D 4, "1, 3 bond,” 1, 6 bond, and I, 4 bond strength is also selected from the group consisting, glycosylation ribosome of claim 100.
  • (Item 102) At least two sugar chains selected from the group consisting of the bond between Man 1 and D 2 , the bond between D 2 and D 3, and the bond strength between D 3 and D 4
  • the bond between Man 1 and D 2 is selected from the group of ⁇ 1, 2 bond, ⁇ 1, 3 bond and ⁇ 1, 6 bond force
  • D 2 bond between the 81, 4 is selected from the binding force becomes the group, the D 3 and D 4
  • the liposomal distal end of the sugar chain consists of Man-Man-Man-Man, Man-Man-Man-GlcNAc and Man-Man-GlcNAc-GlcNAc from the distal end side. 101.
  • the sugar chain-modified ribosome according to Item 100 having a structure selected from the group.
  • the ribosome distal end of the sugar chain is from the distal end side of Mana 1, 2Manal, 2Manal, 3Man, Mana 1, 2Mana 1, 3Mana 1, 6Man, Mana 1, 2Mana 1, 3Manj81, 4Glc NAc , Mana 1, 2Mana 1, 6Mana 1, 6Man, Mana 1, 3Mana 1, 6Manj81, 4GlcNAc, Mana 1, 3Manj81, 4GlcNAc ⁇ 1, 4GlcNAc, Mana 1, 6Man a 1, 6Manj81, 4GlcNAc and Man a 1, 6Manj81, 105.
  • the sugar chain-modified ribosome according to Item 104 which has a structure selected from the group consisting of 4GlcNAcj81 and 4GlcNAc.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Man 1 — D 2 — D 3 — D 4 — D 5 — R z , where D 2 is Man, the D 3 is Man, the D 4 is Man or GlcNAc, the D 5 is GlcNAc, and the R z is a force that is hydrogen, or any Item 2.
  • the sugar chain-modified ribosome according to Item 1, wherein (Item 107) The bond between Man 1 and D 2 , the bond between D 2 and D 3 , the bond between D 3 and D 4 and the connection between D 4 and D 5
  • At least one sugar chain bond selected from the group consisting of the binding forces between the Man 1 and D 2 is defined as ⁇ ⁇ , 2 bond, ⁇ ⁇ , 3 bond and ⁇ , selected from the group consisting of 6 bonds
  • the bond between D 2 and D 3 is selected from the group of ⁇ 1, 2 bond, ⁇ 1, 3 bond and ⁇ 1, 6 bond force
  • the bond between D 3 and D 4 is selected from the group consisting of ⁇ ⁇ , 3 bond, ⁇ 1, 6 bond and ⁇ 8 1, 4 bond force
  • the bond between D 4 and D 5 is ⁇ 109.
  • the sugar chain-modified ribosome according to Item 106 which is a 1,4 bond.
  • (Item 108) Bonds between Man 1 and D 2 , bonds between D 2 and D 3 , bonds between D 3 and D 4 and bonds between D 4 and D 5
  • At least two sugar chain bonds selected from the above are defined, wherein the bond between Man 1 and D 2 consists of ⁇ ⁇ , 2 bond, ⁇ ⁇ , 3 bond and ⁇ ⁇ , 6 bond Selected from the group, and the bond between D 2 and D 3 is selected from the group of ⁇ 1, 2 bond, ⁇ 1, 3 bond and ⁇ 1, 6 bond force, and D 3 and D 4 coupling force a 1, 3 bond between, it is selected from the group consisting of a 1, 6 bond and 1, 4 bond, a bond strength beta 1, 4 bond between the D 4 and D 5, item 106
  • Man 1 and D 2 bond, D 2 and D 3 bond, D 3 and D 4 bond, and D 4 and D 5 bond force At least three sugar chain bonds selected from the above are defined, and the bond between Man 1 and D 2 is ⁇ 1, 2 bond, ⁇ ⁇ , 3 bond and a 1, 6 bond force Selected from the group, and the bond between D 2 and D 3 is selected from the group consisting of al, 2 bond, ⁇ 1, 3 bond and a 1, 6 bond force, and between D 3 and D 4
  • the bond of is selected from the group consisting of a 1, 3 bond, a 1, 6 bond and 1, 4 bond force, and is a bond force ⁇ 1, 4 bond between D 4 and D 5
  • Ribosome distal end force of the sugar chain The sugar according to item 106, which has a structure of Man-Man-Man-Man-GlcNAc or Man-Man-Man-GlcNAc-GlcNAc from the distal end side. Strand-modified ribosome.
  • (Item 112) The ribosome distal end of the sugar chain, from the distal end side, Man 1, 2Mana 1, 2Mana 1, 3Man j81, 4GlcNAc, Mana 1, 2Mana 1, 3Man a 1, 6Man ⁇ 1, 4GlcNAc, Man a 1, 2Man a 1, 3Man ⁇ 1, 4GlcNAc ⁇ ⁇ , 4 GlcNAc, Mana 1, 2Mana 1, 6Mana 1, 6Manj81, 4GlcNAc, Mana 1, 6 Mana 1, 6Manj81, 4GlcNAcj81, 4GlcNAc and Man a 1, 3Mana Item 1.
  • the sugar chain-modified ribosome according to Item 111 having a structure selected from the group consisting of 1,6M anjS 1,4GlcNAc ⁇ 1,4GlcNAc.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: Man -D 2 — D 3 — D 4 — D 5 — D 6 — R Z , where The D 2 is Man, the D 3 is Man, the D 4 is Man, the D 5 is GlcNAc, the D 6 is GlcNAc, and the R z is The sugar chain-modified ribosome according to Item 1, which is hydrogen or any sugar.
  • the sugar chain-modified ribosome according to Item 113 wherein (Item 115) Bond between Man 1 and D 2 , Bond between D 2 and D 3 , Bond between D 3 and D 4 , Bond between D 4 and D 5 and D
  • At least two sugar chain bonds selected from the group consisting of binding forces between 5 and D 6 are defined, where the bonds between Man 1 and D 2 are ⁇ 1, 2 bonds.
  • the bond between D 2 and D 3 is selected from the group consisting of ⁇ 1, 2 bond, ⁇ 1, 3 bond and ⁇ 1, 6 bond, and the bond between D 3 and D 4 Binding force ⁇ , 3 bond or a 1, 6 bond, bond between D 4 and D 5 is ⁇ 1, 4 bond, bond between D 5 and D 6 is ⁇ 1, 114.
  • the sugar chain-modified ribosome according to Item 113 which is a 4-bond.
  • (Item 116) Bond between Man 1 and D 2 , Bond between D 2 and D 3 , Bond between D 3 and D 4 , Bond between D 4 and D 5 and D 5
  • at least three sugar chain bonds selected from the group consisting of the binding forces between D 6 and D 6 , where the binding forces between Man 1 and D 2 are «1, 2 bonds
  • the binding force between D 2 and D 3 is selected from the group consisting of 1, 2 bond, ⁇ 1, 3 bond and ⁇ 1, 6 bond force, and between D 3 and D 4
  • the bond is ⁇ ⁇ , 3 bond or a 1, 6 bond
  • the bond between D 4 and D 5 is 1, 4 bond
  • the bond between D 5 and D 6 is ⁇ 1 114.
  • a sugar chain-modified liposome according to Item 113 which is a 4-bond.
  • (Item 117) Bond between Man 1 and D 2 , Bond between D 2 and D 3 , Bond between D 3 and D 4 , Bond between D 4 and D 5 and D 5
  • at least four sugar chain bonds selected from the group consisting of the binding forces between D 6 and D 6 , wherein the bond between Man 1 and D 2 is an ⁇ 1,2 bond
  • the binding force between D 2 and D 3 is selected from the group consisting of ⁇ ⁇ , 2 bond, ⁇ 1, 3 bond and ⁇ 1, 6 bond force, and the bond force between D 3 and D 4 «1 , 3 bond or ⁇ 1, 6 bond, bond between D 4 and D 5 is / 3 1, 4 bond, bond between D 5 and D 6 is ⁇ 1, 4 bond 114.
  • the sugar chain bond of the bond between D 5 and D 6 is defined, where the bond between Man 1 and D 2 is ⁇ ⁇ , 2 bond, and D 2 and D 3 Is selected from the group consisting of a 1, 2, 1 bond, a 1, 3 bond, and an ⁇ ⁇ , 6 bond force, and the bond force between D 3 and D 4 «1, 3 bond Or a 1, 6 bond, bond between D 4 and D 5 is / 3 1, 4 bond, bond between D 5 and D 6 is ⁇ 1, 4 bond 114.
  • the sugar chain-modified ribosome according to item 113 (Item 119) The sugar chain-modified ribosome according to Item 113, wherein the ribosome distal end of the sugar chain has a structure of Man-Man-Man-Man-GlcN Ac-GlcNAc from the distal end side. (Item 120) Ribosome distal end force of the sugar chain From the distal end side Man al, 2Man al, 2Man al, 3Man j8 1, 4GlcNAc j8 1, 4GlcNAc, Man a 1, 2Man a 1, 3Man a 1, 6Man j8 1, 4GlcNAc j8 1, 401. .
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: NeuSAc 1 — E 2 — R z , where E 2 is Ga or GalNAc.
  • the sugar according to item 121 having a structure of Neu5Ac-Gal or Neu5Ac-GalNAc Strand-modified ribosome.
  • the sugar chain-modified ribosome according to item 123 wherein the ribosome distal end of the sugar chain has a structure of Neu5Aca2,3Gal or Neu5Aca2,6GalNAc from the distal end side.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: NeuSAc 1 — E 2 — E 3 — R z , where E 2 is Gal or GalNAc
  • E 3 is selected from the group consisting of GlcNAc, Glc, GalNAc and Ser, and R Z is hydrogen or an arbitrary sugar.
  • NeuSAc 1 and at least one carbohydrate binding avidity is also selected from the group consisting are defined between the coupling and E 2 and E 3 between E 2, wherein said NeuSAc 1 Bond between E 2 and E 2 is ⁇ 2,3 bond or a 2,6 bond, and the binding force between E 2 and E 3 is ⁇ 1,3 bond, ⁇ 1,4 bond and al— 126.
  • a sugar chain-modified ribosome according to Item 125 wherein the —O— bond is selected from the group consisting of: al—O— bond present when E 3 is Ser (Item 128) Ribosome distal end force of the sugar chain The distal end side is selected from the group consisting of Neu5Ac-Gal-GalNAc, Neu5Ac-Gal-GlcNAc ⁇ Neu5Ac-Gal-Glc and Neu5Ac-GalNAc-Ser 126.
  • a sugar chain-modified ribosome according to Item 125 which has a structure as described above.
  • Ribosome distal end force of the sugar chain From the distal end side Neu5Ac; 2, 3Gal j8 1, 3GalNAc, Neu5Ac a 2, 3Gal 1, 3GlcNAc, Neu5Ac a 2, 3Gal 1, 4Glc, Neu5Ac 129.
  • the ribosome distal end of the sugar chain has the following structure from the distal end side: NeuSAc 1 — E 2 — E 3 — E 4 — R z , where E 2 is , Gal, E 3 is selected from the group consisting of Glc and GalNAc, E 4 is selected from the group consisting of Gal and Cer forces, and R z is hydrogen or any Item 2.
  • the sugar chain-modified ribosome according to Item 1 which is a sugar.
  • Ne U5AC Bond between 1 and E 2 , bond between E 2 and E 3, and bond between E 3 and E 4 At least one sugar chain bond selected from the group is defined, wherein the bond between NeuSAc 1 and E 2 is an ⁇ 2,3 bond, and the bond between ⁇ 2 and ⁇ 3 131, wherein ⁇ is a ⁇ ⁇ , 3 bond or 1, 4 bond, and the binding force between ⁇ 3 and ⁇ 4 is selected from the group consisting of ⁇ 1, 4 bond or 1, 1 bond.
  • Sugar chain-modified ribosome is defined, wherein the bond between NeuSAc 1 and E 2 is an ⁇ 2,3 bond, and the bond between ⁇ 2 and ⁇ 3 131, wherein ⁇ is a ⁇ ⁇ , 3 bond or 1, 4 bond, and the binding force between ⁇ 3 and ⁇ 4 is selected from the group consisting of ⁇ 1, 4 bond or 1, 1 bond.
  • At least two sugar chain bonds selected from the group consisting of a bond between Neu5Ac 1 and ⁇ 2 , a bond between E 2 and E 3 and a bond force between E 3 and E 4 are defined, wherein the binding between the NeuSAc 1 and E 2, [alpha] 2, a 3 bond, the bond between the E 2 and E 3 are, beta I, 3 bond or I, 4 a bond, bonding force 1 between the E 3 and E 4, 4 bond or
  • the item wherein the ribosome distal end of the sugar chain has a structure selected from the group consisting of Neu5 Ac-Gal-GalNAc-Gal and Neu5 Ac-Gal-Glu-Cer from the distal end side 130.
  • the sugar chain-modified ribosome according to 130. (Item 135) Ribosome distal end force of the sugar chain Structure selected from the group consisting of Neu5Aco; 2, 3Galj81, 3Gal NAcjS 1, 4Gal and Neu5Ac ⁇ 2, 3Galj81, 4Gluj81, ICer from the distal end side 135.
  • the sugar chain-modified ribosome according to item 134 wherein (Item 136) Ribosome distal end force of the sugar chain From the distal end side, it has the following structure: NeuSAc 1 — E 2 — E 3 — E 4 — E 5 — R z , where E 2 Is Gal, the E 3 is GalNAc, the E 4 is Gal, the E 5 is Glc, and the R z is hydrogen or any sugar
  • the sugar chain-modified ribosome according to item 136 wherein the bond between 5 and / 3 1, 4 is (item 141) the ribosome distal end force of the sugar chain from the distal end side to Neu5Ac—Gal—GalN Ac —
  • the sugar chain-modified ribosome according to item 136 having a structure of Gal—Clc (Item 142) The ribosome distal end force of the sugar chain from the distal end side Neu5Ac; 2, 3Gal j8 1, 3G alNA 142.
  • the sugar chain-modified liposome according to item 141 which has a structure of C j 8 1, 4Gal
  • a ribosome distal end of the sugar chain is Structure: NeuSAc 1 — E 2 — E 3 — E 4 — E 5 — E 6 — R z , where E 2 is Gal, E 3 is GalNAc, and E 4
  • Modified liposomes (items M ⁇ NeuSAc 1 and E 2 , E 2 and E 3 , E 3 and E 4 , E 4 and E 5 , and E 5 and E 6
  • At least one sugar chain bond selected from the group is defined, where the binding force between the NeuSAc 1 and E 2 is «2, 3 bond, and the E 2 and E 3 bond
  • the bond between ⁇ 3 and ⁇ 4 is a ⁇ 1, 4 bond
  • the bond between ⁇ 4 and ⁇ 5 is 1, 4
  • the glycosylation ribosome of claim 143 bond is j8 1, 1 between E 6 and the E 5.
  • At least two sugar chain bonds selected from the group of binding force are defined, wherein the bond between NeuSAc 1 and E 2 is an ⁇ 2,3 bond, and ⁇ 2 and ⁇ 3 Is a ⁇ 1,3 bond, a bond between ⁇ 3 and ⁇ 4 is a ⁇ 1,4 bond, and a bond between ⁇ 4 and ⁇ 5 is 1, 4 a and, glycosylation ribosome of claim 143 bonds are 1, 1 between E 6 and the E 5.
  • At least three glycosylation is defined is selected from the binding force becomes the group between, wherein coupling between said NeuSAc 1 and E 2 is the "2, 3 bond, the E 2 Is the bond between ⁇ and E 3 , the bond between ⁇ 3 and ⁇ 4 is the / 3 1, 4 bond, and the bond between ⁇ 4 and ⁇ 5
  • beta 1, 4, and glycosylation ribosome of claim 143 bonds are beta 1, 1 between E 6 and the E 5.
  • the bond between Neu5Ac 1 and ⁇ 2 , the bond between E 2 and E 3 , the bond between E 3 and E 4 , the bond between E 4 and E 5 and E 5 and has at least four glycosylation is defined is selected Ri by the group consisting of binding force between the E 6, wherein coupling between said NeuSAc 1 and E 2 are, be alpha 2, 3 bond
  • the bond between ⁇ 2 and ⁇ 3 is a ⁇ ⁇ , 3 bond
  • the bond between ⁇ 3 and ⁇ 4 is a ⁇ 1, 4 bond
  • ⁇ 4 and ⁇ 5 144 is selected Ri by the group consisting of binding force between the E 6, wherein coupling between said NeuSAc 1 and E 2 are, be alpha 2, 3 bond
  • the bond between ⁇ 2 and ⁇ 3 is a ⁇ ⁇ , 3 bond
  • the bond between ⁇ 3 and ⁇ 4 is a ⁇ 1, 4 bond
  • ⁇ 4 and ⁇ 5 144 is selected Ri by the group consisting of binding force between the E 6, wherein coupling between
  • the ribosome distal end of the sugar chain has a structure of Neu5Ac a 2, 3Gal j8 1, 3GalNAc ⁇ 1, 4Gal j8 1, 4Clc ⁇ 1, ICer from the distal end side.
  • Ribosome proximal end force of the aforementioned sugar chain It has the following structure: R 1 — F 2 — GlcNAc 3 , where R 1 Is independently hydrogen or any sugar chain, and the F 2 is selected from the group consisting of Gal, Fuc, GlcNA c and 3, one (O—SO 2 H) Gal, The GlcNAc 3 is liposomal
  • the sugar chain-modified ribosome according to item 1 present at the most proximal end of the mouse.
  • the sugar chain-modified ribosome according to Item 151 which is selected.
  • the ribosome proximal end of the sugar chain is 3,-(O-SO H) Gal— GlcNAc, Fuc—
  • the sugar chain-modified ribosome according to Item 151 which has a structure selected from the group consisting of GlcNAc, Gal—GlcNAc and GlcNAc—GlcNAc.
  • the proximal end of the ribosome of the sugar chain is 3, 1 (O—SO 2 H) Galj81, 3GlcNAc ⁇ Fuc a 1, 3GlcNAc ⁇ Fuc a 1,
  • the sugar chain-modified ribosome of Item 153 having a structure selected from the group consisting of 4GlcNAc, GaljS1,3GlcNAc, GaljS1,4GlcNAc, GaljS1,6GlcNAc and GlcNAciS1,4GlcNAc.
  • the ribosome proximal end of the sugar chain has the following structure: R 1 — F 2 — F 3 — GlcNAc 4 , wherein R 1 is independently hydrogen, or Any sugar chain, wherein F 2 is selected from the group consisting of Man, Fuc and Neu5Ac, and F 3 is Gal or GlcNAc, wherein GlcNAc 4 is present at the proximal end of the ribosome, Item 2.
  • the sugar chain-modified ribosome according to item 1.
  • the bond between 3 and F 2 is selected from the group consisting of: 1, 2 bond, ⁇ ⁇ , 4 bond and ⁇ 2, 3 bond force, and the bond force between F 3 and GlcNAc 4 ⁇ ⁇ , 156.
  • the sugar chain-modified ribosome according to Item 155 which is a 3-bond or a 1,4-bond.
  • the liposomal proximal end of the sugar chain has a structure selected from the group consisting of Fuc-Gal-GlcNAc, Man-GlcNAc-GlcNAc and Neu5Ac-Gal-GlcNAc force.
  • the sugar chain-modified ribosome described.
  • Ribosome proximal end force of the sugar chain Fuc 1, 2 ⁇ 1, 4GlcNAc, ManjS 1, 4GlcNAc ⁇ 1, 4GlcNAc, Neu5Ac a 2, 3Galj81, 3Glc 164.
  • the sugar chain-modified ribosome according to Item 158 having a structure selected from the group consisting of NAc and Neu5Ac ⁇ 2,3Gal j81,4GlcNAc.
  • the ribosome proximal end of the sugar chain has the following structure: R 1 — F 2 — F 3 — F 4 — GlcNAc 5 , where F 1 is independently hydrogen Or any sugar chain, the F 2 is Man, the F 3 is Man, and the F 4 is GlcNAc, where the GlcNAc 5 is present at the proximal end of the ribosome
  • the sugar chain-modified ribosome according to Item 1.
  • At least one sugar chain bond selected from the group consisting of a bond between F 2 and F 3 , a bond between F 3 and F 4 and a bond force between F 4 and GlcNAc 5
  • the binding force between the F 2 and F 3 is ⁇ ⁇ , 3 bond or 1, 6 bond
  • the bond between the F 3 and F 4 is ⁇ 1, 4 bond
  • the bond between the F 4 and GlcNAc 5 is beta 1, 4 bonds
  • (Item 162) At least two sugar chain bonds selected from the group consisting of the bond between F 2 and F 3 , the bond between F 3 and F 4 and the bond force between F 4 and GlcNAc 5
  • the bond between the F 2 and F 3 is an ⁇ 1,3 bond or an ⁇ 1,6 bond
  • the bond between the F 3 and F 4 is ⁇ 1,4 binding a case
  • the bond between the F 4 and GlcNAc 5 is beta 1, 4 bonds, glycosylation ribosome of claim 160.
  • All the sugar chain bonds selected from the group consisting of the bond between F 2 and F 3 , the bond between F 3 and F 4 and the bond force between F 4 and GlcNAc 5 are specified.
  • the sugar chain-modified ribosome according to Item 160 wherein the bond between F 4 and GlcNAc 5 is a ⁇ 1,4 bond.
  • the ribosome proximal end force Man al, 3Man j8 1, 4 GlcNAc j8 1, 4GlcNAc or Man a 1, 6Man j8 1, 4GlcNAc j8 1, 4GlcNAc of the sugar chain has a structure of Item 164 Sugar chain-modified ribosome.
  • (Item 166) Liposome proximal end force of the sugar chain
  • the structure has the following structure: R 1 — F 2 — F 3 — F 4 — F 5 — GlcNAc 6 , wherein R 1 is independently Hydrogen or any sugar chain, the F 2 is Man, the F 3 is Man, the F 4 is Man, and the F 5 is GlcNAc, where 2.
  • At least one sugar chain bond selected from the group consisting of the binding forces between and F 2 and F 3 is defined as ⁇ 1, 2 bond, ⁇ 1, 3 bond Selected from the group consisting of 1, 6 bonds, and the binding force between F 3 and F 4 is ⁇ , 3 bond or a 1, 6 bond, and the bond between F 4 and F 5 166.
  • the sugar chain-modified ribosome according to Item 166 wherein is a ⁇ 1,4 bond, and the bond between F 5 and GlcNAc 6 is a ⁇ 1,4 bond.
  • Item 168 From the bond between F 2 and F 3 , the bond between F 3 and F 4 , the bond between F 4 and F 5 and the bond between F 5 and GlcNAc 6 Wherein at least two sugar chain bonds selected from the group are defined, wherein the bond between F 2 and F 3 is defined as al, 2 bond, ⁇ 1, 3 bond and a 1, 6 bond strength
  • the bond between F 3 and F 4 is selected from the group consisting of al, 3 bonds or a 1, 6 bond, and the bond between F 4 and F 5 is ⁇ 1, 4 bond , the bond between the F 5 and GlcNAc 6 is beta 1, 4 bonds, glycosylation ribosome of claim 166.
  • All of the glycan bonds selected from the group consisting of: the bond between F 3 and F 4 , the bond between F 4 and F 5 and the bond force between F 5 and GlcNAc 6
  • the bond between F 2 and F 3 is selected from the group consisting of al, 2 bond, ⁇ 1, 3 bond and a 1, 6 bond force
  • F 3 and F 4 A bond between the F 4 and F 5 is a ⁇ 1,4 bond
  • a bond between the F 5 and GlcNAc 6 is 166.
  • the sugar chain-modified ribosome according to Item 166 which is a ⁇ 1,4 bond.
  • the sugar chain-modified ribosome according to item 166 which has a structure of ribosome proximal end force Man-Man-Man-GlcNAc-GlcNAc of the sugar chain.
  • Sugar chain-modified ribosome according to item 171 having a structure selected from the group consisting of 1 ⁇ &110; 1, 6Mana 1, 6Manj81, 4GlcNAc ⁇ 1, 4GlcN Ac.
  • the ribosome proximal end of the sugar chain has the following structure: R 1 — F 2 — F 3 — F 4 — F 5 — F 6 — GlcNAc 7 , where R 1 is independent And F 2 is Man, F 3 is Man, F 4 is Man, and F 5 is Man. There, the F 6 is GlcNAc, wherein said GlcNAc 7 is present in the proximal-most end of the ribosome, glycosylation ribosome of claim 1.
  • the bond between F 3 and F 4 is selected from the group consisting of ⁇ 1, 2 bond, ⁇ 1, 3 bond and a 1, 6 bond, and the bond between F 4 and F 5 Binding force al, 3 bond or a 1, 6 bond, bond between F 5 and F 6 is ⁇ 1, 4 bond, bond between F 6 and GlcNAc 7 is ⁇ 1 ,
  • Item 1 The sugar chain-modified liposome according to Item 173, which has a structure of ribosome proximal end force Man-Man-Man-Man-GlcNAc-GlcNAc of the sugar chain.
  • the sugar chain-modified ribosome according to Item 178 which has a structure selected from the group consisting of 1 ⁇ 110; 1,2Mana 1,6Mana 1,6M anjS 1,4GlcNAc ⁇ 1,4GlcNAc.
  • Ribosome proximal end force of the sugar chain The following structure: R 1 —G 2 —Gal 3 wherein R 1 is independently hydrogen or any sugar chain
  • (Item 18 2) The sugar chain-modified ribosome according to Item 181, wherein the bond between G 2 and Gal 3 is ⁇ 1, 2 bond or ⁇ 1, 3 bond.
  • (Item 183) The sugar chain-modified ribosome according to item 181, wherein the sugar chain has a structure selected from the group consisting of Fuc-Gal, Ga 1-Gal and GalNAc-Gal.
  • (Item 184) The sugar chain modification according to item 183, wherein the ribosome proximal end of the sugar chain has a structure selected from the group consisting of Fuc a 1, 2Gal, Gala 1, 3Gal and GalNAc a 1, 3Gal Ribosome.
  • the ribosome proximal end of the sugar chain has the following structure: I ⁇ —H 2 —GalNAc 3 , wherein R 1 is independently hydrogen or any sugar 2.
  • (Item 186) H 2 and GalN 184.
  • the sugar chain-modified ribosome according to Item 184 which is a binding force between Ac 3 and ⁇ 3.
  • the sugar chain-modified ribosome according to Item 184 which has a structure of a ribosome proximal end force Gal—GalNAc of the sugar chain.
  • the sugar chain-modified ribosome according to item 187 which has a structure of ribosome proximal end force Gal ⁇ 1,3GalNAc of the sugar chain.
  • Ribosome proximal end force of the sugar chain having the following structure: R 1 —I 2 — Ser 3 , wherein the R 1 is independently hydrogen or any sugar chain , and the and said I 2 is GalNAc, where Ser 3 is present in the proximal-most end of the ribosome, glycosylation ribosome of claim 1.
  • the sugar chain-modified ribosome according to Item 189 which has a structure of a ribosome proximal end force GalNAc-Ser of the sugar chain.
  • the sugar chain-modified ribosome according to Item 191 having a structure of a liposomal proximal end force GalNAcal-OL-L-Ser of the sugar chain.
  • the ribosome proximal end of the sugar chain has the following structure: R 1 —I 2 —I 3 — Ser 4 , wherein R 1 is independently hydrogen, or The sugar chain-modified ribosome according to item 1, wherein the sugar chain is an arbitrary sugar chain, and the I 2 is Neu5Ac and the f is GalNAc, wherein Ser 4 is present at the most proximal end of the ribosome. 194.
  • At least one Tokusariyui case selected from the binding force becomes a group are defined between the coupling and I 3 and Ser 4 between I 2 and I 3, wherein said I 2 and a bond is a 2, 6 bond between I 3, coupling between the I 3 and Ser 4 are alpha 1-O-bonds, glycosylation ribosome of claim 193.
  • I 2 and all binding force of glycosylation also be selected from the group consisting are defined between the coupling and I 3 and Ser 4 between I 3, wherein said I 2 and I 194.
  • the sugar chain-modified ribosome according to item 193 which has the structure of ribosome proximal end force Neu5Ac-GalNAc-Ser of the sugar chain.
  • the sugar chain-modified ribosome according to item 196 wherein the ribosome proximal end of the sugar chain has a structure of Neu5Ac a 2,6GalNAc ⁇ 1-O-L-Ser.
  • the ribosome proximal end of the sugar chain has the following structure: R 1 —J 2 —Glc 3 , wherein R 1 is independently hydrogen or any sugar a chain and Xie 2 is Gal or Fuc, wherein Glc 3 is present in the proximal-most end of the ribosome, glycosylation ribosome of claim 1. Coupling between (item 199) and Glc 3 Is ⁇ , 3 bonds or
  • At least one sugar chain bond selected from the group consisting of the bond between J 2 ⁇ J 3 and the bond strength between J 3 and Glc 4 is defined, where 3 ⁇ 4J 3 The bond between ⁇ ⁇ , 2 bond, ⁇ 2, 3 bond and j81, 3 bond force, and the bond between Xie 3 and Glc 4 is ⁇ 1, 4 bond, item 202 The sugar chain-modified ribosome described in 1. (Item 204) All of the glycan bonds selected from the group consisting of the bond between J 2 ⁇ J 3 and the bond strength between J 3 and Glc 4 are defined.
  • a sugar chain-modified ribosome according to Item 202 (Item 205) The sugar chain-modified ribosome according to item 202, wherein the sugar chain has a structure selected from the group consisting of Fuc-Gal-G1c, GlcNAc Gal-Glc and Neu5Ac-Gal Glc.
  • Ribosome proximal end force of the sugar chain Fuc a 1, 2Galj81, 4Glc, GlcNAc ⁇ 1, 3Galj81, 4Glc and Neu5 Ac a 2, 3Gal
  • a sugar chain-modified ribosome according to Item 203. The ribosome proximal end of the sugar chain has the following structure: R 1 — J 2 — J 3 — J 4 — Glc 5 where R 1 is independently hydrogen.
  • Xie 2 is Fuc or Gal
  • Xie 3 is GlcNAc
  • Xie 4 is Gal
  • Glc 5 is at the proximal end of the ribosome 2.
  • the sugar chain-modified liposome according to item 1. At least one sugar chain bond selected from the group consisting of a bond between J 2 ⁇ J 3 , a bond between J 3 iJ 4 and a bond force between J 4 and Glc 5 Where the bond between m 2 ij 3 is a 3,4 bond or
  • the sugar chain-modified ribosome according to Item 207 which is a ⁇ 1,3 bond or a 13 1,4 bond, and the bond between Xie 4 and Glc 5 is a 13 1,4 bond.
  • Item 209 At least two sugar chain bonds selected from the group consisting of a bond between J 2 ⁇ J 3 , a bond between J 3 iJ 4 and a bond force between J 4 and Glc 5 Where the binding force between Xie 2 ⁇ J 3 is a 1,4 bond or ⁇ 1,3 bond and the bond between Xie 3 ⁇ J 4 is ⁇ 1,3 bond or 209.
  • the sugar chain-modified ribosome according to Item 207 which is a ⁇ 1,4 bond
  • the bond between Xie 4 and Glc 5 is a ⁇ 1,4 bond.
  • All of the glycan bonds selected from the group consisting of the bond between J 2 ⁇ J 3 , the bond between J 3 ⁇ J 4 and the bond strength between J 4 and Glc 5 Where the bond between Xie 2 ⁇ [ 3 is an a 1, 4 bond or
  • the sugar chain-modified ribosome according to Item 207 which is a bond or
  • the sugar chain-modified ribosome according to item 207 which has a structure of ribosome proximal end force Fuc-GlcNAc-Gal Glc or Gal-GlcNAc-Gal-Glc of the sugar chain.
  • the sugar chain modified ribosome (Item 213) The ribosome proximal end of the sugar chain has the following structure: ⁇ ----f -Glc 6 where R 1 is independently hydrogen or any Sugar chain, word 2 is Fuc, word 3 is Gal, word 4 is G1 cNAc or GalNAc, Xie 5 is Gal, where Glc 6 is the proximal end of the ribosome 2.
  • the sugar chain-modified ribosome according to item 1, which is present in item 1. (Item 21 4 ) From the group consisting of the bond between J 2 iJ 3 , the bond between J 3 ij 4 , the bond between J 4 ⁇ J 5 and the bond between J 5 and Glc 6 At least one selected sugar chain bond is defined, where the bond between Xie 2 ⁇ J 3 is an a 1, 2 bond and the bond between Xie 3 ⁇ J 4 is ⁇ Item 213, which is a 1,3 bond, a bond between Xie 4 ⁇ J 5 is a ⁇ 1,3 bond, and a bond between Xie 5 and Glc 6 is a ⁇ 1,4 bond.
  • Ribosome proximal end force of the sugar chain having the following structure: R 1 — K 2 — Man 3 wherein R 1 is independently hydrogen or any sugar 2.
  • the sugar chain-modified liposome according to Item 1 wherein the K 2 is a chain, and Man 3 is present at the most proximal end of the ribosome.
  • the sugar chain-modified ribosome according to Item 220 which has a structure of ribosome proximal end force Man-Man of the sugar chain.
  • the sugar chain-modified ribosome according to item 222 which has a structure selected from the group consisting of ribosome proximal end force Man «1, 2Man, Man al, 3Man and Man ⁇ 1, 4Man of the sugar chain .
  • the ribosome proximal end of the sugar chain has the following structure: R 1 — L 2 — Cer 3 , wherein R 1 is independently hydrogen or optional
  • the sugar chain-modified ribosome according to Item 224 wherein the bond between L 2 and Cer 3 is a j81,1 bond.
  • the sugar chain-modified ribosome according to Item 224 which has a structure of ribosome proximal end force Glc-Cer of the aforementioned sugar chain.
  • the ribosome proximal end of the sugar chain has the following structure: R 1 — L 2 — L 3 — Cer 4 , wherein R 1 is independently hydrogen, or 2.
  • At least one sugar chain bond selected from the group consisting of a bond between L 2 and L 3 and a binding force between L 3 and Cer 4 is defined, wherein the L 2 and the bond between L 3, a beta 1, 4 bond, the bond between the L 3 and Cer 4 are beta 1, 1 binding, glycosylation ribosome of claim 228.
  • Item 228 A sugar chain-modified ribosome.
  • the ribosome proximal end of the sugar chain has the following structure: R 1 — L 2 — L 3 — L 4 — Cer 5 where R 1 is independently hydrogen Or any sugar chain, and the L 2 is GalNAc or Neu5Ac, the L 3 is Gal, and the L 4 is Glc, where Cer 5 is the proximal end of the ribosome 2.
  • the sugar chain-modified ribosome according to item 1, which is present in item 1. At least one sugar chain bond selected from the group consisting of a bond between L 2 and L 3 , a bond between L 3 and L 4, and a bond between L 4 and Cer 5 Where the bond between L 2 and L 3 is an ⁇ 2,3 bond or ⁇ 1,4 bond, and the bond between L 3 and L 4 is ⁇ 1
  • (Item 235) At least two sugar chain bonds selected from the group consisting of a bond between L 2 and L 3 , a bond between L 3 and L 4, and a bond force between L 4 and Cer 5 Where the bond between L 2 and L 3 is a ⁇ 2, 3 bond or 1, 4 bond, and the bond between L 3 and L 4 is ⁇ 1, 4 209.
  • Ribosome proximal end force of the sugar chain selected from the group consisting of GalNAc j8 1, 4Gal j8 1, 4Gl C j 8 1, ICer and Neu5Ac ⁇ 2, 3Gal j8 1, 4Gl U j 8 1, ICer 209.
  • the sugar chain-modified ribosome according to Item 237 which has the structure of: (Item 239)
  • Liposome proximal end force of the sugar chain The following structure: R 1 — L 2 — L 3 — L 4 — L 5 — Cer 6 where R 1 is independent Or L 2 is Gal, L 3 is GalN Ac, L 4 is Gal, and L 5 is Glc.
  • the sugar chain-modified ribosome according to Item 239 wherein (Item 242) The bond between L 2 and L 3 , the bond between L 3 and L 4 , the bond between L 4 and L 5 and the bond force between L 5 and Cer 6 And at least three sugar chain bonds selected from the above, wherein the bond between L 2 and L 3 is a ⁇ 1,3 bond, and between L 3 and L 4 The bond is / 3 1, 4 bond, the bond between L 4 and L 5 is / 3 1, 4 bond, and the bond between L 5 and Cer 6 is / 3 1, 1 241.
  • the sugar chain-modified ribosome according to Item 239 which is a bond.
  • the bond between L 3 and L 4 is a j8 1,3 bond
  • the bond between L 4 and L 5 is a / 3 1,4 bond
  • the bond between L 5 and L 6 27 is a ⁇ 1, 1 bond.
  • (Item 261) Sugar chain strength selected from the group consisting of Manal, 2Man, Manal, 4Man and Mana 1, 3Man About 0.0075 mg sugar chain Zmg
  • (Item 264) Man a 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 3) Man ⁇ 1, 4 261.
  • GlcNAciS 1, 4 GlcNAc force Approx. 0.0275 mg
  • Sugar chain The sugar chain-modified ribosome according to Item 258, which is contained at a modified binding density of Zmg lipid.
  • (Item 269) Fu ca 1, 2Galj81, 4 (Fuca 1, 3) Glc, Neu5Ac a 2, 3Galj81, 4Glc, GaljS 1, 3 GalNAc, GaljS 1, 3GlcNA C j 81, 3Galj81, 4Glc, GaljS 1, 4 ( Fucal, 3) Glc, Fuc a 1, 2Gal, GalNAc a 1, 3 (Fuc a 1, 2) Gal, GalNAc al— O— L— Ser GaljS 1, 6GlcNAc ⁇ Galal, 3Gal, 3, one (O— SO H) Galj81, 3 (Fuc a 1, 4) G1
  • Sugar chain strength selected from the group consisting of cNAc, Neu5Ac a 2, 3Galj81, 4 (Fuc a 1, 3) GlcNAc and Neu5Ac a 2, 3G aljS 1, 3 (Fuc a 1, 4) GlcNAc About 0.5 mg sugar 259.
  • (Item 271) Sugar selected from the group consisting of Fuc al, 2Gal, GalNAc al, 3 (Fucal, 2) Gal, GaljS 1, 3GalNAc, GaljS 1, 4Glc and GaljS 1, 4 (Fuc a 1, 3) Glc
  • (Item 272) The sugar chain-modified ribosome according to any one of items 1 to 271, wherein the sugar chain-modified ribosome is bound to the membrane of the ribosome via the sugar chain handler.
  • the sugar chain-modified ribosome is made hydrophilic by binding a hydrophilic compound to at least one of the ribosome membrane or the linker.
  • the sugar chain-modified ribosome described. (Item 278) The sugar chain-modified ribosome according to any one of items 1 to 271, wherein the ribosome and the sugar chain are bound by a peptide bond. (Item 279) The above-mentioned linker milieu on the ribosome membrane and the linker are bound by a covalent bond, and the terminal force of the linker is bound by a peptide bond.
  • the sugar chain-modified ribosome according to 72. (Item 280) The sugar chain-modified ribosome according to Item 277, wherein the hydrophilic property is a tris (hydroxyalkyl) aminoalkane. (Item 281) Ribosome number 27, 29, 40, 45, 50, 53, 56, 67, 68, 69, 70, 71, 87, 105, 11 7, 120, 125, 139, 142, 150, 152, 153 154, 175, 184, 186, 197, 204, 2 24, 225, 230, 237, 240, 273, 285, 288, 290 or 301, a glycosylated ribosome having a structure of shear force.
  • (Item 282) A drug delivery vehicle for intravenous administration and oral administration, comprising the sugar chain-modified ribosome according to any one of items 1 to 281.
  • (Item 283) Any one of Items 1 to 281 A composition for intravenous administration and oral administration comprising the sugar chain-modified ribosome according to Item 1 and a substance desired to be administered.
  • the diagnostic agent is a DNA probe diagnostic agent, X-ray contrast agent, radioactive reagent, radioactive contrast agent, radioactive diagnostic agent, fluorescent reagent, fluorescent contrast agent, fluorescent diagnostic agent, CT contrast agent, PET contrast agent, SPECT contrast agent Agents, MRI contrast agents, AIDS diagnostic agents, hematology testing reagents, functional testing reagents, microbial testing reagents, molecular imaging, in vivo imaging, fluorescence imaging, luminescence imaging, cell sorter, PET and SPECT 284.
  • the functional food is a food containing vitamins, minerals, amino acids, and carbohydrates.
  • the drug is a biopharmaceutical or biotherapeutic substance (eg, siRNA, shRNA, siRNA derivative, shRNA derivative, RNA, RNA derivative, DNA, DNA derivative, monoclonal antibody, vaccine, interferon, hormone, prosta Glandin, transcription factor, recombinant protein, antibody drug, nucleic acid>
  • the composition for intravenous administration and oral administration is for delivering a biological factor into a tumor to a subject in need of the biological factor, and the substance is the living agent. 290.
  • Intravenous and oral drug delivery vehicles for treating mammals with respiratory, circulatory, digestive, urinary, genital, central or peripheral nervous system disorders The drug delivery vehicle for intravenous administration and oral administration comprises the sugar chain-modified ribosome according to Item 1 and a pharmaceutically acceptable carrier, and the sugar chain-modified ribosome is effective for treating the disorder.
  • a pharmaceutical composition for intravenous and oral administration comprising an amount of the drug.
  • composition for intravenous administration and oral administration is a medicament for treating disorders of the respiratory system, circulatory system, digestive system, urinary / genital system, central nervous system or peripheral nervous system. Including use of item 293.
  • a method for treating a subject having a disorder of the respiratory system, the circulatory system, the digestive system, the urinary organs, the genital system, the central nervous system, or the peripheral nervous system, the subject comprising Including a step of administering a pharmaceutical composition for intravenous administration and oral administration for treating a disorder, the pharmaceutical composition for intravenous administration and oral administration comprising a sugar chain-modified liposome and a pharmaceutically acceptable A method wherein the glycosylated ribosome contains an amount of an agent effective to treat the disorder.
  • a method wherein the glycosylated liposome contains an effective amount of the biological agent (Item 297)
  • a method for producing a sugar chain-modified liposome which comprises the following steps: (a) a step of providing a ribosome; (b) a step of hydrophilizing the ribosome if necessary (C) if necessary, a step of binding a linker to the lyosomally treated ribosome to form a linker-bound ribosome; and (d) binding a sugar chain to the ribosome to form a sugar. Producing a chain-modified ribosome.
  • step (Item 298) A method for producing a sugar chain-modified ribosome according to Item 297, wherein the ribosome of step (b) is treated with a hydrophilic treatment, directly or directly on the lipid membrane or linker of the ribosome.
  • the linker is used by indirectly binding a low molecular weight hydrophilic compound and used in step (c) is a human-derived protein, and in step (d), Sugar directly or indirectly A method comprising a step of binding a sugar chain to produce a sugar chain-modified ribosome under conditions for binding the chain.
  • (Item 299) A method for producing the sugar chain-modified ribosome according to item 297, wherein in the step (d), the sugar chain and the ribosome are bound under conditions suitable for oral administration.
  • (Item 300) A method for producing a sugar chain-modified ribosome according to item 297, wherein the sugar chain is the sugar chain described in any one of items 1 to 257.
  • a method for producing a sugar chain-modified ribosome for delivering a drug to a target delivery site comprising the following: (a) having various sugar chain densities to the target delivery site Providing a sugar chain-modified ribosome that achieves delivery; (b) determining, for the sugar chain density on the sugar chain-modified ribosome, a density that achieves optimal delivery to the delivery site; and (c) the A method comprising the step of incorporating a drug into the determined optimal sugar chain-modified ribosome to produce a drug-containing liposome.
  • Ribosome was improved by a previously reported method (Yamazaki, N., Kodama, M. and Gabius, H. —J. (1994) Methods Enzymol. 242, 56—65).
  • a modified cholate dialysis method In other words, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, gandarioside and dipalmitoyl phosphatidylethanolamine were mixed at a molar ratio of 35: 40: 5: 15: 5 to give a total lipid amount of 45.6 mg. Then add sodium cholate 46.9 mg Z was dissolved in 3 ml of methanol solution.
  • the solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane.
  • the obtained lipid membrane was suspended in 3 ml of TAPS buffer (pH 8.4) and sonicated to obtain a transparent micelle suspension.
  • the micelle suspension was mixed with PM10 membrane (Amicon Co., USA) and pH 7.2 phosphate buffer (Phosphate Buffred Saline (PBS): Na HPO (25. 55g) / KH PO (2.72g) / NaN (0.8g) /NaCl(35.4
  • Example 2 Hydrophilization treatment on ribosome lipid membrane surface
  • 10 ml of the ribosome solution prepared in Example 1 was used with XM300 membrane (Amicon Co., USA) and CBS buffer (pH 8.5). The solution was subjected to ultrafiltration to a pH of 8.5.
  • 10 ml of a crosslinking reagent bis (sulfosuccinimidyl) s liberate (BS 3; Pierce Co., USA) was added, and the mixture was stirred at 25 ° C. for 2 hours. Thereafter, the mixture was further stirred at 7 ° C to complete the chemical binding reaction between the lipid dipalmitoylphosphatidylethanolamine on the ribosome membrane and BS3.
  • this ribosome solution was subjected to ultrafiltration with XM300 membrane and CBS buffer (pH 8.5).
  • the chemical coupling reaction between BS 3 bound to lipid on the membrane and tris (hydroxymethyl) aminomethane was completed.
  • the hydroxyl group of tris (hydroxymethyl) aminomethane was coordinated on the lipid dipalmitoylphosphatidylethanolamine of the liposomal membrane to make it hydrated and hydrophilic.
  • ganlioside ⁇ ml of TAPs N-Tris (hydroxymethyl) metnyl- 3-ammopropanesulfoni c) present on the 10 ml ribosome membrane surface obtained in Example 2 was used.
  • acid) buffer solution pH 8.4 dissolved in sodium metaperiodate (43 mg), stirred at room temperature for 2 hours, and then periodate acidified, XM300 membrane and PBS buffer solution (pH 8.0) 10 ml of ribosome that was acidified was obtained by ultrafiltration.
  • HSA was bound by a coupling reaction between the HSA and HSA. After ultrafiltration with XM300 membrane and CBS buffer (pH 8.5), 10 ml of HSA-binding ribosome solution was obtained.
  • each sugar chain was measured and pretreated for use in Example 5 below. When using a combination of two or more sugar chains, each sugar chain was mixed.
  • Example 5 Binding of sugar chain to ribosome membrane surface-bound human serum albumin (HSA)
  • 50 g of each sugar chain prepared in Example 4 was dissolved in 0.25 g NH 4 HCO 0.5 ml water
  • filtration through a 0.45 m filter completes the amination reaction of the sugar chain's reducing end, and the glycosamine amine compound of each sugar chain. 50 g was obtained.
  • Table 5 shows the results of binding to ribosome membrane surface-bound human serum albumin (HSA) when each sugar chain is used. Unless otherwise specified, these sugar chains were bound to ribosome membrane surface bound human serum albumin by the same method and conditions as in Example 5.
  • compound (1) represents a darcosylamine compound of each sugar chain.
  • Example 6 Hydrophilic treatment on ribosome membrane-bound human serum albumin (HSA)
  • the prepared ribosomes to which sugar chains were bound were each subjected to hydrophilic treatment on the surface of the HSA protein on the liposome by the following procedure. Separately, 13 ml of tris (hydroxymethyl) aminomethane was separately added to 2 ml of sugar chain-bound ribosome, stirred at 25 ° C for 2 hours, and then at 7 ° C overnight, and then XM300 membrane and PBS buffer ( Unfiltered to remove the unreacted product by pH 7.2), 2 ml each of the glycosylated ribosome complex hydrophilized as the final product (total lipid amount 2 mg, total protein amount 200 ⁇ g, average Particle size lOOnm) was obtained.
  • Example 7 Measurement of lectin-binding activity inhibition effect by various sugar chain-bound ribosome complexes.
  • lectin-immobilized microplate according to a conventional method (Yamazaki, N. (1999) Drug Delivery System, 14, 498-505). That is, lectin (E-selectin; R & D Systems Co., USA) Fixed to a 96-well microplate.
  • fucosyl pheotuine which is a comparative ligand
  • various glycan-binding ribosome complexes with different concentrations (as protein mass, 0. Ol ⁇ g, 0.04). / ⁇ , 0.11, 0.33 g, 1 g) was added and incubated at 4 ° C for 2 hours. After washing 3 times with PBS (pH 7.2), horse radish peroxidase (HRPO) -conjugated streptavidin was added. The plate was further incubated at 4 ° C for 1 hour and washed 3 times with PBS (pH 7.2).
  • HRPO horse radish peroxidase
  • the peroxidase substrate was added and left at room temperature, and the absorbance at 405 nm was measured with a microplate reader (Molecular Devices Corp., USA).
  • Biotinylation of fucosylated pheutains was purified by Centricon 30 (Amicon Co., USA) after treatment with sulfo-NHS-biotin reagent (Pierce Co., USA).
  • HRPO-conjugated streptavidin is used to bind streptavidin by oxidation of HRPO and reductive amination using NaBHCN.
  • the difference between the values is expressed as a ratio.
  • Fig. 6 shows graph 1 of sample LY-1 and series IC50 created based on Tables 6 and 7.
  • Graph 1 is based on Table 6.
  • the X axis is a logarithmic memory. Each point on the line graph represents the average ratio of the measured values at each concentration (horizontal axis) of sample LY-1. Since the control value varies depending on the sample, the vertical axis of the graph is expressed as a ratio with the difference between hot and cold as 1, for easy comparison.
  • the X coordinate of the intersection of the Sample LY—1 graph and the series IC50 graph is the IC value. The intersection is at coordinate 1 (0.11, 562) and coordinate 2 (0.33,0)
  • Example 8. 1 ⁇ labeling of various sugar chain-bound ribosomes by the chloramine T method Chloramine T (Wako Pure Chemical Co., Japan) solution and sodium disulfite solution were prepared at the time of use to be 3 mgZml and 5 mgZml, respectively. Used. The sugar chain-bound ribosome and the tris (hydroxymethyl) aminomethane-bound ribosome prepared according to Example 6 were separately placed in an Eppendorf tube at a rate of 50 / zl, followed by 125 I—NaI (NEN Life Science Product, Inc. USA). ) And 15 ⁇ l of chloramine T solution were added and reacted. Chloramine solution 101 was added every 5 minutes, and this operation was repeated twice.
  • Example 9 Measurement of intestinal force blood translocation in mice of various sugar chain-linked ribosome complexes
  • 125 1 Labeled glycosylation and tris (hydroxymethyl) aminomethane-binding ribosome complex 0.2 g of protein is forced to enter the intestinal tract with an oral sonde for mice so that the amount of protein is 3 gZ-rat
  • lml blood was collected from the lower aorta under Nembutal anesthesia.
  • 125 1 radioactivity in blood was measured with a gamma counter (Alola ARC300).
  • Example 10 Examination of in vivo kinetics of sugar chain-modified ribosome
  • Experiments were performed on normal mice and tumor-bearing mice. The procedure is as follows. Various sugar chain modifications Measurement of the distribution of posomes and ribosomes without glycosylation in each tissue was performed using normal mice and Ehrlich ascites tumor (EAT) cells (approximately 2 X 10 7 cells) in male ddY mice (7 weeks old). Transplanted subcutaneously in the thigh, and cancer tissue grown to 0.3 to 0.6 g (6 to 8 days later) was used in this experiment.
  • EAT Ehrlich ascites tumor
  • mice were orally administered at 0.2 ml of various ribosomes labeled with 125 1 according to Example 8 as a protein amount—or injected into the tail vein, and the tissue was collected 10 minutes or 5 minutes later.
  • tissue was collected 10 minutes or 5 minutes later.
  • a gamma counter Aloka ARC 300. The amount of radioactivity distributed to each tissue was measured by the ratio of radioactivity per lg of each tissue to the total radioactivity administered (% dose Zg tissue).
  • the sugar chain-modified ribosome and the ribosome bound with tris (hydroxymethyl) aminomethane instead of the sugar chain as a reference liposome were intravenously administered 5 minutes later, and the sugar chain-modified ribosome delivered to the blood or each tissue
  • the magnification of the 4 measured averages and the 4 measured averages on the reference ribosome was calculated. Based on this calculation result, the transferability to blood after oral administration and the target directivity to each organ were evaluated using a ribosome combined with tris (hydroxymethyl) aminomethane as a reference ribosome. The results are shown in the following table.
  • the medium that has been transferred into the blood by oral administration shows the same tendency as intravenous injection.
  • Tables 10 and 12 show the evaluation results showing the accumulation effect of various types of radioactive sugar chain-modified ribosomes on each tissue in mice after oral administration and intravenous administration. It is fruit. These results show that this sugar chain-modified ribosome utilizes the function of the sugar chain as a ligand to efficiently accumulate and deliver drugs, fluorescent substances, radiolabeled substances, etc. to diseased areas and various organs by active targeting. It shows that. Therefore, since the sugar chain-modified ribosome of the present invention can visualize the accumulation in target tissues such as tumors, it can be used not only as a therapeutic drug delivery vehicle but also as a research reagent or diagnostic drug. Also provide.
  • Ribosome is a previously reported technique
  • dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, gandarioside and dipalmitoyl phosphatidylethanolamine were mixed in a molar ratio of 35: 40: 5: 15: 5 to give a total lipid content of 45.6 mg, 46.9 mg of sodium cholate was added and dissolved in 3 ml of Kuroguchi Form Z methanol solution. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane.
  • the obtained lipid membrane was suspended in 10 ml of TAPS buffered physiological saline (pH 8.4) and sonicated to obtain 10 ml of a transparent micelle suspension.
  • TAPS buffered physiological saline pH 8.4
  • the anticancer drug doxorubicin completely dissolved in TAPS buffer (pH 8.4) to 3 mg / lml was slowly added dropwise with stirring, and then mixed uniformly, and then this micelle suspension containing doxorubicin was added.
  • Uniform anticancer drug doxorubicin-encapsulated liposome particle suspension 1 Oml was prepared by ultrafiltration using PM10 membrane (Amicon Co., USA) and TAPS buffered saline (pH 8.4).
  • the particle size and zeta potential of the anticancer drug doxorubicin-encapsulated ribosome particles in the obtained physiological saline suspension (37 ° C) were determined by measuring the zeta potential ⁇ particle size ⁇ molecular weight measuring device (Model Nano ZS, Malvernlnstruments Ltd,, (UK), the particle size was 50 to 350 nm, and the zeta potential was 30 to 10 mV.
  • Example 12 Hydrophilization treatment on anticancer drug doxorubicin-encapsulated ribosome lipid membrane surface
  • 1 ml of anticancer drug doxorubicin-encapsulated ribosome solution prepared in Example 11 was added to XM300 membrane (A micon Co., USA) and CBS buffer The solution was subjected to ultrafiltration using a liquid ( ⁇ 58.5) to make the solution ⁇ 8.5.
  • the crosslinking reagent bis (sulfosuccinimidyl) suberate (BS3; Pierce (Co., USA) 10 ml was added and stirred at 25 ° C. for 2 hours.
  • the hydroxyl group of tris (hydroxymethyl) aminomethane was coordinated on the lipid dipalmitoyl phosphatidylethanolamine of the liposomal membrane encapsulating the anticancer drug doxorubicin to make it hydrated and hydrophilic.
  • Example 15 Anticancer drug doxorubicin-encapsulated ribosome membrane surface bound human serum albumin (HSA) binding to sugar chain and linker protein (HSA) hydrophilization
  • HSA human serum albumin
  • HSA linker protein
  • Example 13 Add 1 mg of cross-linking reagent 3, 3, -dithiobis (sulfosucci-midylpropionate) (DTSSP; Pierce Co., USA) to 1 ml of a part of ribosome solution encapsulated with anticancer drug doxorubicin obtained in 2 hours at 25 ° C, Subsequently, the mixture was stirred at 7 ° C and ultrafiltered with XM300 membrane and CBS buffer (pH 8.5) to obtain 1 ml of ribosome with DTSSP bound to HSA on ribosome.
  • DTSSP cross-linking reagent 3
  • XM300 membrane and CBS buffer pH 8.5
  • a ribosome was obtained that was treated with a hydrophilic protein of linker protein (HSA) in which tris (hydroxymethyl) aminomethane, human serum albumin and ribosome were bound.
  • HSA hydrophilic protein of linker protein
  • 2 ml of anticancer drug doxorubicin encapsulated ribosome treated with a hydrophilic protein of linker protein (HSA) in which each sugar chain, human serum albumin and liposome were bound total lipid amount 2 mg, total protein amount 200 ⁇ g
  • the particle size and zeta potential of the anticancer drug doxorubicin-encapsulated ribosome particles in the obtained physiological saline suspension (37 ° C) were measured using the zeta potential ⁇ particle size ⁇ molecular weight measuring device (Model Nano ZS, Malvern Instruments Ltd, , UK), the particle size was 50 to 350 nm, and the zeta potential was 30 to 10 mV.
  • Glycolipid ribosomes (starting with FEE, EE, eg, ribosome number 3, ribosome number 37, ribosome number 67, ribosome number 218, etc.) are as follows: Prepared.
  • Ribosomes were prepared using the cholate dialysis method. That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, gandarioside (containing 100% GM1 as a glycolipid sugar chain) and dipalmitoyl phosphatidylethanolamine in a molar ratio of 35: 40: 5: 15 : Mixed to a total lipid content of 45.6 mg at a ratio of 5, 46.9 mg of sodium cholate was added, and 3 ml of black mouth form Z methanol solution was dissolved. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane.
  • the obtained lipid membrane was suspended in 3 ml of TAPS buffer (pH 8.4) and sonicated to obtain 3 ml of a clear micelle suspension.
  • 10 ml of a ribosome particle suspension was prepared without subjecting it to ultrafiltration and carrying out a uniform hydrophilic treatment.
  • Example 16 Hydrophilic treatment on ribosome membrane surface-bound human serum albumin (HSA)
  • HSA human serum albumin
  • Example 17 Measurement of lectin binding activity inhibition effect by various sugar chain-binding ribosome complexes
  • Example 17 In vitro lectin binding activity of each sugar chain-binding ribosome complex prepared by the means of Example 16 According to the method (Yamazaki, N. (1999) Drug Delivery System, 14, 498-505), it was measured in an inhibition experiment using a lectin-fixed microplate. That is, lectin (E-selectin; R & D Systems Co., USA) was immobilized on a 96-well microphone opening plate.
  • chloramine 125 iota labeling of various sugar chain binding ribosomes by T method chloramine ⁇ (Wako Pure Chemical Co., Japan ) solution and a sodium disulfite solution, respectively it 3mgZml and 5mgZml prepared Used.
  • the sugar chain-linked ribosome and tris (hydroxymethyl) aminomethane-linked liposome prepared according to Example 16 were separately placed in an Eppendorf tube, followed by 125 1-NaI (NEN Life Science Product, Inc. USA). 15 ⁇ 1, 10 ⁇ l of chloramine T solution was reacted. Add Chloramine ⁇ ⁇ solution 10 1 every 5 minutes and repeat this procedure twice.
  • Example 19 Measurement of the amount of intestinal force blood translocation in mice of various sugar chain-binding ribosome complexes
  • Example 19 Measurement of the amount of intestinal force blood translocation in mice of various sugar chain-binding ribosome complexes
  • 12 5 1 Labeled sugar chain bond and tris (hydroxymethyl) aminomethane-linked ribosome complex 0.2 mg of protein was forced into the intestine with an oral sonde so that the amount of protein was 3 gZ—in the ratio of 3 animals.
  • blood lm 1 was collected from the lower aorta under Nembutal anesthesia. Then, 125 1 radioactivity in blood was measured with a gamma counter (Alola ARC300).
  • the power of rechromatography of blood serum with Sephadex G-50 was found in most high-molecular-weight void fractions.
  • the ribosome complex was also stable in vivo.
  • the amount of radioactivity transferred into the blood of the intestinal tract was also expressed as the ratio of radioactivity per ml of blood to the total radioactivity administered (% dose of Zml blood).
  • % dose of Zml blood Depending on the type of sugar chain used, there were those that migrated from the intestinal tract into the blood and those that did not migrate. The results are shown in the table below.
  • Example 20 Treatment effect in mice with tumors by intravenous injection of various sugar chain-linked ribosome complexes (1) Treatment effects of intravenous tail administration in tumor-bearing mice Fibrosarcoma, myoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, hemangiosarcoma, lymphangiosarcoma, periosteum, mesothelioma, smooth Myoma, rhabdomyosarcoma, stomach cancer, esophageal cancer, rectal cancer, spleen cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, brain cancer, squamous cell carcinoma, sebaceous carcinoma , Papillary carcinoma, cystadenocarcinoma, medullary carcinoma, primary bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma,
  • mice are divided into two groups: a sugar chain-modified ribosome administration group encapsulating a drug that can be used to treat the target disease, and a physiological saline administration group as a control.
  • sugar chain-modified ribosomes encapsulating drugs or physiological saline are administered 4 times a week for 2 weeks by tail vein administration. Observe the disease site twice a week for 4 weeks.
  • the drug-encapsulated sugar chain-modified ribosome-administered group showed a good treatment effect from the start of administration despite the extremely small dose.
  • the drug-encapsulated sugar chain-modified ribosome-administered group showed a good treatment effect from the start of administration despite the extremely small dose.
  • Observation with a fluorescence microscope is performed as follows.
  • the skin at the cancer site of a mouse with a tumor is excised, and the tumor site is exposed and fixed to a glass slide. Place the mouse on the stage of the fluorescence microscope, search for blood vessels around the tumor site, and determine the position where the blood vessel image can be clearly observed.
  • the same drug-encapsulated sugar chain-modified ribosome as in (1) above is administered into the 0.2 ml tail vein. Drug accumulation at the diseased site immediately after administration is observed with a fluorescence microscope.
  • 0.2 mL of the modified sugar chain solution (60 mM) is administered 5 minutes before administration of the drug-encapsulated sugar chain-modified ribosome, and observation is performed in the same manner as described above.
  • the fluorescence of the drug in the blood vessels around the disease site Force S observed.
  • Drug fluorescence is observed in the blood vessel wall 5 minutes after administration.
  • drug transfer to the diseased site is observed over time, and after 2 hours, fluorescence of the drug is seen inside the tissue surrounding the blood vessel of the diseased site.
  • Example 21 Treatment effect in mice with tumors by oral administration of various sugar chain-linked ribosome complexes
  • Fibrosarcoma muscle sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, lymphangiosarcoma, periosteum, mesothelioma, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, rectal cancer , Spleen cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, brain cancer, squamous cell carcinoma, sebaceous carcinoma, papillary carcinoma, cystadenocarcinoma, medullary cancer, bronchial progenitor Cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, cervical cancer, testicular cancer, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelium Cell carcinoma,
  • mice are divided into two groups: a sugar chain-modified ribosome administration group encapsulating a drug that can be used to treat the target disease, and a physiological saline administration group as a control. These mice are orally administered sugar-modified ribosome encapsulating the drug or physiological saline 4 times a week for 2 weeks. Observe the disease site twice a week for 4 weeks. As a result of comparing changes in disease sites in the drug-encapsulated sugar chain-modified ribosome-administered group and the physiological saline-administered group, the drug-encapsulated sugar chain-modified ribosome-administered group showed good treatment from the start of administration despite the extremely small dose.
  • Drug-encapsulated sugar chain-modified ribosomes have a significant therapeutic effect by oral administration.
  • (2) Observation of drug transfer to the tumor site by oral administration using a fluorescence microscope Observation using a fluorescence microscope is performed as follows. The skin at the cancer site of a mouse with a tumor is excised, and the tumor site is exposed and fixed to a glass slide. Place the mouse on the stage of the fluorescence microscope, search for blood vessels around the tumor site, and determine the position where the blood vessel image can be clearly observed. Orally administer 0.2 ml of the same drug-encapsulated sugar chain-modified ribosome as in (1) above.
  • Drug accumulation at the site of disease immediately after administration is observed with a fluorescence microscope.
  • 0.2 mL of the modified sugar chain solution 60 mM
  • fluorescence of the drug is observed in the blood vessels around the disease site.
  • Drug fluorescence is observed in the blood vessel wall 5 minutes after administration.
  • drug transfer to the diseased site is observed over time, and after 2 hours, fluorescence of the drug is seen inside the tissue around the blood vessel at the diseased site.
  • the target directivity of the sugar chain-modified ribosome is controlled by the type of sugar chain. Furthermore, considering the binding density of sugar chains, more appropriate tumor-directed sugar chain-modified ribosomes can be selected. This targeting is not altered whether or not the glycosylated ribosome contains or does contain a drug.
  • Ribosomes were prepared using the cholate dialysis method.
  • dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, gandarioside and dipalmitoyl phosphatidylethanolamine were mixed in a molar ratio of 35: 40: 5: 15: 5 to give a total lipid amount of 45.6 mg. 46.9 mg of sodium cholate was added and dissolved in 3 ml of chloroform Z methanol solution. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane.
  • the obtained lipid membrane was suspended in 3 ml of TAPS buffered physiological saline (pH 8.4) and sonicated to obtain 10 ml of a transparent micelle suspension.
  • This micelle suspension Vitamin A completely dissolved in TAPS buffer (pH 8.4) to 3 mg / lml is slowly added dropwise with stirring and mixed uniformly, and this micelle suspension containing vitamin A is added to a PM 10 membrane ( AmiconCo., USA) and ultrafiltration using TAPS buffered saline (pH 8.4) to prepare 10 ml of a uniform suspension of ribosome particles encapsulating vitamin A.
  • Ribosomes were prepared according to a previously reported method (Yamazaki, N., Kodama, M. and Gabius, H. —J. (1994) Methods Enzymol. 242, 56-65) using an improved cholate dialysis method. That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, and dipalmitoyl phosphatidylethanolamine were mixed so that the total lipid amount was 45.6 mg, and sodium cholate 46.9 mg was added to the mixture, followed by Kuroguchi Form Z methanol. Dissolve in 3 ml of solution. The solution is evaporated and the precipitate is dried in vacuo to obtain a lipid membrane.
  • the obtained lipid membrane is suspended in 3 ml of TAPS buffer (pH 8.4) and sonicated to obtain a transparent micelle suspension. Furthermore, the micelle suspension is subjected to ultrafiltration using a PM 10 membrane (A micon Co., USA) and PBS buffer (pH 7.2) to prepare 10 ml of a uniform liposome (average particle size lOOnm).
  • 10 ml of the ribosome solution prepared in 1 above is subjected to ultrafiltration using XM300 membrane (Amicon Co., USA) and CBS buffer (pH 8.5) to adjust the pH of the solution to 8.5.
  • XM300 membrane Amicon Co., USA
  • CBS buffer pH 8.5
  • 10 ml of the crosslinking reagent bis (sulfosuccinimidyl) suberate BS3; Pierce Co., USA
  • Example 24 Measurement of anticancer effect in tumor-bearing mice by intravenous injection of various sugar chain-binding ribosome complexes
  • the tumor-bearing mice were prepared by shaving the back hair of a ddY 7-week-old mouse (male, body weight 35-40 g) with an electric hair clipper and transplanting Ehrlich Ascites Tumor (approximately 5xl0 6 cells / mouse) subcutaneously. They were kept for about 10 days and observed, and those with cancer cells engrafted were selected and used for the experiment.
  • the doxorubicin-encapsulated ribosome number 155 prepared in 0.0625 mgZkg encapsulated as the drug to be administered, and the physiological saline group as a control were administered to the tumor-bearing mice via the tail vein.
  • Cancer volume (mm 3 ) (major axis + minor axis 2 ) Z2
  • Fig. 2 is a diagram showing the anticancer effect in tumor-bearing mice after intravenous administration of doxorubicin-encapsulated ribosome # 155 to the tail.
  • Fig. 3 is a fluorescence micrograph showing the accumulation effect of doxorubicin on tumor tissue and cells in tumor-bearing mice after intravenous injection of doxorubicin-encapsulated ribosome # 155.
  • the left and right images are green and red fluorescence micrographs of the same tumor tissue 'cell, respectively. Green (left image) shows blood vessels and tissues.
  • the red fluorescence (right image) shows the fluorescence of doxorubicin, a fluorescent substance, in tumor tissues and cancer cells.
  • the sugar chain-modified ribosome of the present invention can visualize accumulation in a target tissue such as a tumor, it also provides a delivery medium for use as a research drug or a diagnostic agent as well as a therapeutic drug delivery medium. To do.
  • Example 25 Measurement of anticancer effect in cancer-bearing mice by oral administration of various sugar chain-binding ribosome complexes
  • the tumor-bearing mice were prepared by shaving the back hair of a ddY 7-week-old mouse (male, body weight 35-40 g) with an electric hair clipper and transplanting Ehrlich Ascites Tumor (approximately 5xl0 6 cells / mouse) subcutaneously. They were kept for about 10 days and observed, and those with cancer cells engrafted were selected and used for the experiment.
  • the doxorubicin-encapsulated ribosome number 237 administration group prepared at 0.375 mgZkg encapsulated as the drug to be administered and the physiological saline administration group as a control were administered orally to tumor-bearing mice.
  • Cancer volume (mm 3 ) (major axis + minor axis 2 ) Z2
  • FIG. Comparison of changes in tumor growth volume between the doxorubicin-encapsulated ribosome No. 237 administration group and the physiological saline as a control group was extremely small. The growth-suppressing effect was remarkable, and the ability to start administration was suppressed.
  • Fig. 4 is a graph showing the anticancer effect in tumor-bearing mice after oral administration of doxorubicin-encapsulated ribosome number 237.
  • FIG. 5 is a fluorescence micrograph showing the effect of doxorubicin accumulation from tumor blood vessels to tumor tissues and cells in tumor-bearing mice after oral administration of doxorubicin-encapsulated ribosome No. 237.
  • the left and right images are fluorescent micrographs of the same tumor tissue and cells, respectively, in green and red.
  • Green (left image) shows the natural fluorescence of blood vessels, tissues and cells, and red (right image).
  • the sugar chain-modified ribosome of the present invention can visualize accumulation in target tissues such as tumors, it also provides a delivery medium for use as a therapeutic drug delivery medium as well as a research reagent or a diagnostic drug. To do. [0237] As described above, the power that has exemplified the present invention using the preferred embodiment of the present invention. The present invention should not be construed as being limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range based on the description of the present invention and the common general technical knowledge from the description of specific preferred embodiments of the present invention. Patents, patent applications and literature references cited in this specification should be incorporated by reference as if the contents themselves were specifically described in the present specification. Is understood.
  • the present invention has utility that a drug can be delivered to a target delivery site by oral administration or intravenous administration. Therefore, the present invention provides a drug delivery composition in which a drug or gene is encapsulated in a sugar chain-modified ribosome and utility related thereto.

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  • Medicinal Preparation (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

It is intended to provide a sugar-modified liposome which is useful for the internal delivery such as oral administration and a composition for drug delivery in which an agent or a gene is enclosed in the sugar-modified liposome. The sugar-modified liposome of the invention preferably has a sugar chain which has at least one specific sequence bound via a linker such as human serum albumin and can be used as a material constituting the composition for drug delivery by carrying the agent.

Description

明 細 書  Specification

糖鎖修飾リボソーム及び該リボソームを含有する薬剤送達組成物 技術分野  Sugar chain-modified ribosome and drug delivery composition containing the ribosome

[0001] 本発明は、医薬品、化粧品をはじめ医学'薬学分野において応用し得る、癌などの 標的細胞 ·組織を認識し局所的に薬剤や遺伝子を患部に送り込むための治療用の ドラッグデリバリーシステムや診断用の細胞'組織センシングプローブとして利用でき るものであって、特に腸管吸収性に優れた糖鎖修飾リボソーム、およびこれに体内に 送達される物質を封入した薬剤送達組成物に関する。  [0001] The present invention relates to a drug delivery system for treatment for recognizing a target cell / tissue such as cancer and locally delivering a drug or gene to an affected area, which can be applied in the medical and pharmaceutical fields including pharmaceuticals and cosmetics. The present invention relates to a sugar chain-modified ribosome excellent in intestinal absorbability and a drug delivery composition encapsulating a substance to be delivered into the body, which can be used as a diagnostic cell 'tissue sensing probe.

背景技術  Background art

[0002] 米国の国家ナノテク戦略 (NNI)によって実現を目指す具体的目標の一例として、「 癌細胞や標的組織を狙 ヽ撃ちする薬物や遺伝子送達システム (DDS：ドラッグデリ バリーシステム)」を掲げた。 日本の総合科学技術会議のナノテクノロジー ·材料分野 推進戦略でも、重点領域として「医療用極小システム '材料、生物のメカニズムを活用 し制御するナノバイオロジー」があり、その 5年間の研究開発目標の 1つとして「健康 寿命延伸のための生体機能材料 ·ピンポイント治療等技術の基本シーズ確立」が掲 げられている。一方、高齢ィ匕社会となるに伴い癌の発症率 ·死亡率は年々増えており 、新規な治療材料である標的指向 DDSの開発が待望されている。その他の病気に おいても副作用のない標的指向 DDSナノ材料の重要性が注目されており、その巿 場規模は近い将来に 10兆円を超えると予測されている。また、これらの材料は治療と ともに診断への利用にお 、ても期待されて 、る。  [0002] As an example of a specific goal to be realized by the US National Nanotechnology Strategy (NNI), “Drug and gene delivery system (DDS: drug delivery system) targeting and targeting cancer cells and target tissues” . The nanotechnology / materials promotion strategy of the Council for Science and Technology in Japan also includes “Nanobiology that uses and controls the mechanisms of materials and organisms” as an important area, and is one of the five years of research and development goals. One example is “Establishment of basic seeds for biofunctional materials and pinpoint treatment technologies for extending health and life expectancy”. On the other hand, the incidence and mortality of cancer has been increasing year by year as it becomes an aging society, and the development of target-oriented DDS, which is a novel therapeutic material, is awaited. The importance of targeted DDS nanomaterials with no side effects in other diseases is drawing attention, and the scale of the field is expected to exceed 10 trillion yen in the near future. These materials are also expected to be used for diagnosis as well as treatment.

[0003] 医薬品の治療効果は、薬物が特定の標的部位に到達し、そこで作用することにより 発現される。その一方で、医薬品による副作用とは、薬物が不必要な部位に作用し てしまうことである。従って、薬物を有効かつ安全に使用するためにもドラッグデリバリ 一システムの開発が求められている。その中でも特に標的指向（ターゲティング) DD Sとは、薬物を「体内の必要な部位に」、「必要な量を」、「必要な時間だけ」送り込むと V、つた概念である。そのための代表的な材料としての微粒子性キャリアであるリポソ ームが注目されている。この粒子に標的指向機能をもたせるために、リボソームの脂 質の種類、組成比、粒子径、表面電荷を変化させるなどの受動的ターゲティング法 が試みられているが、いまだ本法は不十分であり更なる改良が求められている。 [0003] The therapeutic effect of a drug is expressed by the drug reaching a specific target site and acting there. On the other hand, the side effect of drugs is that the drug acts on unnecessary parts. Therefore, the development of a drug delivery system is required for effective and safe use of drugs. In particular, targeting DD (targeting) DD S is the concept of V when drug is delivered "to the necessary site in the body", "necessary amount", "only for the required time". Liposome, which is a fine particle carrier as a representative material for that purpose, has attracted attention. In order to give this particle a targeting function, Passive targeting methods such as changing the quality type, composition ratio, particle size, and surface charge have been tried, but this method is still insufficient and further improvement is required.

[0004] 一方、高機能のターゲティングを可能にするために、能動的ターゲティング法も試み られて 、る。これは「ミサイルドラッグ」ともよばれ理想的なターゲティング法であるが、 国内外にお 、て 、まだ完成されたものはなく今後の発展が大 ヽに期待されて 、るも のである。本法は、リボソーム膜面上にリガンドを結合させ、標的組織の細胞膜面上 に存在するレセプターに特異的に認識させることによって、積極的にターゲティング を可能にさせる方法である。この能動的ターゲティング法での標的となる細胞膜面上 に存在するレセプターのリガンドとしては、抗原、抗体、ペプチド、糖脂質や糖蛋白質 などが考えられる。これらのうち、糖脂質や糖蛋白質の糖鎖は、生体組織の発生や 形態形成、細胞の増殖や分化、生体防御や受精機構、癌化とその転移機構などの 様々な細胞間コミュニケーションにお 、て情報分子としての重要な役割を果たして!/ヽ ることが明らかにされつつある。  [0004] On the other hand, in order to enable highly functional targeting, an active targeting method is also attempted. This is an ideal targeting method, also called “missile drug”, but it has not been completed in Japan and overseas, and future development is greatly expected. In this method, a ligand is bound on the ribosome membrane surface, and it is allowed to actively target by allowing the receptor present on the cell membrane surface of the target tissue to specifically recognize. Receptor ligands present on the cell membrane surface targeted by this active targeting method may include antigens, antibodies, peptides, glycolipids and glycoproteins. Among these, glycolipids and glycoprotein sugar chains are involved in various cell-to-cell communications such as the generation and morphogenesis of biological tissues, cell proliferation and differentiation, biological defense and fertilization mechanisms, canceration and metastasis mechanisms. It is becoming clear that it plays an important role as an information molecule!

[0005] また、その標的となる各組織の細胞膜面上に存在するレセプターとしてのセレクチン 、シグレック、ガレクチンなどの各種のレクチン (糖鎖認識蛋白質）についての研究も 進んできたことから、各種の分子構造を有する糖鎖は新しい DDSリガンドとして注目 されてきて 、る (非特許文献 1および非特許文献 2を参照のこと)。  [0005] In addition, research on various lectins (sugar chain recognition proteins) such as selectin, siglec, and galectin as receptors existing on the cell membrane surface of each target tissue has been advanced. A sugar chain having a structure has attracted attention as a new DDS ligand (see Non-Patent Document 1 and Non-Patent Document 2).

[0006] 外膜表面にリガンドを結合したリボソームについては、癌などの標的部位に選択的に 薬物や遺伝子などを送達するための DDS材料として多くの研究がな一されてきた。 しかしながら、それらは、生体外では標的細胞に結合するが、生体内では期待される 標的細胞や組織にターゲティングされな 、ものがほとんどである（非特許文献 3およ び非特許文献 4を参照のこと)。糖鎖の分子認識機能を利用した DDS材料の研究開 発においても、糖鎖を有する糖脂質を導入したリボソームについて若干の研究が知 られているが、それらの機能評価は生体外 (インビトロ）によるもののみであり、糖鎖を 有する糖蛋白質を導入したリボソームの研究はほとんど進んで 、な ヽ（非特許文献 5 、非特許文献 6、非特許文献 7および非特許文献 8)を参照のこと)。したがって、糖脂 質や糖蛋白質の多種多様な糖鎖を結合したリボソームについての調製法と生体内 動態 (in vivo)解析を含めた体系的な研究は、これまで未開発で今後の進展が期 待される重要課題である。さらに新しいタイプの DDS材料研究として、投与が最も簡 便 ·安価に行える経口投与で使用可能な DDS材料開発も重要課題である。たとえば 、ペプチド性医薬品などは一般的に水溶性で高分子量であり消化管の小腸粘膜透 過性が低いため酵素分解を受けるなどにより経口投与してもほとんど腸管吸収されな い。そこでこれらの高分子量の医薬品や遺伝子などを腸管から血液中へ送達するた めの DDS材料としてリガンド結合リボソームの研究が注目されつつある（非特許文献 9を参照のこと)。 [0006] With regard to ribosomes having a ligand bound to the outer membrane surface, many studies have been made as DDS materials for selectively delivering drugs, genes, and the like to target sites such as cancer. However, most of them bind to target cells in vitro but are not targeted to target cells or tissues expected in vivo (see Non-Patent Document 3 and Non-Patent Document 4). thing). In research and development of DDS materials that utilize the molecular recognition function of sugar chains, some studies have been made on ribosomes into which glycolipids with sugar chains have been introduced, but their function evaluation is performed in vitro (in vitro). However, research on ribosomes into which glycoproteins having sugar chains have been introduced is almost advanced. (See Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7, and Non-Patent Document 8) . Therefore, systematic research including preparation methods and in vivo kinetics (in vivo) analysis of ribosomes that bind a wide variety of sugar chains of glycolipids and glycoproteins has not been developed so far, and future progress is expected. It is an important issue to be awaited. Furthermore, as a new type of DDS material research, the development of DDS materials that can be used by oral administration, which is the easiest and cheapest to administer, is also an important issue. For example, peptidic drugs are generally water-soluble and have a high molecular weight, and the gastrointestinal tract has a low permeability to the small intestinal mucosa. Therefore, research on ligand-bound ribosomes is attracting attention as a DDS material for delivering these high molecular weight drugs and genes from the intestinal tract into the blood (see Non-Patent Document 9).

[0007] 特許文献 1は、医薬として許容される担体と、セレクチンレセプターに選択的に結合 する成分を含む化合物とを有する医薬組成物を開示している。しかし、この医薬組成 物は、炎症性疾患および細胞の付着により媒介される他の病気を阻害するための医 薬自体として、経口投与を目的とした糖鎖が用いられており、糖鎖修飾リボソームと は異なる。  [0007] Patent Document 1 discloses a pharmaceutical composition having a pharmaceutically acceptable carrier and a compound containing a component that selectively binds to a selectin receptor. However, in this pharmaceutical composition, a sugar chain intended for oral administration is used as a pharmaceutical agent itself for inhibiting inflammatory diseases and other diseases mediated by cell adhesion. Is different.

[0008] 本発明者らは、糖鎖をリンカ一蛋白質を介してリボソームに結合させた糖鎖修飾リポ ソームを開発した (特許文献 2)。さらに、糖鎖の種類および糖鎖結合量が各標的細 胞または標的組織への指向性に関連するようであることを見出した (特許文献 3〜5 および非特許文献 10)。しかし、現在までに、小腸送達に最適な糖鎖修飾リボソーム は開発されていない。また、小腸送達において有用な糖鎖について体系的な研究は なされておらず、具体的にどのような糖鎖を用いればよいかは不明のままであった。  [0008] The present inventors have developed a sugar chain-modified liposome in which a sugar chain is bound to a ribosome via a linker protein (Patent Document 2). Furthermore, it was found that the type of sugar chain and the amount of sugar chain binding seem to be related to the directivity to each target cell or target tissue (Patent Documents 3 to 5 and Non-Patent Document 10). However, to date, no glycosylated ribosome optimal for delivery to the small intestine has been developed. In addition, there has been no systematic study on sugar chains useful in small intestine delivery, and it has remained unclear what kind of sugar chains should be used.

[0009] 従って、経口投与等の体内送達に最適な糖鎖修飾リボソームを効率よく設計し、提 供することに対して需要がある。 Accordingly, there is a demand for efficiently designing and providing a sugar chain-modified ribosome that is optimal for in-vivo delivery such as oral administration.

特許文献 1：特表平 5 - 507519公報  Patent Literature 1: Japanese Patent Publication No. 5-507519

特許文献 2：特開 2003 - 226638公報  Patent Document 2: Japanese Patent Laid-Open No. 2003-226638

特許文献 3：特開 2003 - 226647公報  Patent Document 3: Japanese Patent Laid-Open No. 2003-226647

特許文献 4： WO 2005/011632  Patent Document 4: WO 2005/011632

特許文献 5： WO 2005/011633  Patent Document 5: WO 2005/011633

非特許文献 l :Yamazaki, N. , Kojima, S. , Bovin, Ν. V. , Andre, S. , Gabiu s, S. and Gabius, H. —J. (2000) Adv. Drug Delivery Rev. 43, 225— 24 非特許文献 2 :Yamazaki, N. , Jigami, Υ. , Gabius, Η. —J. , Kojima, S (200 1) Trends in Glycoscience and Glycotechnology 13, 319— 329. http : / / www. gak. co. jp/TIGG/ 71PDF/ yamazaki. pdf Non-patent literature l: Yamazaki, N., Kojima, S., Bovin, Ν. V., Andre, S., Gabius, S. and Gabius, H. —J. (2000) Adv. Drug Delivery Rev. 43 , 225— 24 Non-Patent Document 2: Yamazaki, N., Jigami, Υ., Gabius, Η. —J., Kojima, S (200 1) Trends in Glycoscience and Glycotechnology 13, 319— 329. http: / / www. Gak. Co .jp / TIGG / 71PDF / yamazaki.pdf

非特許文献 3 : Forssen, E. and Willis, M. (1998) Adv. Drug Delivery Rev . 29, 249 - 271.  Non-Patent Document 3: Forssen, E. and Willis, M. (1998) Adv. Drug Delivery Rev. 29, 249-271.

非特許文献 4：高橋俊雄 '橋田充編（ 1999)、今日の DDS ·薬物送達システム、 159 167頁、医薬ジャーナノレ社、大阪）  Non-Patent Document 4: Toshio Takahashi 'Hashida Mitsuru (1999), Today's DDS · Drug Delivery System, 159, 167, Pharmaceutical Jana Nano, Osaka)

非特許文献 5 : DeFrees, S. A. , Phillips, L. , Guo, L. and Zalipsky, S. (19 96)J. Am. Chem. Soc. 118, 6101— 6104.  Non-Patent Document 5: DeFrees, S. A., Phillips, L., Guo, L. and Zalipsky, S. (19 96) J. Am. Chem. Soc. 118, 6101— 6104.

非特許文献 6 : Spevak, W. , Foxall, C. , Charych, D. H. , Dasqupta, F. and Non-Patent Document 6: Spevak, W., Foxall, C., Charych, D.H., Dasqupta, F. and

Nagy, J. O. (1996)J. Med. Chem. 39, 1018— 1020. Nagy, J. O. (1996) J. Med. Chem. 39, 1018—1020.

非特許文献 7 : Stahn, R. , Schafer, H. , Kernchen, F. and Schreiber, J. (1 998) Glycobiology 8, 311— 319.  Non-Patent Document 7: Stahn, R., Schafer, H., Kernchen, F. and Schreiber, J. (1 998) Glycobiology 8, 311—319.

非特許文献 8 : Yamazaki, N. , Jigami, Y. , Gabius, H. —J. , Kojima, S (200 Non-Patent Document 8: Yamazaki, N., Jigami, Y., Gabius, H. —J., Kojima, S (200

1) Trends in Glycoscience and Glycotechnology 13, 319— 329. http :1) Trends in Glycoscience and Glycotechnology 13, 319— 329. http:

/ / www. gak. co. jp/TIGG/ 71PDF/ yamazaki. pdf / / www.gak.co.jp/TIGG/71PDF/yamazaki.pdf

非特許文献 9 : Lehr, C. — M. (2000) J. Controlled Release 65, 19— 29 非特許文献 10 :山寄登（2005)、アクティブ 'ターゲティング DDSナノ粒子の開発、ナ ノ学会会報、 3, 97- 102  Non-patent document 9: Lehr, C. — M. (2000) J. Controlled Release 65, 19—29 Non-patent document 10: Noboru Yamayose (2005), Development of active 'targeting DDS nanoparticles, 3, 97- 102

発明の開示  Disclosure of the invention

発明が解決しょうとする課題  Problems to be solved by the invention

[0010] そこで、本発明の課題は、経口投与等の体内送達に有用な糖鎖修飾リボソーム、お よび糖鎖修飾リボソームに薬剤や遺伝子を封入した薬剤送達用組成物を提供するこ とにある。 Accordingly, an object of the present invention is to provide a sugar chain-modified ribosome useful for in-vivo delivery such as oral administration, and a drug delivery composition in which a drug or gene is encapsulated in the sugar chain-modified ribosome. .

課題を解決するための手段  Means for solving the problem

[0011] 上記の課題を解決するために、本発明者等は鋭意研究の結果、リボソーム表面が特 定の糖鎖で修飾されたリボソームが、経口投与等の薬剤送達にぉ ヽて有用な製剤構 IBUB M [0011] In order to solve the above-mentioned problems, the present inventors have conducted intensive research and found that a ribosome whose surface is modified with a specific sugar chain is useful for drug delivery such as oral administration. Structure IBUB M

、。VN。IOS'I O ,. VN. IOS'I O

、。VN。IO ' iq。VN。IO iqus^(s' ^UBWS' ^UB^)9' ^UB^(S' ^UB^)9' ^UB^ ,. VN. IO 'iq. VN. IO iqus ^ (s' ^ UBWS '^ UB ^) 9 ' ^ UB ^ (S '^ UB ^) 9 ' ^ UB ^

、。VN。I09'I 0 ,. VN. I09'I 0

、。VN。IO ' iq。VN。IO iqus^(s' UB^S' ^UBWS' ^UB^)9' ^UB^(S' ^UB^)9' ^UB^ ,. VN. IO 'iq. VN. IO iqus ^ (s 'UB ^ S' ^ UBWS '^ UB ^) 9' ^ UB ^ (S '^ UB ^) 9' ^ UB ^

、。VN。io 'iq。v ,. VN. io 'iq. v

N°10^' i u^ CS' ΐ^ ζ' ΐ^ ζ' ΐ^ )9' TBUB (S' ΐΏυΏ 2' ΐΏυΏ )9' ΐΏυΏ 2' TBUB N ° 10 ^ 'iu ^ CS ' ΐ ^ ζ 'ΐ ^ ζ' ΐ ^) 9 'T BUB (S' ΐ ΏυΏ 2 'ΐ ΏυΏ) 9' ΐ ΏυΏ 2 'T BUB

、。VN。IO ,. VN. IO

i °VNoio^' i u^ Cs' T^ S' T^ S' Ϊ^ )9' ΐΏΥΏ (ε' ΐΏΥΏ )9' ΐΏΥΏ 2' TBUB i ° VN o io ^ 'iu ^ Cs' T ^ S 'T ^ S' Ϊ ^) 9 'ΐ ΏΥΏ (ε' ΐ ΏΥΏ ) 9 'ΐ ΏΥΏ 2' T BUB

^VN^lOCS'T^Wiqpo^eOS-O)-^^ VN ^ lOCS'T ^ Wiqpo ^ eOS-O)-^

FO(2'TBont[)S'T∞VNFO FO (2'T Bon t [) S'T∞VNFO

、。VN。 ΐ 0 ,. VN. ΐ 0

、おつ ΐ ' ΐ q。IO ' ΐ PO(S'2BOVen9N8 ' ^。VSn。N) ΐ q^VNPOS'T qpo , Otsu ΐ 'ΐ q. IO 'ΐ PO (S'2 BO Ven9N8' ^ .VSn.N) ΐ q ^ VNPOS'T qpo

iq OS' 。 VSnsN

Figure imgf000006_0001
iq OS '. VSnsN
Figure imgf000006_0001

：錤 o)止 «(τ) ^凝 ¾ ^ o)止^ r 本 βτοο]  : 錤 o) Stop «(τ) ^ Coupling ¾ ^ o) Stop ^ r This βτοο]

0¾¾ )¾^¾ 、つ？ ^  0¾¾) ¾ ^ ¾ ^

Z88STC/900Zdf/X3d 9 Galbl,4(Fucal,3)GlcNAcゝ Z88STC / 900Zdf / X3d 9 Galbl, 4 (Fucal, 3) GlcNAc ゝ

Galal,3Gal、 Galal, 3Gal,

Fucal,2Galbl,4Glcゝ Fucal, 2Galbl, 4Glc ゝ

Manal ,6(Manal ,3)Manal ,6Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manal, 6Manbl, 4GlcNAcbl, 4GlcNAc,

Galbl,4(Fucal,3)Glcゝ  Galbl, 4 (Fucal, 3) Glc ゝ

GalNAca 1—O—L— serine、  GalNAca 1—O—L—serine,

Neu5Aca2,3Galbl,4(Fucal,3)GlcNAcゝ  Neu5Aca2,3Galbl, 4 (Fucal, 3) GlcNAc ゝ

Fucal ,2Galbl ,4(Fucal ,3)GlcNAcゝ  Fucal, 2Galbl, 4 (Fucal, 3) GlcNAc ゝ

Galbl,4Glc、  Galbl, 4Glc,

Manal,6Man、  Manal, 6Man,

Neu5Aca2,6GalNAcal— O—L— serineゝ  Neu5Aca2,6GalNAcal— O—L— serine ゝ

Manal ,6(Manal ,3)Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,

Fucal ,2Galbl ,3(Fucal ,4)GlcNAcゝ  Fucal, 2Galbl, 3 (Fucal, 4) GlcNAc ゝ

Manal,4Man^  Manal, 4Man ^

Neu5Ac2 ,6GalNAcaト O-L- serine、  Neu5Ac2, 6GalNAca to O-L-serine,

Neu5Aca2,6Galbl,4Glcゝ Neu5Aca2,6Galbl, 4Glc ゝ

Fucal ,2Galbl ,3(Fucal ,4)GlcNAcbl ,3Galbl ,4Glc,  Fucal, 2Galbl, 3 (Fucal, 4) GlcNAcbl, 3Galbl, 4Glc,

Galb l,3GalNAcb 1 ,4(Neu5Aca2 , 3)Galb 1 ,4Glcb 1 , 1 Cer、  Galb l, 3GalNAcb 1, 4 (Neu5Aca2, 3) Galb 1, 4Glcb 1, 1 Cer,

Manal ,6(Manal ,3)Manal ,6(Manal ,3)Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manal, 6 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,

Manal,3Man、  Manal, 3Man,

Neu5Aca2,3Galbl,3(Fucal,4)GlcNAcゝ  Neu5Aca2,3Galbl, 3 (Fucal, 4) GlcNAc ゝ

3'- (O- S03H)Galbl,3(Fucal,4)GlcNAc、 3'- (O- S03H) Galbl, 3 (Fucal, 4) GlcNAc,

Neu5Aca2 ,3Galb 1 ,4GlcNAc、 Neu5Aca2, 3Galb 1, 4GlcNAc,

Galbl,3(Fucal,4)GlcNAcゝ Galbl, 3 (Fucal, 4) GlcNAc ゝ

から選択された少なくとも 1つの糖鎖が結合している、糖鎖修飾リボソーム。 （2)前記 糖鎖の修飾結合密度が、 0. 0075〜0. 75mg糖鎖 Zmg脂質であることを特徴とす る（1)に記載の糖鎖修飾リボソーム。 (3)前記糖鎖カ^ンカ一を介して前記リボソーム の膜に結合していることを特徴とする（1)又は（2)に記載の糖鎖修飾リボソーム。（4) 前記リンカ一が生体由来蛋白質であることを特徴とする（3)に記載の糖鎖修飾リポソ ーム。（5)前記リンカ一がヒト血清アルブミンまたはゥシ血清アルブミンであることを特 徴とする (4)に記載の糖鎖修飾リボソーム。（6)前記糖鎖修飾リボソーム力 リポソ一 ム膜またはリンカ一の少なくとも一方に親水性ィ匕合物を結合させることにより親水性 化されて!/、ることを特徴とする（1)〜（5)の 、ずれかに記載の糖鎖修飾リボソーム。 ( 7)前記リボソームと前記糖鎖力 ペプチド結合により結合していることを特徴とする（1 )〜（6)の 、ずれかに記載の糖鎖修飾リボソーム。 (8)前記リボソームの膜上にあるガ ングリオシドと前記リンカ一が共有結合により結合し、該リンカ一の末端がペプチド結 合により結合して 、ることを特徴とする（3)に記載の糖鎖修飾リボソーム。 (9)前記親 水性化合物が、低分子の親水性化合物、好ましくは少なくとも 1つの OH基を有する 低分子の親水性化合物、さらに好ましくは、少なくとも 2つの OH基を有する低分子の 親水性ィ匕合物であることを特徴とする、又はトリス (ヒドロキシアルキル)アミノアルカン であることを特徴とする（1)に記載の糖鎖修飾リボソーム。 (10) (1)〜（9)のいずれ カゝ 1項に記載の糖鎖修飾リボソーム及び薬剤を含有することを特徴とする薬剤送達 組成物。 （11)前記薬剤が、医薬、研究試薬、化粧品および機能性食品から選択さ れる物質であることを特徴とする（10)に記載の薬剤送達組成物。 (12)前記薬剤が、 抗癌剤、抗炎症剤、バイオ医薬品又はビタミン剤であることを特徴とする（10)又は（1 1)に記載の薬剤送達組成物。 ( 13)前記薬剤送達組成物が経口投与されるものであ ることを特徴とする（10)〜（12)のいずれかに記載の薬剤送達組成物。（14)前記薬 剤送達組成物が経口投与されるものであることを特徴とする（10)〜（12)のいずれか に記載の薬剤送達組成物。 A sugar chain-modified ribosome to which at least one sugar chain selected from is bound. (2) The sugar chain-modified ribosome according to (1), wherein the modified bond density of the sugar chain is 0.0075 to 0.75 mg sugar chain Z mg lipid. (3) The sugar chain-modified ribosome according to (1) or (2), wherein the sugar chain-modified ribosome is bound to the ribosome membrane through the sugar chain handler. (Four) The sugar chain-modified liposome according to (3), wherein the linker is a biological protein. (5) The sugar chain-modified ribosome according to (4), wherein the linker is human serum albumin or ushi serum albumin. (6) The sugar chain-modified ribosome force is made hydrophilic by binding a hydrophilic compound to at least one of a liposome membrane or a linker, and is characterized in that (1) to ( The sugar chain-modified ribosome according to 5). (7) The sugar chain-modified ribosome according to any one of (1) to (6), wherein the ribosome and the sugar chain force are bound by a peptide bond. (8) The saccharide according to (3), wherein the ganglioside on the ribosome membrane and the linker are bonded by a covalent bond, and the terminal ends of the linker are bonded by a peptide bond. Strand-modified ribosome. (9) The hydrophilic compound is a low molecular weight hydrophilic compound, preferably a low molecular weight hydrophilic compound having at least one OH group, more preferably a low molecular weight hydrophilic compound having at least two OH groups. The sugar chain-modified ribosome according to (1), which is a compound or a tris (hydroxyalkyl) aminoalkane. (10) A drug delivery composition comprising the sugar chain-modified ribosome according to any one of (1) to (9) and a drug. (11) The drug delivery composition according to (10), wherein the drug is a substance selected from pharmaceuticals, research reagents, cosmetics, and functional foods. (12) The drug delivery composition according to (10) or (11), wherein the drug is an anticancer drug, an anti-inflammatory drug, a biopharmaceutical or a vitamin drug. (13) The drug delivery composition according to any one of (10) to (12), wherein the drug delivery composition is orally administered. (14) The drug delivery composition according to any one of (10) to (12), wherein the drug delivery composition is orally administered.

発明の効果 The invention's effect

本発明によって、経口投与に有用な糖鎖修飾リボソームならびにその製造法および その利用法が提供される。本発明の糖鎖修飾リボソームは、 目的送達部位に所望の 薬物を提供することが可能な DDS製剤開発の幅を大いに広げるものである。本発明 により、癌治療、遺伝子治療、再生医療などの各分野での新しい治療を実現させる ために必要なデリバリーシステムの開発 ·実用化が可能となる。このような経口投与に 有用な種々の糖鎖修飾リボソームは、本発明によって初めて提供されるものである。 図面の簡単な説明 The present invention provides a sugar chain-modified ribosome useful for oral administration, a method for producing the same, and a method for using the same. The sugar chain-modified ribosome of the present invention greatly expands the scope of development of a DDS preparation capable of providing a desired drug at a target delivery site. According to the present invention, it is possible to develop and put into practical use a delivery system necessary for realizing new treatments in various fields such as cancer treatment, gene therapy, and regenerative medicine. Various sugar chain-modified ribosomes useful for such oral administration are provided for the first time by the present invention. Brief Description of Drawings

[0014] [図 1]本発明において使用され得る糖鎖修飾リボソームの製造模式図である。  FIG. 1 is a schematic diagram of production of a sugar chain-modified ribosome that can be used in the present invention.

[図 2]図 2は、ドキソルビシン封入リボソーム番号 155の尾静注投与での担癌マウスに おける制癌効果を示す図である。  [FIG. 2] FIG. 2 is a graph showing the antitumor effect in tumor-bearing mice after intravenous injection of doxorubicin-encapsulated ribosome # 155.

[図 3]図 3は、ドキソルビシン封入リボソーム番号 155の尾静注投与での担癌マウスに おける腫瘍血管カゝら腫瘍組織へのドキソルビシンの集積効果を示す蛍光顕微鏡写 真である。左側並びに右側の画像は、同一腫瘍組織のそれぞれ緑色並びに赤色の 蛍光顕微鏡写真である。  [FIG. 3] FIG. 3 is a fluorescence micrograph showing the effect of doxorubicin accumulation in tumor tissues in tumor-bearing mice after intravenous injection of doxorubicin-encapsulated ribosome # 155 in tumor-bearing mice. The left and right images are green and red fluorescence micrographs of the same tumor tissue, respectively.

[図 4]図 4は、ドキソルビシン封入リボソーム番号 237の経口投与での担癌マウスにお ける制癌効果を示す図である。  [FIG. 4] FIG. 4 is a graph showing the antitumor effect in tumor-bearing mice after oral administration of doxorubicin-encapsulated ribosome No. 237.

[図 5]図 5は、ドキソルビシン封入リボソーム番号 237の経口投与での担癌マウスにお ける腫瘍血管カゝら腫瘍組織へのドキソルビシン集積効果を示す蛍光顕微鏡写真で ある。左側並びに右側の画像は、同一腫瘍組織のそれぞれ緑色並びに赤色の蛍光 顕微鏡写真である。  FIG. 5 is a fluorescence micrograph showing the effect of doxorubicin accumulation on tumor tissues in tumor-bearing mice after oral administration of doxorubicin-encapsulated ribosome No. 237. The left and right images are green and red fluorescence micrographs of the same tumor tissue, respectively.

[図 6]図 6は、 IC50を計算するときのグラフである。 X軸には、対象となる薬物の濃度 がふられ、 Y軸には結合したリガンドの量を示す。  FIG. 6 is a graph when calculating IC50. The X axis shows the concentration of the drug of interest, and the Y axis shows the amount of ligand bound.

発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION

[0015] 以下、本発明を最良の形態を示しながら説明する。本明細書の全体にわたり、単数 形の表現は、特に言及しない限り、その複数形の概念をも含むことが理解されるべき である。従って、単数形の冠詞 (例えば、英語の場合は「a」、「an」、「the」など）は、 特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。また、 本明細書において使用される用語は、特に言及しない限り、当上記分野で通常用い られる意味で用いられることが理解されるべきである。したがって、他に定義されない 限り、本明細書中で使用される全ての専門用語および科学技術用語は、本発明の 属する分野の当業者によって一般的に理解されるのと同じ意味を有する。矛盾する 場合、本明細書 (定義を含めて)が優先する。  Hereinafter, the present invention will be described with reference to the best mode. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. Thus, it should be understood that singular articles (eg, “a”, “an”, “the”, etc. in English) also include the plural concept unless otherwise stated. In addition, it should be understood that the terms used in the present specification are used in the meaning normally used in the above field unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.

[0016] 以下に提供される実施形態は、本発明のよりよい理解のために提供されるものであり 、本発明の範囲は以下の記載に限定されるべきでないことが理解される。従って、当 業者は、本明細書中の記載を参酌して、本発明の範囲内で適宜改変を行うことがで きることは明らかである。 [0016] It is understood that the embodiments provided below are provided for a better understanding of the present invention, and the scope of the present invention should not be limited to the following description. Therefore, this It is apparent that a person skilled in the art can make appropriate modifications within the scope of the present invention in consideration of the description in the present specification.

[0017] 以下に本明細書において特に使用される用語の定義を適宜説明する。  [0017] Hereinafter, definitions of terms particularly used in the present specification will be described as appropriate.

[0018] 本明細書において「糖鎖」とは、単位糖 (単糖および Zまたはその誘導体）が 1っ以 上連なってできたィ匕合物をいう。単位糖が 2つ以上連なる場合は、各々の単位糖同 士の間は、グリコシド結合による脱水縮合によって結合する。このような糖鎖としては 、例えば、生体中に含有される多糖類 (グルコース、ガラクトース、マンノース、フコー ス、キシロース、 N—ァセチルダルコサミン、 N—ァセチルガラタトサミン、シアル酸な らびにそれらの複合体および誘導体)の他、分解された多糖、糖蛋白質、プロテオグ リカン、グリコサミノダリカン、糖脂質などの複合生体分子から分解または誘導された 糖鎖など広範囲なものが挙げられるがそれらに限定されない。したがって、本明細書 では、糖鎖は、「多糖 (ポリサッカリド)」、「糖質」、「炭水化物」と互換可能に使用され 得る。また、特に言及しない場合、本明細書において「糖鎖」は、糖鎖および糖鎖含 有物質の両方を包含することがある。代表的には、約 20種類の単糖 (グルコース、ガ ラタトース、マンノース、フコース、キシロース、 N—ァセチルダルコサミン、 N—ァセチ ルガラタトサミン、シアル酸ならびにそれらの複合体および誘導体など）が鎖状につな 力 た物質で、生体の細胞内外の蛋白質や脂質に付いている。単糖の配列によって 機能が異なり、通常は複雑に枝分かれしていて、人体には数百種類以上の多様な 構造の糖鎖があると予想されており、さらに、人体において有用な構造は数万種類 以上あると考えられている。細胞間での分子 ·細胞認識機能など蛋白質や脂質が生 体内で果たす高次機能に関係していると見られている力 そのメカニズムは未解明の 部分が多い。核酸、蛋白質に次ぐ第 3の生命鎖として現在のライフサイエンスで注目 されている。とりわけ、細胞認識におけるリガンド (情報分子）としての糖鎖の機能が期 待され、その高機能材料開発への応用が研究されている。 [0018] As used herein, the term "sugar chain" refers to a compound comprising one or more unit sugars (monosaccharide and Z or a derivative thereof). When two or more unit sugars are connected, each unit sugar is linked by dehydration condensation using a glycosidic bond. Examples of such sugar chains include polysaccharides contained in the living body (glucose, galactose, mannose, fucose, xylose, N-acetylethyldarcosamine, N-acetylethylgalatosamine, sialic acid and In addition to their conjugates and derivatives), there are a wide range of sugar chains that are degraded or derived from complex biomolecules such as degraded polysaccharides, glycoproteins, proteoglycans, glycosaminodarlicans, glycolipids, etc. It is not limited to. Therefore, in the present specification, the sugar chain can be used interchangeably with “polysaccharide”, “sugar”, and “carbohydrate”. Further, unless otherwise specified, the “sugar chain” in the present specification may include both sugar chains and sugar chain-containing substances. Typically, about 20 monosaccharides (such as glucose, galatose, mannose, fucose, xylose, N-acetylethyldarcosamine, N-acetylgalatatosamine, sialic acid, and complexes and derivatives thereof) are chained. It is a strong substance that is attached to proteins and lipids inside and outside the body of cells. The functions differ depending on the sequence of monosaccharides, and they are usually branched in a complex manner. The human body is expected to have several hundreds of sugar chains with various structures, and there are tens of thousands of useful structures in the human body. There are thought to be more than types. Molecules between cells · Forces that are considered to be related to higher-order functions that proteins and lipids perform in the body, such as cell recognition functions. It is attracting attention in current life sciences as the third life chain after nucleic acids and proteins. In particular, the function of sugar chains as ligands (information molecules) in cell recognition is expected, and its application to the development of highly functional materials is being studied.

[0019] 本明細書において「糖」または「単糖」とは、少なくとも 1つの水酸基および少なくとも 1 つのアルデヒド基またはケトン基を含む、ポリヒドロキシアルデヒドまたはポリヒドロキシ ケトンをいい、糖鎖の基本単位を構成する。本明細書において、糖はまた、炭水化物 ともいい、両者は互換的に用いられる。本明細書において、特に言及するときは、糖 鎖は、 1つ以上糖が連なった鎖または配列をいい、糖または単糖というときは、糖鎖を 構成する 1つの単位をいう。ここで、 n= 2、 3、 4、 5、 6、 7、 8、 9および 10であるもの を、それぞれジオース、トリオース、テトロース、ペントース、へキソース、ヘプトース、 オタトース、ノノースおよびデコースという。一般に鎖式多価アルコールのアルデヒドま たはケトンに相当するもので、前者をアルドース，後者をケトースという。本発明では、 V、ずれの形式のものでも使用され得る。 As used herein, “sugar” or “monosaccharide” refers to a polyhydroxyaldehyde or polyhydroxyketone containing at least one hydroxyl group and at least one aldehyde group or ketone group, and represents the basic unit of a sugar chain. Constitute. In this specification, sugar is also referred to as carbohydrate, and both are used interchangeably. In this specification, when specifically referred to, sugar A chain refers to a chain or sequence in which one or more sugars are linked, and a sugar or monosaccharide refers to one unit that constitutes a sugar chain. Here, those in which n = 2, 3, 4, 5, 6, 7, 8, 9 and 10 are called diose, triose, tetrose, pentose, hexose, heptose, otatose, nonose and decourse, respectively. Generally, it is equivalent to an aldehyde or ketone of a chain polyhydric alcohol, the former being called aldose and the latter being called ketose. In the present invention, the V, misalignment type can also be used.

[0020] 本発明にお 、て糖を記載するために使用する命名法および略称は、通常の命名法 に従う。例えば、 β D ガラクトース  [0020] In the present invention, the nomenclature and abbreviations used to describe sugars follow the usual nomenclature. For example, β D galactose

[0021] [化 1]  [0021] [Chemical 1]

β-D-Ga lactose

Figure imgf000011_0001
β-D-Ga lactose
Figure imgf000011_0001

[0022] は、 Gal ; N ァセチノレー a—D ガラクトサミン  [0022] is Gal; N acetylenore a-D galactosamine

[0023] [化 2] [0023] [Chemical 2]

N-Acetyl-a-D-galactosamine

Figure imgf000011_0002
N-Acetyl-aD-galactosamine
Figure imgf000011_0002

[0024] は、 GalNAc ; α— D マンノース [0024] is GalNAc; α-D mannose

[0025] [化 3] [0025] [Chemical 3]

； -D- artnose

Figure imgf000011_0003
-D- artnose
Figure imgf000011_0003

[0026] は、 Man ; β—D グノレコ  [0026] is Man; β-D

[0027] [化 4] p-D-Glucose

Figure imgf000012_0001
[0027] [Chemical 4] pD-Glucose
Figure imgf000012_0001

[0028] は、 Glc;N ァセチル— β—D—ダルコサミン [0028] is Glc; N-acetyl-β-D-darcosamine

[0029] [化 5] [0029] [Chemical 5]

N-Acetyl-P-D-glucosamine

Figure imgf000012_0002
N-Acetyl-PD-glucosamine
Figure imgf000012_0002

[0030] は、 GlcNAc;ひ Lーフコース [0030] is GlcNAc;

[0031] [化 6] [0031] [Chemical 6]

,-Fucose

Figure imgf000012_0003
, -Fucose
Figure imgf000012_0003

[0032] は、 Fuc; a—N ァセチルノイラミン酸 [0032] is Fuc; a-N acetylneuraminic acid

[0033] [化 7]  [0033] [Chemical 7]

α-Ν-Acetyl neuraminic acid  α-Ν-Acetyl neuraminic acid

Figure imgf000012_0004
Figure imgf000012_0004

[0034] は、 Neu5Ac;セラミド  [0034] is Neu5Ac; Ceramide

[0035] [化 8] [0035] [Chemical 8]

Ceramide  Ceramide

Figure imgf000012_0005
Figure imgf000012_0005

[0036] は、 Cer;L セリン CH (OH)CH(COOH)NHは、 Serにより表す。なお、 Cerは  [0036] is Cer; L Serine CH (OH) CH (COOH) NH is represented by Ser. Cer is

2 2 通常脂質に分類されるが、本明細書では、糖鎖を構成する糖の一種の定義にも入る ことから特に言及しない限り、糖として扱う。また、 Serは通常アミノ酸に分類されるが 、本明細書では、糖鎖を構成する糖の一種の定義にも入ることから特に言及しない 限り、糖として扱う。環状の 2つのァノマーは、 αおよび j8により表す。表示上の理由 により、 aまたは bと表すことがある。従って、本明細書において、 aと a、 βと bは、ァノ マー表記については交換可能に使用される。 twenty two Usually, it is classified as lipid, but in this specification, it is also treated as sugar unless otherwise mentioned because it also falls within the definition of one kind of sugar constituting the sugar chain. In addition, Ser is usually classified as an amino acid, but in the present specification, since it falls within the definition of a kind of sugar constituting a sugar chain, it is treated as a sugar unless otherwise specified. The two cyclic anomers are represented by α and j8. It may be indicated as a or b for display reasons. Accordingly, in the present specification, a and a, and β and b are used interchangeably for the anomeric notation.

[0037] 本明細書において、ガラクトースとは、任意の異性体を指すが、代表的には j8 - D- ガラクトースであり、特に言及しないときには、 j8— D ガラクトースを指すものとして 使用される。 [0037] In this specification, galactose refers to any isomer, but is typically j8-D-galactose, and is used to refer to j8-D galactose unless otherwise specified.

[0038] 本明細書において、ァセチルガラタトサミンとは、任意の異性体を指すが、代表的に は N ァセチノレー a D ガラクトサミンであり、特に言及しないときには、 N ァセ チル一 a—D ガラクトサミンを指すものとして使用される。  [0038] In the present specification, acetylylgalatatosamine refers to any isomer, but is typically N-acetinole a D galactosamine, and unless otherwise specified, N-acetyl-a-D galactosamine Used to refer to

[0039] 本明細書において、マンノースとは、任意の異性体を指すが、代表的には a - D - マンノースであり、特に言及しないときには、 ex D—マンノースを指すものとして使 用される。 In the present specification, mannose refers to any isomer, but is typically a-D-mannose, and is used to refer to ex D-mannose unless otherwise specified.

[0040] 本明細書において、グルコースとは、任意の異性体を指すが、代表的には j8 - D - グルコースであり、特に言及しないときには、 13 D—グルコースを指すものとして使 用される。  [0040] In the present specification, glucose refers to any isomer, but is typically j8-D-glucose, and is used to refer to 13D-glucose unless otherwise specified.

[0041] 本明細書において、ァセチルダルコサミンとは、任意の異性体を指すが、代表的に は N ァセチノレー β D ダルコサミンであり、特に言及しないときには、 Ν ァセチ ルー β—D—ダルコサミンを指すものとして使用される。  [0041] As used herein, acetylyldarcosamine refers to any isomer, but is typically N-acetylenic β D darcosamine, and unless otherwise specified, refers to ァ acetylene β-D-darcosamine. Used as a thing.

[0042] 本明細書において、フコースとは、任意の異性体を指すが、代表的には a Lーフコ ースであり、特に言及しないときには、 a—L フコースを指すものとして使用される。  In the present specification, fucose refers to any isomer, but is typically a L-fucose, and is used to refer to a-L fucose unless otherwise specified.

[0043] 本明細書において、ァセチルノイラミン酸とは、任意の異性体を指すが、代表的には a—N ァセチルノイラミン酸であり、特に言及しないときには a N ァセチルノィ ラミン酸を指すものとして使用される。 [0043] In the present specification, acetylylneuraminic acid refers to any isomer, but is typically a-N acetylneuraminic acid, and unless otherwise specified, refers to aN acetylneuraminic acid. Used as a thing.

[0044] 本明細書において、セリンとは、任意の異性体を指すが、代表的には Lーセリンであ り、特に言及しないときには Lーセリンを指すものとして使用される。 [0044] In the present specification, serine refers to any isomer, typically L-serine. Unless otherwise stated, it is used to refer to L-serine.

[0045] 本明細書において、糖の表示記号、呼称、略称 (Glcなど)などは、単糖を表すときと 、糖鎖中で使用されるときとは、異なることに留意する。糖鎖中、単位糖は、結合先の 別の単位糖との間に脱水縮合があるので、相方力 水素または水酸基を除いた形で 存在することになる。従って、これらの糖の略号は、単糖を表すときに使用されるとき は、すべての水酸基が存在するが、糖鎖中で使用されるときは、水酸基が結合先の 糖の水酸基とが脱水縮合されて酸素のみが残存した状態を示していることが理解さ れる。 [0045] In the present specification, it is noted that the sugar symbols, designations, abbreviations (Glc, etc.) and the like are different when they represent a monosaccharide and when used in a sugar chain. In the sugar chain, the unit sugar exists in a form excluding hydrogen or hydroxyl group due to dehydration condensation with another unit sugar to which it is bonded. Therefore, these sugar abbreviations, when used to represent monosaccharides, have all hydroxyl groups present, but when used in sugar chains, the hydroxyl groups of the sugar to which the hydroxyl group is attached are dehydrated. It can be seen that only oxygen remains after condensation.

[0046] 糖力 アルブミンと共有結合されるときには、糖の還元末端がァミノ化され、そのアミン 基を介してアルブミンなどの他の成分に結合することができる力 その場合は還元末 端の水酸基がァミン基に置換されたものを指すことに留意する。  [0046] Sugar power When covalently bonded to albumin, the reducing end of the sugar is aminated, and is capable of binding to other components such as albumin via its amine group. In this case, the hydroxyl group at the reducing end Note that it refers to those substituted with an amine group.

[0047] 単糖は一般に、グリコシド結合により結合されて二糖および多糖を形成する。環の平 面に関する結合の向きは、 αおよび j8により示す。 2つの炭素の間の結合を形成す る特定の炭素原子も記載する。  [0047] Monosaccharides are generally joined by glycosidic bonds to form disaccharides and polysaccharides. The direction of the bond relative to the plane of the ring is indicated by α and j8. The specific carbon atom that forms the bond between the two carbons is also described.

[0048] 本明細書において糖鎖は、  [0048] In the present specification, the sugar chain is

[0049] [化 9]

Figure imgf000014_0001
[0049] [Chemical 9]
Figure imgf000014_0001

[0050] により表される。従って、例えば、ガラクトースの C— 1とグルコースの C— 4との間の β グリコシド結合は、 Gal |8 1, 4Glcにより表される。  [0050] Thus, for example, the β-glycoside bond between galactose C-1 and glucose C-4 is represented by Gal | 8 1,4Glc.

[0051] 糖鎖の分岐は、括弧により表し、結合する単位糖のすぐ左に配置して表記する。例え ば、 [0051] Branches of sugar chains are represented by parentheses, and are arranged and placed immediately to the left of the unit sugar to be bound. For example,

[0052] [化 10]  [0052] [Chemical 10]

単糖 T マ- 1 結合様式 (  Monosaccharide T-mer 1 binding mode (

と表され、括弧の中は、  And in parentheses are

[化 11]  [Chemical 11]

単糖 ァノマー 結合様式  Monosaccharide anomer binding mode

[0055] と表記される。従って、例えば、ガラクトースの C— 1とグルコースの C— 4との間が β グリコシド結合し、さらにこのグルコースの C— 3がフコースの C—1と αグリコシド結合 している場合、 Gal jS 1, 4 (Fuc a l, 3) Glcと表される。単糖は、（潜在）カルボ-ル 原子団になるだけ小さい番号を付けることを基本にして表される。有機化学命名法の 一般基準では (潜在)カルボ-ル原子団より優位な原子団が分子中に導入されたとき でも、通常上記の番号付けで表される。 [0055]. Thus, for example, the gap between C-1 in galactose and C-4 in glucose When the glycoside is linked and C-3 of this glucose is α-glycosidically linked to fucose C-1, it is expressed as Gal jS 1, 4 (Fucal, 3) Glc. Monosaccharides are represented on the basis of the lowest possible number of (latent) carbo groups. According to the general standard of organic chemical nomenclature, even when a group superior to a (latent) carbo group is introduced into a molecule, it is usually represented by the above numbering.

[0056] [化 12]  [0056] [Chemical 12]

Figure imgf000015_0001
Figure imgf000015_0001

[0057] [化 13]  [0057] [Chemical 13]

Figure imgf000015_0002
Figure imgf000015_0002

[0058] 本明細書において使用される糖鎖としては、例えば、 Gal, GalNAc、 Man, Glc、 Gl cNAc、 Fuc、 Neu5Acおよび Serからなる群より選択される少なくとも 1つの単位糖 を有する糖鎖が挙げられる。そのような糖鎖としては、例えば、  [0058] Examples of the sugar chain used in the present specification include a sugar chain having at least one unit sugar selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc, Fuc, Neu5Ac and Ser. Be mentioned. As such a sugar chain, for example,

Neu5Aca2 ,3Galb l,3GalNAcb 1 ,4(Neu5Aca2,3)Galb l,4Glcb 1 , 1 Cer、  Neu5Aca2, 3Galb l, 3GalNAcb 1, 4 (Neu5Aca2, 3) Galb l, 4Glcb 1, 1 Cer,

Fucal ,2Galbl ,4(Fucal ,3)Glcゝ  Fucal, 2Galbl, 4 (Fucal, 3) Glc ゝ

Neu5Aca2,3Galbl,4Glcゝ  Neu5Aca2,3Galbl, 4Glc ゝ

Galb l,3GalNAcb 1 ,4(Neu5Aca2 , 8Neu5Aca2,3)Galb l,4Glcb 1 , 1 Cer、  Galb l, 3GalNAcb 1, 4 (Neu5Aca2, 8Neu5Aca2,3) Galb l, 4Glcb 1, 1 Cer,

Galbl,4GlcNAcゝ  Galbl, 4GlcNAc ゝ

GalNAcal ,3(Fucal ,2)Gal、  GalNAcal, 3 (Fucal, 2) Gal,

3'— (O— S03H)Galbl,4(Fucal,3)GlcNAc、  3'— (O— S03H) Galbl, 4 (Fucal, 3) GlcNAc,

Fucal, 2Gal、  Fucal, 2Gal,

Manal ,2Manal ,6(Manal ,3)Manal ,6(Manal ,2Manal ,2Manal ,3)Manbl ,4GlcNAcbl ,4 GlcNAc、  Manal, 2Manal, 6 (Manal, 3) Manal, 6 (Manal, 2Manal, 2Manal, 3) Manbl, 4GlcNAcbl, 4 GlcNAc,

Fucal ,2Galbl ,3GlcNAcbl ,3Galbl ,4Glc, Manal ,2Manal ,6(Manal ,2Manal ,3)Manal ,6(Manal ,2Manal ,2Manal ,3)Manbl ,4GlcNFucal, 2Galbl, 3GlcNAcbl, 3Galbl, 4Glc, Manal, 2Manal, 6 (Manal, 2Manal, 3) Manal, 6 (Manal, 2Manal, 2Manal, 3) Manbl, 4GlcN

Acbl,4GlcNAc、 Acbl, 4GlcNAc,

Neu5Aca2 , 6Galb 1 ,4GlcNAc、  Neu5Aca2, 6Galb 1, 4GlcNAc,

Galb l,3GalNAcb 1 ,4Galb l,4Glcb 1 , 1 Cer + Neu5Aca2,3Galb 1 ,3GalNAcb 1 ,4(Neu5A ca2,3)Galbl,4Glcbl,lCer、  Galb l, 3GalNAcb 1, 4Galb l, 4Glcb 1, 1 Cer + Neu5Aca2,3Galb 1, 3GalNAcb 1, 4 (Neu5A ca2,3) Galbl, 4Glcbl, lCer,

Manal ,6(Manal ,3)Manal ,6(Manal ,2Manal ,2Manal ,3)Manbl ,4GlcNAcbl ,4GlcNAc, Manal, 6 (Manal, 3) Manal, 6 (Manal, 2Manal, 2Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,

Galbl ,3(Fucal ,4)GlcNAcbl ,3Galbl ,4Glc, Galbl, 3 (Fucal, 4) GlcNAcbl, 3Galbl, 4Glc,

Galbl, 3GlcNAcbl,3Galbl,4Glc,  Galbl, 3GlcNAcbl, 3Galbl, 4Glc,

Galal ,3(Fucal ,2)Gal、  Galal, 3 (Fucal, 2) Gal,

Galbl, 3GalNAc,  Galbl, 3GalNAc,

Galbl, 6GlcNAc,  Galbl, 6GlcNAc,

Manal ,6(Manal ,3)Man^  Manal, 6 (Manal, 3) Man ^

Manal ,6(Manal ,3)Manal ,6(Manal ,2Manal ,3)Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manal, 6 (Manal, 2Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,

Galbl, 3GlcNAc,  Galbl, 3GlcNAc,

Manal, 2Man、  Manal, 2Man,

Galbl, 4(Fucal,3)GlcNAc,  Galbl, 4 (Fucal, 3) GlcNAc,

Galal, 3Gal、  Galal, 3Gal,

Fucal, 2Galbl,4Glc,  Fucal, 2Galbl, 4Glc,

Manal ,6(Manal ,3)Manal ,6Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manal, 6Manbl, 4GlcNAcbl, 4GlcNAc,

Galbl, 4(Fucal,3)Glc,  Galbl, 4 (Fucal, 3) Glc,

GalNAca 1—O—L— serine、  GalNAca 1—O—L—serine,

Neu5Aca2,3Galbl,4(Fucal,3)GlcNAcゝ  Neu5Aca2,3Galbl, 4 (Fucal, 3) GlcNAc ゝ

Fucal ,2Galbl ,4(Fucal ,3)GlcNAcゝ  Fucal, 2Galbl, 4 (Fucal, 3) GlcNAc ゝ

Galbl,4Glc、  Galbl, 4Glc,

Manal, 6Man、  Manal, 6Man,

Neu5Aca2,6GalNAcal— O—L— serineゝ  Neu5Aca2,6GalNAcal— O—L— serine ゝ

Manal ,6(Manal ,3)Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,

Fucal ,2Galbl ,3(Fucal ,4)GlcNAcゝ Manal,4Man^ Fucal, 2Galbl, 3 (Fucal, 4) GlcNAc ゝ Manal, 4Man ^

Neu5Ac2 ,6GalNAcaト O-L- serine、  Neu5Ac2, 6GalNAca to O-L-serine,

Neu5Aca2,6Galbl,4Glcゝ  Neu5Aca2,6Galbl, 4Glc ゝ

Fucal ,2Galbl ,3(Fucal ,4)GlcNAcbl ,3Galbl ,4Glc,  Fucal, 2Galbl, 3 (Fucal, 4) GlcNAcbl, 3Galbl, 4Glc,

Galb l,3GalNAcb 1 ,4(Neu5Aca2 , 3)Galb 1 ,4Glcb 1 , 1 Cer、  Galb l, 3GalNAcb 1, 4 (Neu5Aca2, 3) Galb 1, 4Glcb 1, 1 Cer,

Manal ,6(Manal ,3)Manal ,6(Manal ,3)Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manal, 6 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,

Manal,3Man、  Manal, 3Man,

Neu5Aca2,3Galbl,3(Fucal,4)GlcNAcゝ  Neu5Aca2,3Galbl, 3 (Fucal, 4) GlcNAc ゝ

3'- (O- S03H)Galbl,3(Fucal,4)GlcNAc、  3'- (O- S03H) Galbl, 3 (Fucal, 4) GlcNAc,

Neu5Aca2 ,3Galb 1 ,4GlcNAc、  Neu5Aca2, 3Galb 1, 4GlcNAc,

Galbl,3(Fucal,4)GlcNAcゝ  Galbl, 3 (Fucal, 4) GlcNAc ゝ

ならびにそれらの 2つ以上の組み合わせ力 なる群より選択される糖鎖が挙げられる 力 これらに限定されない。 2つ以上の組み合わせが使用可能な理由としては、理論 に束縛されないが、上記糖鎖の各々が目的の送達部位の組織または細胞に局在す るレクチンに対して特異性を有しており、混在してもその特異性を発揮すると考えら れるカゝらである。  And a sugar chain selected from the group consisting of two or more combinations of these forces, but is not limited to these. The reason why two or more combinations can be used is not limited by theory, but each of the sugar chains has specificity for a lectin localized in the tissue or cell of the intended delivery site, Even if they are mixed, they are considered to exhibit their uniqueness.

[0059] 本明細書において糖鎖の組み合せは、含まれる糖鎖と糖鎖との間に「 +」を挿入する ことにより表される。例えば、 Gal jS 1, 3GalNAC j8 1, 4Gal j8 1, 4GlC j8 1 , lCer+ Neu5Ac a 2, 3Gal β 1 , 3GalNAc β 1, 4 (Neu5Ac a 2, 3) Gal j8 1 , 4Glc β 1 , ICer (リボソーム番号 67)と! /、う表記は、 Gal jS 1, 3GalNAC j8 1, 4Gal j8 1, 4Glc β 1, ICerという糖鎖と Neu5Ac α 2, 3Gal j8 1, 3GalNAC j8 1, 4 (Neu5Ac a 2, 3) Gal j8 1, 4G1C J8 1, ICerという糖鎖が混在して含まれることを表す。 [0059] In the present specification, a combination of sugar chains is represented by inserting "+" between the sugar chains contained. For example, Gal jS 1, 3GalNA C j 8 1, 4Gal j8 1, 4Gl C j 8 1, lCer + Neu5Ac a 2, 3Gal β 1, 3GalNAc β 1, 4 (Neu5Ac a 2, 3) Gal j8 1, 4Glc β 1 , ICer (ribosome number 67)! /, The notation is Gal jS 1, 3GalNA C j 8 1, 4Gal j8 1, 4Glc β 1, ICer sugar chain and Neu5Ac α 2, 3Gal j8 1, 3GalNA C j 8 1, 4 (Neu5Ac a 2, 3) Gal j8 1, 4G1 CJ 8 1, represents that ICer contains a mixed sugar chain.

[0060] (リボソーム） 本明細書において「リボソーム」とは、通常、膜状に集合した脂質層お よび内部の水層から構成される閉鎖小胞を意味する。代表的に使用されるリン脂質 のほか、コレステロール、糖脂質などを組み込ませることも可能である。リボソームは 内部に水を含んだ閉鎖小胞であるため、水溶性の薬剤などを小胞内に保持させるこ とも可能である。したがって、このようなリボソームによって、細胞膜を通過しえない薬 物や遺伝子などを細胞内に送達するのに使われる。また、生体適合性も良いので D DS用のナノ粒子性キャリアー材料としての期待が大きい。 [0060] (Ribosome) In this specification, "ribosome" usually means a closed vesicle composed of a lipid layer assembled in a membrane and an aqueous layer inside. In addition to phospholipids typically used, cholesterol, glycolipids, and the like can also be incorporated. Since ribosomes are closed vesicles that contain water inside, it is possible to retain water-soluble drugs in the vesicles. Therefore, these ribosomes are used to deliver drugs and genes that cannot pass through the cell membrane into the cell. Also, because of its good biocompatibility, D There is great expectation as a nanoparticulate carrier material for DS.

[0061] リボソームの調製は、当該分野において公知の任意の手法により製造することができ る。例えば、その中でもコール酸透析法による方法が挙げられる。コール酸透析法で は、 a)脂質と界面活性剤の混合ミセルの調製、および b)混合ミセルの透析により製 造を実施する。次に本発明の糖鎖リボソームにおいて好ましい実施形態では、リンカ 一としてタンパク質を使用することが好ましぐタンパク質に糖鎖が結合した糖タンパ ク質のリボソームへのカップリングは、以下の 2段階反応によって行うことができる。 a) リボソーム膜上のガンダリオシド部分の過ヨウ素酸酸化、および b)還元的アミノ化反 応による酸化リボソームへの糖タンパク質のカップリングである。その反応フローの一 例を図 1に示す。このような手法によって望まし!/ヽ糖鎖を含む糖タンパク質をリポソ一 ムに結合することができ、所望の糖鎖を有する多種多様な糖タンパク質'リボソームコ ンジュゲートを得ることができる。リボソームの純度や安定性を見るために粒径サイズ 分布を調べることが非常に重要である。その方法として、ゲル濾過クロマト法 (GPC) および走査型電顕（SEM)や動的光散乱法 (DLS)などを使うことができる。ジパルミ トイルホスファチジルコリン（DPPC)、コレステロール、ジセチルリン酸（DCP)、ガング リオシドのモル比 35 :45： 5： 15のタイプのリボソームを製造することができる。なお、 このリボソームは 4°Cで数ケ月保存しても安定である。リボソームの in vivoでの安定 性は、マウスを使って調べることができる。リボソームをマウスに静注し、 3時間後に採 血して血清を調製し、孔径 0. 03 mの膜を用いて限外濾過を行いリボソームを精製 し回収する。その SEM観察の結果、このリボソームの形態は in vivoでの 3時間処理 •回収前後にお 、ても変化がな 、ことを確認することができる。  [0061] Ribosomes can be prepared by any technique known in the art. For example, among them, a method using a cholic acid dialysis method is exemplified. In the cholic acid dialysis method, production is carried out by a) preparation of mixed micelles of lipid and surfactant, and b) dialysis of mixed micelles. Next, in a preferred embodiment of the sugar chain ribosome of the present invention, coupling of a glycoprotein having a sugar chain bound to a protein that preferably uses a protein as a linker to the ribosome is performed by the following two-step reaction. Can be done by. a) Periodate oxidation of the gandioside moiety on the ribosome membrane, and b) Coupling of the glycoprotein to the oxidized ribosome by reductive amination reaction. Figure 1 shows an example of the reaction flow. By such a method, a glycoprotein containing a desired! / Sucrose chain can be bound to liposomes, and a wide variety of glycoproteins' ribosome conjugates having the desired sugar chain can be obtained. It is very important to examine the particle size distribution to see the purity and stability of the ribosome. As the method, gel filtration chromatography (GPC), scanning electron microscope (SEM), dynamic light scattering (DLS), and the like can be used. A ribosome of the molar ratio 35: 45: 5: 15 of dipalmitoylphosphatidylcholine (DPPC), cholesterol, dicetyl phosphate (DCP), ganglioside can be produced. This ribosome is stable even when stored at 4 ° C for several months. The stability of ribosomes in vivo can be examined using mice. The ribosome is intravenously injected into the mouse, and after 3 hours, blood is collected to prepare serum, and the ribosome is purified and collected by ultrafiltration using a membrane with a pore size of 0.03 m. As a result of SEM observation, it can be confirmed that the ribosome morphology does not change even before and after recovery for 3 hours in vivo.

[0062] 本発明の糖鎖修飾リボソームを構成する脂質としては、例えば、ホスファチジルコリン 類、ホスファチジルエタノールアミン類、ホスファチジン酸類、長鎖アルキルリン酸塩 類、糖脂質類 (ガンダリオシド類など）、ホスファチジルグリセロール類、スフインゴミエ リン類、コレステロール類等が挙げられる。  [0062] Lipids constituting the sugar chain-modified ribosome of the present invention include, for example, phosphatidylcholines, phosphatidylethanolamines, phosphatidic acids, long-chain alkyl phosphates, glycolipids (gandariosides, etc.), phosphatidylglycerols, and the like. , Sphingomyelins, cholesterols and the like.

[0063] ホスファチジルコリン類としては、ジミリストイルホスファチジルコリン、ジパルミトイルホ スファチジルコリン、ジステアロイルホスファチジルコリン等が挙げられる。  [0063] Examples of phosphatidylcholines include dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, and the like.

[0064] ホスファチジルエタノールアミン類としては、ジミリストイルホスファチジルエタノールァ ミン、ジパルミトイルホスファチジルエタノールァミン、ジステアロイルホスファチジルェ タノールァミン等が挙げられる。 [0064] Examples of phosphatidylethanolamines include dimyristoyl phosphatidylethanolamine. Min, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine and the like.

[0065] ホスファチジン酸類としては、ジミリストイルホスファチジン酸、ジパルミトイルホスファ チジン酸、ジステアロイルホスファチジン酸が挙げられる。長鎖アルキルリン酸塩類と してはジセチルリン酸等が挙げられる。  [0065] Examples of the phosphatidic acids include dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, and distearoyl phosphatidic acid. Examples of long chain alkyl phosphates include dicetyl phosphate.

[0066] 糖脂質類としては、ガラクトシルセラミド、ダルコシルセラミド、ラタトシルセラミド、ホス フナチド、グロボシド、ガンダリオシド類等が挙げられる。ガンダリオシド類としては、ガ ングリオシド GMl (Gal j8 1, 3GalNAC j8 1, 4 (NeuA a 2, 3) Gal j8 1, 4GlC j8 1, 1 ，Cer)、ガンダリオシド GDla、ガンダリオシド GTlb等が挙げられる。 [0066] Examples of the glycolipids include galactosylceramide, dalcosylceramide, latatosylceramide, phosphatide, globoside, and gandiosides. Gandriosides include ganglioside GMl (Gal j8 1, 3GalNA C j 8 1, 4 (NeuA a 2, 3) Gal j8 1, 4Gl C j 8 1, 1, Cer), gandarioside GDla, gandarioside GTlb, etc. It is done.

[0067] ホスファチジルグリセロール類としては、ジミリストイルホスファチジルグリセロール、ジ パルミトイルホスファチジルグリセ口ール、ジステアロイルホスファチジルグリセロール 等が好ましい。  [0067] As the phosphatidylglycerols, dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycose mouth, distearoyl phosphatidylglycerol and the like are preferable.

[0068] このうち、ホスファチジン酸類、長鎖アルキルリン酸塩類、糖脂質類、およびコレステ ロール類はリボソームの安定性を上昇させる効果を有するので、構成脂質として添加 するのが望ましい。例えば、本発明のリボソームを構成する脂質として、ホスファチジ ルコリン類（モル比 0〜70%)、ホスファチジルエタノールアミン類（モル比 0〜30%) 、ホスファチジン酸類、および長鎖アルキルリン酸塩力 なる群力 選択される 1種以 上の脂質 (モル比 0〜30%)、糖脂質類、ホスファチジルグリセロール類およびスフィ ンゴミエリン類力もなる群力も選択される 1種以上の脂質 (モル比 0〜40%)、ならび にコレステロール類（モル比 0〜70%)を含むものが挙げられる。ガンダリオシドのよう な糖脂質を含むことが好まし 、。アルブミンのようなリンカ一の結合が容易になるから である。  [0068] Of these, phosphatidic acids, long-chain alkyl phosphates, glycolipids, and cholesterol have the effect of increasing the stability of ribosomes, so it is desirable to add them as constituent lipids. For example, the lipids constituting the ribosome of the present invention include phosphatidylcholines (molar ratio 0 to 70%), phosphatidylethanolamines (molar ratio 0 to 30%), phosphatidic acids, and long-chain alkyl phosphate groups. Power One or more lipids selected (molar ratio 0-30%), glycolipids, phosphatidylglycerols and sphingomyelins also selected group power One or more lipids (molar ratio 0-40%) And those containing cholesterol (molar ratio 0 to 70%). It is preferable to include glycolipids such as gandarioside. This is because the binding of a linker such as albumin becomes easy.

[0069] 好ま 、実施形態にぉ 、て、本発明におけるリボソームは、ガンダリオシドを含ませて それにペプチドなどのリンカ一を結合させ、糖鎖を結合させることが可能である。  [0069] Preferably, according to the embodiment, the ribosome according to the present invention can contain a gandioside, to which a linker such as a peptide is bound, and to which a sugar chain is bound.

[0070] リボソームを作製するときに糖脂質を合わせることによって、この糖脂質中に含まれる 糖鎖を構成成分として含む、本発明の糖鎖修飾リボソームを作製することができる。  [0070] By combining the glycolipid when producing the ribosome, the sugar chain-modified ribosome of the present invention containing the sugar chain contained in the glycolipid as a constituent component can be produced.

[0071] (糖鎖修飾リボソーム） 1つの局面において、本発明は、糖鎖修飾リボソームを提供 する。従来、生体内では所望の標的細胞または組織に十分にターゲティングするも のは提供されてこな力つた。本発明は、生体内の所望の標的細胞または組織に指向 性有する糖鎖修飾リボソームを提供することにより、従来 DDS材料では不可能であ つたターゲティングが可能になるという効果を有する。具体的な実施形態では、このよ うな糖鎖修飾リボソームは、 Gal、 GalNAc、 Man, Glc、 GlcNAc、 Fuc、 Neu5Ac および Serからなる群より選択される少なくとも 1つの構造を有する糖鎖が結合されて いる。 (Sugar chain modified ribosome) In one aspect, the present invention provides a sugar chain modified ribosome. Traditionally, it is well targeted to the desired target cell or tissue in vivo. It was a great strength that was offered. The present invention has an effect that targeting that has been impossible with conventional DDS materials becomes possible by providing a sugar chain-modified ribosome directed to a desired target cell or tissue in a living body. In a specific embodiment, such a sugar chain-modified ribosome is bound with a sugar chain having at least one structure selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc, Fuc, Neu5Ac and Ser. Yes.

[0072] 本明細書にぉ 、て「糖鎖修飾リボソーム」とは、糖鎖とリボソームとを含む物質を 、 ヽ 、好ましくは、糖鎖が直接または間接的に結合することによって修飾されたリボソーム をいう。糖鎖がリボソームに結合した形態を具体的に表すと、 S—（M)— L (S :糖 鎖、 M :リンカ一（あってもなくてもよい）、 L:リボソーム、—：共有結合のような結合ま たは架橋剤（例えば、 3, 3，一ジチォビス（スルホスクシ-ミジルプロピオネート） (DT SSP) ) )となる。  [0072] As used herein, the term "sugar chain-modified ribosome" refers to a substance containing a sugar chain and a ribosome, preferably a ribosome modified by direct or indirect binding of a sugar chain. Say. Specifically, the form of the sugar chain bound to the ribosome is represented by S— (M) —L (S: sugar chain, M: linker (may or may not be present), L: ribosome, —: covalent bond Or a cross-linking agent such as 3,3,1 dithiobis (sulfosuccinimidyl propionate) (DT SSP))).

[0073] ガンダリオシドをリボソームに入れる場合、本発明の糖鎖修飾リボソームは、 S— M  [0073] When gandarioside is put into a ribosome, the sugar chain-modified ribosome of the present invention contains S—M

-GS -L (GS :ガンダリオシドの糖鎖部分)で表される。  -GS -L (GS: Gandarioside sugar chain)

[0074] より具体的に表すと、本明細書において、糖鎖修飾リボソームの「糖鎖のリボソーム近 位端」とは、リボソームに対して最も近位にある糖鎖の末端部分をいう。糖鎖が分岐し ている場合は、該当する末端部分のすべてを近位端と呼ぶ。糖鎖のリボソーム近位 端の糖は、好ましくは、 Gal、 GalNAc、 Man, Glc、 GlcNAc、 Serまたは Cerであり、 特定の好まし 、実施形態では、 Serまたは Cerである。  More specifically, in this specification, “the ribosome proximal end of a sugar chain” of a sugar chain-modified ribosome refers to the terminal portion of the sugar chain that is most proximal to the ribosome. When the sugar chain is branched, all the corresponding end parts are called the proximal ends. The sugar at the ribosome proximal end of the sugar chain is preferably Gal, GalNAc, Man, Glc, GlcNAc, Ser or Cer, and in a particularly preferred embodiment, Ser or Cer.

[0075] 「糖鎖のリボソーム最近位端」とは、リボソームに対して最も近位にある糖 (単糖)をい う。従って、本明細書において、「糖鎖のリボソーム近位端に二糖以上力もなる糖鎖 が含まれる」というときは、糖鎖のリボソーム近位端には、糖鎖のリボソーム最近位端 にある糖 (単糖)のほかに、上記二糖以上力 なる糖鎖中に含まれる他の糖 (単糖;こ れは、最近位端の糖と同じであっても異なっていてもよい。）も含まれることが理解さ れる。  [0075] The ribosomal proximal end of a sugar chain refers to the sugar (monosaccharide) that is most proximal to the ribosome. Therefore, in the present specification, when “the ribosome proximal end of the sugar chain includes a sugar chain that has more than two sugars”, the proximal ribosome end of the sugar chain is located at the proximal end of the ribosome of the sugar chain. In addition to sugars (monosaccharides), other sugars contained in sugar chains that are more powerful than the above disaccharides (monosaccharides; this may be the same as or different from the most proximal sugar) Is also included.

[0076] 本明細書にぉ 、て、糖鎖修飾リボソームの「糖鎖のリボソーム遠位端」とは、リポソ一 ムに対して最も遠位にある糖鎖の末端部分をいう。糖鎖が分岐している場合は、該当 する末端部分のすべてを遠位端と呼ぶ。糖鎖のリボソーム遠位端の糖は、好ましくは 、 Gal、 3' - (O-SO H) Gal、 GalNAc、 Manおよび Fucまたは Neu5Acであり、特 In the present specification, the “distal end of the ribosome of the sugar chain” of the sugar chain-modified ribosome refers to the terminal portion of the sugar chain that is most distal to the liposome. When the sugar chain is branched, all the corresponding end parts are called the distal ends. The sugar at the ribosome distal end of the sugar chain is preferably Gal, 3 '-(O-SO H) Gal, GalNAc, Man and Fuc or Neu5Ac

3  Three

定の好ましい実施形態では、 3'—（O— SO H) Galである。  In certain preferred embodiments, 3 ′-(O—SO 2 H) Gal.

3  Three

[0077] 「糖鎖のリボソーム最遠位端」とは、リボソームに対して最も遠位にある糖 (単糖)をい う。従って、本明細書において、「糖鎖のリボソーム遠位端に二糖以上力もなる糖鎖 が含まれる」というときは、糖鎖のリボソーム遠位端には、糖鎖のリボソーム最遠位端 にある糖 (単糖)のほかに、上記二糖以上力 なる糖鎖中に含まれる他の糖 (単糖;こ れは、最遠位端の糖と同じであっても異なっていてもよい。）も含まれることが理解さ れる。  [0077] "The most distal end of the ribosome of a sugar chain" refers to a sugar (monosaccharide) that is most distal to the ribosome. Therefore, in the present specification, when “the sugar chain having a disaccharide or more force is included at the distal end of the ribosome of the sugar chain”, the distal end of the sugar chain is the distal end of the ribosome of the sugar chain. In addition to a certain sugar (monosaccharide), other sugars (monosaccharide; this may be the same as or different from the sugar at the most distal end). .) Is also included.

[0078] 特定の好ましい実施形態において、本発明の糖鎖修飾リボソームは、場所にかかわ らず特定の糖鎖パターンを有し得る。「糖鎖パターン」とは、特定の糖鎖の種類、結合 、ァノマーによって決定されるパターンをいう。この糖鎖パターンは、腸粘膜を通過す るのに好ましい糖鎖パターンである。理論に束縛されないが、特定の「相性のよい」パ ターンの糖鎖がどこかに含まれることによって腸粘膜に存在するポンプによる吸収経 路に乗りやすくなるものと考えられる。本発明では、体系的に調査したことろ、以下の 糖鎖パターンを含むと「経口吸収がょ 、」ことがわ力つた。  [0078] In certain preferred embodiments, the sugar chain-modified ribosome of the present invention may have a specific sugar chain pattern regardless of location. “Sugar chain pattern” refers to a pattern determined by the type, bond, and anomer of a specific sugar chain. This sugar chain pattern is a preferable sugar chain pattern for passing through the intestinal mucosa. Without being bound by theory, it is considered that the sugar chain of a specific “good” pattern is included somewhere, making it easier to get on the absorption path by the pump present in the intestinal mucosa. In the present invention, systematic investigations revealed that the following sugar chain patterns included “oral absorption”.

[0079] 場所にかかわらず特定の糖鎖パターンを有し得る糖鎖のパターンとしては、例えば、 以下が挙げられるが、これらに限定されない： 糖鎖修飾リボソームの糖鎖は、以下 の構造: R1— X1— X2— R2を有し、ここで、該 R1および該 R2は、独立して、水素である 力 または任意の糖鎖であり、該 X1は、 Fuc、 GalNAc、 Gal, 3， - (O— SO H) Gal [0079] Examples of sugar chain patterns that may have a specific sugar chain pattern regardless of location include, but are not limited to, the following: The sugar chain of a sugar chain-modified ribosome has the following structure: R 1 — X 1 — X 2 — R 2 , wherein R 1 and R 2 are independently hydrogen or any sugar chain, and X 1 is Fuc, GalNAc , Gal, 3,-(O— SO H) Gal

3 Three

、 GlcNAc、 Manおよび Neu5Acからなる群より選択され、そして該 X2は、 Gal、 Glc 、 GlcNAc、 Ser、 GalNAc、 Cerおよび Manからなる群より選択される、パターン； 糖鎖修飾リボソームの糖鎖は、以下の構造: R1— X1— X2— X3— R2を有し、ここで、 該 R1および該 R2は、独立して、水素であるか、または任意の糖鎖であり、該 X1は、 Fu c、 Gal, GalNAc、 GlcNAc、 Manおよび Neu5Acからなる群より選択され、そして 該 X2は、 Gal、 GlcNAc、 GalNAcおよび Manからなる群より選択され、そして該 X3 は、 Glc、 GlcNAc、 Gal、 GalNAc, Ser、 Cerおよび Manからなる群より選択される 、パターン； 糖鎖修飾リボソームの糖鎖は、以下の構造: RLX1— X2— X3— X4— R 2を有 し、ここで、該 R1および該 R2は、独立して、水素であるか、または任意の糖鎖であり、 該 X1は、 Fuc、 Gal、 Neu5Acおよび Manからなる群より選択され、そして該 X2は、 G al、 GalNAc, GlcNAcおよび Manからなる群より選択され、該 X3は、 GlcNAc、 Gal NAc、 Galおよび Manからなる群より選択され、そして該 X4は、 Gal、 Glc、 Man, Ce rおよび GlcNAcからなる群より選択される、パターン； 糖鎖修飾リボソームの糖鎖は 、以下の構造: R1— X1— X2— X3— X4— X5— R2を有し、ここで、該 R1および該 R2は、 独立して、水素であるか、または任意の糖鎖であり、該 X1は、 Fuc、 Neu5Acおよび Manからなる群より選択され、該 X2は、 Gaほたは Manであり、該 X3は、 GlcNAc, G alNAcおよび Manからなる群より選択され、該 X4は、 Gal, GlcNAcおよび Manから なる群より選択され、そして該 X5は、 Glc、 Cerおよび GlcNAcからなる群より選択さ れる、パターン'， 糖鎖修飾リボソームの糖鎖は、以下の構造: R1— X1— X2— X3— X4 —X5—X6—R2を有し、ここで、該 R1および該 R2は、独立して、水素であるか、または 任意の糖鎖であり、該 X1は、 Manまたは Neu5Acであり、該 X2は、 Manまたは Galで あり、該 X3は、 Manまたは GalNAcであり、該 X4は、 Manまたは Galあり、該 X5は、 G1 cNAcまたは Glcあり、そして該 X6は、 GlcNAcまたは Cerである、パターン。 Selected from the group consisting of GlcNAc, Man and Neu5Ac, and the X 2 is selected from the group consisting of Gal, Glc, GlcNAc, Ser, GalNAc, Cer and Man; the sugar chain of the glycosylated ribosome is Having the following structure: R 1 — X 1 — X 2 — X 3 — R 2 , wherein R 1 and R 2 are independently hydrogen or any sugar chain And X 1 is selected from the group consisting of Fuc, Gal, GalNAc, GlcNAc, Man and Neu5Ac, and X 2 is selected from the group consisting of Gal, GlcNAc, GalNAc and Man, and the X 3 Is selected from the group consisting of Glc, GlcNAc, Gal, GalNAc, Ser, Cer and Man; the sugar chain of the glycosylated ribosome has the following structure: RLX 1 — X 2 — X 3 — X 4 — Have R 2 Wherein R 1 and R 2 are independently hydrogen or any sugar chain, and X 1 is selected from the group consisting of Fuc, Gal, Neu5Ac and Man, And X 2 is selected from the group consisting of Gal, GalNAc, GlcNAc and Man, X 3 is selected from the group consisting of GlcNAc, Gal NAc, Gal and Man, and X 4 is Gal, Glc Selected from the group consisting of, Man, Ce r and GlcNAc; the sugar chain of the glycosylated ribosome has the following structure: R 1 — X 1 — X 2 — X 3 — X 4 — X 5 — R 2 Wherein R 1 and R 2 are independently hydrogen or any sugar chain, and X 1 is selected from the group consisting of Fuc, Neu5Ac and Man, the X 2 is, Ga fireflys is Man, the X 3 is GlcNAc, is selected from the group consisting of G AlNAc and Man, the X 4 is selected from the group consisting Gal, a GlcNAc and Man It is, and said X 5 is Glc, is selected from the group consisting of Cer and GlcNAc, pattern ', sugar of glycosylation ribosomes, the following structure: R 1 - X 1 - X 2 - X 3 - X 4 —X 5 —X 6 —R 2 , wherein R 1 and R 2 are independently hydrogen or any sugar chain, and X 1 is Man or Neu5Ac, the X 2 is Man or Gal, the X 3 is Man or GalNAc, the X 4 is Man or Gal, the X 5 is G1 cNAc or Glc, and the X 6 is a pattern, which is GlcNAc or Cer.

[0080] 特定の好ましい実施形態において、本発明の糖鎖修飾リボソームは、リボソーム遠位 端側に特定の糖鎖パターンを有し得る。理論に束縛されないが、このリボソーム遠位 端側の糖鎖構造は、糖鎖修飾リボソームの外側に存在するので腸粘膜に認識され やすいという特徴があると考えられる。本発明では、体系的に調査したところ、以下の 糖鎖パターンが腸粘膜に認識されやすぐ経口投与に適することがわ力つた。  [0080] In certain preferred embodiments, the sugar chain-modified ribosome of the present invention may have a specific sugar chain pattern on the distal end side of the ribosome. Without being bound by theory, it is considered that the sugar chain structure on the distal end side of the ribosome is characterized by being easily recognized by the intestinal mucosa because it exists outside the sugar chain-modified ribosome. In the present invention, a systematic investigation revealed that the following sugar chain pattern was recognized by the intestinal mucosa and was immediately suitable for oral administration.

[0081] リボソーム遠位端側に特定の糖鎖パターンを有し得る糖鎖パターンとしては、例えば 、以下が挙げられる力 これらに限定されない： 糖鎖修飾リボソームの糖鎖のリポソ 一ム遠位端が、該遠位端側より、以下の構造: Fuc1— A2— Rzを有し、ここで該 A2は 、 Gal、 Glcおよび GlcNAcからなる群より選択され、そして該 Rzは、水素であるか、ま たは任意の糖鎖である、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム遠位端 1S 該遠位端側より、以下の構造: Fuc1— A2— A3— Rzを有し、ここで該 A2は、 Gaほ たは GlcNAcであり、該 A3は、 Glc、 Galおよび GlcNAcからなる群より選択され、そ して該 Rzは、水素であるか、または任意の糖鎖である、パターン； 糖鎖修飾リポソ一 ムの糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造: Fuc1— A2— A3— A4 — RZを有し、ここで該 A2は、 Gaほたは GlcNAであり、該 A3は、 Gaほたは GlcNAで あり、該 A4は、 Gaほたは Glcであり、そして該 Rzは、水素であるか、または任意の糖 鎖である、パターン'， 糖鎖修飾リボソームの糖鎖のリボソーム遠位端が、該遠位端側 より、以下の構造: Fuc1— A2— A3— A4— A5— Rzを有し、ここで該 A2は、 Galであり、 該 A3は、 GlcNAであり、該 A4は、 Galであり、該 A5は、 Glcであり、そして該 Rzは、水 素であるか、または任意の糖鎖である、パターン； 糖鎖修飾リボソームの糖鎖のリポ ソーム遠位端力 該遠位端側より、以下の構造: Gal1— B2— RZを有し、ここで該 Gal1 は、硫酸ィ匕されていても硫酸ィ匕されていなくてもよぐ該 B2は、 Gal、 GalNAc、 GlcN Acおよび Glc力もなる群より選択され、そして該 Rzは、水素であるか、または任意の 糖である、パターン'， 糖鎖修飾リボソームの糖鎖のリボソーム遠位端が、該遠位端側 より、以下の構造: Gal1— B2— B3— RZを有し、ここで該 Gal1は、硫酸化されていても 硫酸化されていなくてもよぐ該 B2は、 GalNAcまたは GlcNAcであり、該 B3は、 Gal であり、そして該 RZは、水素であるか、または任意の糖である、パターン； 糖鎖修飾 リボソームの糖鎖のリボソーム遠位端力 該遠位端側より、以下の構造: Gal1— B2— B3— B4— RZを有し、ここで該 Gal1は、硫酸ィ匕されていても硫酸ィ匕されていなくてもよ ぐ該 B2は、 GalNAcまたは GlcNAcであり、該 B3は、 Galであり、該 B4は、 Glcであり 、そして該 RZは、水素であるか、または任意の糖である、パターン'， 糖鎖修飾リポソ 一ムの糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造: Gal1— B2— B3— B 4— B5— Rzを有し、ここで該 Gal1は、硫酸ィ匕されていても硫酸ィ匕されていなくてもよく 、該 B2は、 GalNAcであり、該 B3は、 Galであり、該 B4は、 Glcであり、該 B5は、 Cerで あり、そして該 RZは、水素であるか、または任意の糖である、パターン'， 糖鎖修飾リ ポソ一ムの糖鎖のリボソーム遠位端力 該遠位端側より、以下の構造: GalNAc1— C 2— RZを有し、ここで該 C2は、 Gaほたは Serであり、そして該 Rzは、水素であるか、ま たは任意の糖である、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム遠位端が、 該遠位端側より、以下の構造: Man1— D2— Rzを有し、ここで該 D2は、 Manであり、 そして該 Rzは、水素であるか、または任意の糖である、パターン； 糖鎖修飾リポソ一 ムの糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造: Man -D2— D3— R zを有し、ここで該 D2は、 Manであり、該 D3は、 GlcNAcまたは Manであり、そして該 RZは、水素であるか、または任意の糖である、パターン； 糖鎖修飾リボソームの糖鎖 のリボソーム遠位端力 該遠位端側より、以下の構造: Man -D2— D3— D4— Rzを 有し、ここで該 D2は、 Manであり、該 D3は、 Manまたは GlcNAcであり、該 D4は、 Ma nまたは GlcNAcであり、そして該 Rzは、水素であるか、または任意の糖である、パタ ーン； 糖鎖修飾リボソームの糖鎖のリボソーム遠位端が、該遠位端側より、以下の構 造： Man1— D2— D3— D4— D5— Rzを有し、ここで該 D2は、 Manであり、該 D3は、 M anであり、該 D4は、 Manまたは GlcNAcであり、該 D5は、 GlcNAcであり、そして該 R zは、水素であるか、または任意の糖である、パターン； 糖鎖修飾リボソームの糖鎖 のリボソーム遠位端力 該遠位端側より、以下の構造: Mar^-D2— D3— D4— D5— D6— Rzを有し、ここで該 D2は、 Manであり、該 D3は、 Manであり、該 D4は、 Manであ り、該 D5は、 GlcNAcであり、該 D6は、 GlcNAcであり、そして該 Rzは、水素であるか 、または任意の糖である、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム遠位端 力 該遠位端側より、以下の構造: NeuSAc1— E2— RZを有し、ここで該 E2は、 Gaほ たは GalNAcであり、そして該 RZは、水素であるか、または任意の糖である、パターン ； 糖鎖修飾リボソームの糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造： NeuSAc1— E2— E3— RZを有し、ここで該 E2は、 Galまたは GalNAcであり、該 E3は 、 GlcNAc, Glc、 GalNAcおよび Serからなる群より選択され、そして該 Rzは、水素 であるか、または任意の糖である、パターン； 糖鎖修飾リボソームの糖鎖のリポソ一 ム遠位端が、該遠位端側より、以下の構造: NeuSAc1— E2— E3— E4— Rzを有し、こ こで該 E2は、 Galであり、該 E3は、 Glcおよび GalNAcからなる群より選択され、該 E4 は、 Galおよび Cerからなる群より選択され、そして該 Rzは、水素であるか、または任 意の糖である、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム遠位端が、該遠位 端側より、以下の構造: NeuSAc1— E2— E3— E4— E5— Rzを有し、ここで該 E2は、 G alであり、該 E3は、 GalNAcであり、該 E4は、 Galであり、該 E5は、 Glcであり、そして 該 RZは、水素であるか、または任意の糖である、パターン； 糖鎖修飾リボソームの糖 鎖のリボソーム遠位端力 該遠位端側より、以下の構造: NeuSAc1— E2— E3— E4— E5— E6— RZを有し、ここで該 E2は、 Galであり、該 E3は、 GalNAcであり、該 E4は、 G alであり、該 E5は、 Glcであり、該 E6は、 Cerであり、そして該 Rzは、水素であるか、ま たは任意の糖である、パターン。 [0081] Examples of the sugar chain pattern that can have a specific sugar chain pattern on the distal end side of the ribosome include, but are not limited to, the following: Liposome distal end of the sugar chain of the sugar chain-modified ribosome From the distal end side has the following structure: Fuc 1 — A 2 — R z , where A 2 is selected from the group consisting of Gal, Glc and GlcNAc, and the R z is Hydrogen or any sugar chain, pattern; ribosome distal end of sugar chain of sugar chain modified ribosome 1S From the distal end side, the following structure: Fuc 1 — A 2 — A 3 — or have R z, wherein said a 2 are, Ga ho was is GlcNAc, the a 3 is Glc, is selected from the group consisting of Gal and GlcNAc, the R z and its is hydrogen Or a pattern that is an arbitrary sugar chain; The ribosome distal end of the sugar chain has the following structure from the distal end side: Fuc 1 — A 2 — A 3 — A 4 — R Z , where A 2 is Ga Is GlcNA, the A 3 is Ga or GlcNA, the A 4 is Ga or Glc, and the R z is hydrogen or any sugar chain. Pattern ', The ribosome distal end of the sugar chain of the sugar chain-modified ribosome has the following structure from the distal end side: Fuc 1 — A 2 — A 3 — A 4 — A 5 — R z The A 2 is Gal, the A 3 is GlcNA, the A 4 is Gal, the A 5 is Glc, and the R z is hydrogen, or Any sugar chain, pattern; Liposome distal end force of sugar chain of sugar chain modified ribosome From the distal end side, it has the following structure: Gal 1 — B 2 — R Z , where the Gal 1, Yogu also be sulfuric acid I spoon not be sulfuric acid I spoon B 2 is Gal, GalNAc, is selected from the also the group GlcN Ac and Glc force, and said R z is hydrogen or is any sugar pattern ', far ribosomes sugar chain glycosylation ribosome The distal end has the following structure from the distal end side: Gal 1 — B 2 — B 3 — R Z , where Gal 1 is either sulfated or not sulfated. The B 2 is GalNAc or GlcNAc, the B 3 is Gal, and the R Z is hydrogen or any sugar pattern; sugar chain modification of the ribosomal sugar chain Ribosome distal end force From the distal end side, it has the following structure: Gal 1 — B 2 — B 3 — B 4 — R Z , where Gal 1 is sulfated even though it is sulfated. spoon good instrument the B 2 even though it is not is GalNAc or GlcNAc, the B 3 is Gal, the B 4 is Glc, and said R Z is hydrogen, Others are any sugar, pattern ', ribosome distal end of the sugar chain glycosylation Liposomes Ichimu is from distal end side, the following structure: Gal 1 - B 2 - B 3 - B 4 - B 5 —R z , where the Gal 1 may be sulfated or unsulfated, the B 2 is GalNAc, and the B 3 is Gal The B 4 is Glc, the B 5 is Cer, and the R Z is hydrogen or any sugar, the pattern ', the sugar of the glycosylated liposome Ribosome distal end force of chain From the distal end side, it has the following structure: GalNAc 1 — C 2 — R Z , where C 2 is Ga, Ser, and R z is , Hydrogen, or any sugar, pattern; the ribosome distal end of the sugar chain of the sugar chain-modified ribosome has the following structure: Man 1 — D 2 — R z Where D 2 is Man and The R z is hydrogen or an arbitrary sugar pattern; the ribosome distal end of the sugar chain of the sugar chain-modified liposome has the following structure from the distal end side: Man -D 2 — D 3 — R wherein D 2 is Man, the D 3 is GlcNAc or Man, and the R Z is hydrogen or any sugar, pattern; glycosylation The ribosome distal end force of the ribosomal sugar chain has the following structure from the distal end side: Man -D 2 — D 3 — D 4 — R z , where D 2 is Man, D 3 is Man or GlcNAc, the D 4 is Man or GlcNAc, and the R z is hydrogen or any sugar pattern; sugar of sugar chain-modified ribosome The ribosome distal end of the chain has the following structure from the distal end side: Man 1 — D 2 — D 3 — D 4 — D 5 — R z , where D 2 is Man The D 3 is Man, the D 4 is Man or GlcNAc, the D 5 is GlcNAc, and the R z is hydrogen or any sugar, Pattern; sugar chain-modified ribosome From ribosomal distal end forces the distal end side of the sugar chain, the following structure: Mar ^ -D 2 - D 3 - D 4 - D 5 - D 6 - have R z, wherein said D 2 is Man, the D 3 is Man, the D 4 is Man, the D 5 is GlcNAc, the D 6 is GlcNAc, and the R z is hydrogen Or a pattern that is an arbitrary sugar; the ribosome distal end of the sugar chain of the sugar chain-modified ribosome has the following structure: NeuSAc 1 — E 2 — R Z from the distal end side, where E 2 is Ga or GalNAc, and the R Z is hydrogen or any sugar, the pattern; the ribosome distal end of the sugar chain of the sugar chain-modified ribosome is the distal end From the side, it has the following structure: NeuSAc 1 — E 2 — E 3 — R Z , where E 2 is Gal or GalNAc, where E 3 is a group consisting of GlcNAc, Glc, GalNAc and Ser And R z is , Hydrogen, or any sugar, pattern; the liposome distal end of the sugar chain of the sugar chain-modified ribosome has the following structure: NeuSAc 1 — E 2 — E 3 — E 4 — Rz , where E 2 is Gal, E 3 is selected from the group consisting of Glc and GalNAc, and E 4 is selected from the group consisting of Gal and Cer And the R z is hydrogen or any sugar, the pattern; the ribosome distal end of the sugar chain of the sugar chain-modified ribosome has the following structure from the distal end side: NeuSAc 1 — E 2 — E 3 — E 4 — E 5 — R z , where E 2 is Gal, E 3 is GalNAc, E 4 is Gal, and E 5 is a Glc, and said R Z is hydrogen or is any sugar pattern; of glycosylation ribosomes from ribosomal distal end forces the distal end side of the sugar chains, the following Concrete: NeuSAc 1 - E 2 - E 3 - E 4 - E 5 - E 6 - have a R Z, wherein said E 2 is Gal, the E 3 is a GalNAc, the E 4 is , G a pattern wherein the E 5 is Glc, the E 6 is Cer and the R z is hydrogen or any sugar.

[0082] 特定の好ましい実施形態において、本発明の糖鎖修飾リボソームは、リボソーム近位 端側に特定の糖鎖パターンを有し得る。この糖鎖パターンはリボソーム側にあり、理 論に束縛されないが、糖鎖パターン自体が固定されており、腸粘膜による認識が安 定的になされるので吸収性がよくなると考えられる。さらにこれらの構造パターンを有 することにより、リボソームの安定性が向上されることも経口吸収性の向上に寄与して いるものと考えられる。 [0082] In certain preferred embodiments, the sugar chain-modified ribosome of the present invention may have a specific sugar chain pattern on the proximal end side of the ribosome. Although this sugar chain pattern is on the ribosome side and is not bound by theory, it is thought that the sugar chain pattern itself is fixed and the absorption by the intestinal mucosa is stabilized, so that the absorbability is improved. Furthermore, by having these structural patterns, the stability of ribosome is also considered to contribute to the improvement of oral absorption.

[0083] リボソーム近位端側に特定の糖鎖パターンを有し得る糖鎖パターンとしては、例えば 、以下が挙げられる力 これらに限定されない： 糖鎖修飾リボソームの糖鎖のリポソ 一ム近位端力 以下の構造: R1— F2— GlcNAc3を有し、ここで該 R [0083] Examples of the sugar chain pattern that may have a specific sugar chain pattern on the proximal end side of the ribosome include, but are not limited to, the following: Liposome proximal end of the sugar chain of the sugar chain-modified ribosome Force has the following structure: R 1 — F 2 — GlcNAc 3 where R

1は、独立して、水素であるか、または任意の糖鎖であり、該 F2は、 Gal、 Fuc、 GlcN Acおよび 3，一（O— SO H) Galからなる群より選択され、ここで該 GlcNAc3はリポソ 1 is independently hydrogen or any sugar chain, and the F 2 is selected from the group consisting of Gal, Fuc, GlcN Ac and 3, one (O—SO H) Gal, The GlcNAc 3 is

3  Three

ームの最近位端に存在する、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム近 位端が、以下の構造: R1— F2— F3— GlcNAc4を有し、ここで該 R1は、独立して、水 素であるか、または任意の糖鎖であり、該 F2は、 Man、 Fucおよび Neu5Acから選択 される糖であり、該 F3は、 Gaほたは GlcNAcであり、ここで該 GlcNAc4はリボソーム の最近位端に存在する、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム近位端 力 以下の構造: R1— F2— F3— F4— GlcNAc5を有し、ここで該 F1は、独立して、水 素であるか、または任意の糖鎖であり、該 F2は、 Manであり、該 F3は、 Manであり、該 F4は、 GlcNAcであり、ここで該 GlcNAc5はリボソームの最近位端に存在する、パタ ーン； 糖鎖修飾リボソームの糖鎖のリボソーム近位端が、以下の構造: R1— F2— F3 — F4— F5— GlcNAc6を有し、ここで該 R1は、独立して、水素であるか、または任意の 糖鎖であり、該 F2は、 Manであり、該 F3は、 Manであり、該 F4は、 Manであり、該 F5 は、 GlcNAcであり、ここで該 GlcNAc6はリボソームの最近位端に存在する、パター ン； 糖鎖修飾リボソームの糖鎖のリボソーム近位端が、以下の構造: R1— F2— F3— F4— F5— F6— GlcNAc7を有し、ここで該 R1は、独立して、水素であるか、または任 意の糖鎖であり、該 F2は、 Manであり、該 F3は、 Manであり、該 F4は、 Manであり、該 F5は、 Manであり、該 F6は、 GlcNAcであり、ここで該 GlcNAc7はリボソームの最近 位端に存在する、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム近位端が、以 下の構造: R1— G2— Gal3を有し、ここで該 R1は、独立して、水素であるか、または任 意の糖鎖であり、該 G2は、 Fuc、 Galおよび GalNacからなる群より選択され、ここで G afはリボソームの最近位端に存在する、パターン； 糖鎖修飾リボソームの糖鎖のリ ポソ一ム近位端力 以下の構造: I^— H2— GalNAc3を有し、ここで該 R1は、独立し て、水素であるか、または任意の糖鎖であり、そして該 H2は、 Galであり、ここで GalN Ac3はリボソームの最近位端に存在する、パターン； 糖鎖修飾リボソームの糖鎖のリ ポソ一ム近位端力 以下の構造: R1— I2— Ser3を有し、ここで該 R1は、独立して、水 素であるか、または任意の糖鎖であり、そして該 I2は、 GalNAcであり、ここで Ser3はリ ポソームの最近位端に存在する、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム 近位端が、以下の構造: R1— I2— I3— Ser4を有し、ここで該 R1は、独立して、水素で あるか、または任意の糖鎖であり、そして該 I2は、 Neu5Acであり、該 fは、 GalNAc であり、ここで Ser4はリボソームの最近位端に存在する、パターン； 糖鎖修飾リポソ 一ムの糖鎖のリボソーム近位端力 以下の構造: R1— J2— Glc3を有し、ここで該 R1は 、独立して、水素であるか、または任意の糖鎖であり、そして 2は、 Gaほたは Fuc であり、ここで Glc3はリボソームの最近位端に存在する、パターン； 糖鎖修飾リポソ 一ムの糖鎖のリボソーム近位端力 以下の構造: R1— J2— J3— Glc4を有し、ここで該 R 1は、独立して、水素であるか、または任意の糖鎖であり、そして謝2は、 Fuc、 GlcN Acおよび Neu5Acからなる群より選択され、ここで謝3は、 Galであり、ここで Glc4はリ ポソームの最近位端に存在する、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム 近位端が、以下の構造:

Figure imgf000026_0001
ここで該 R1は、独立して、水 素であるか、または任意の糖鎖であり、そして謝2は、 Fucまたは Galであり、謝3は、 GlcNAcであり、言 4は、 Galであり、ここで Glc5はリボソームの最近位端に存在する、 パターン； 糖鎖修飾リボソームの糖鎖のリボソーム近位端が、以下の構造: R1- - J3— J4 J5— Glc6を有し、ここで該 R1は、独立して、水素であるか、または任意の糖鎖 であり、善 2は、 Fucであり、善 3は、 Galであり、善 4は、 GlcN Acまたは GalN Acで あり、謝5は、 Galであり、ここで Glc6はリボソームの最近位端に存在する、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム近位端力 以下の構造: R1— K2— Man3を 有し、ここで該 R1は、独立して、水素であるか、または任意の糖鎖であり、そして該 K2 は、 Manであり、ここで Man3はリボソームの最近位端に存在する、パターン； 糖鎖 修飾リボソームの糖鎖のリボソーム近位端力 以下の構造: R1— L2— Cer3を有し、こ こで該 R1は、独立して、水素であるか、または任意の糖鎖であり、そして該 L2は、 Glc であり、ここで Cer3はリボソームの最近位端に存在する、パターン； 糖鎖修飾リポソ 一ムの糖鎖のリボソーム近位端力 以下の構造: R1— L2— L3— Cer4を有し、ここで該 R1は、独立して、水素であるか、または任意の糖鎖であり、そして該 L2は、 Galであり 、該 L3は、 Glcであり、ここで Cer4はリボソームの最近位端に存在する、パターン； 糖 鎖修飾リポソ一ムの糖鎖のリボソーム近位端が、以下の構造： R1— L2— L3— L4— Ce r5を有し、ここで該 R1は、独立して、水素であるか、または任意の糖鎖であり、そして 該 L2は、 GalNAcまたは Neu5Acであり、該 L3は、 Galであり、該 L4は、 Glcであり、こ こで Cer5はリボソームの最近位端に存在する、パターン； 糖鎖修飾リボソームの糖 鎖のリボソーム近位端力 以下の構造: R1— L2— L3— L4— L5— Cer6を有し、ここで 該 R1は、独立して、水素であるか、または任意の糖鎖であり、該 L2は、 Galであり、該 L3は、 GalNAcであり、該 L4は、 Galであり、該 L5は、 Glcであり、ここで Cer6はリポソ ームの最近位端に存在する、パターン； 糖鎖修飾リボソームの糖鎖のリボソーム近 位端が、以下の構造: R1— L2— L3— L4— L5— L6— Cer7を有し、ここで該 R1は、独立 して、水素であるか、または任意の糖鎖であり、該 L2は、 Neu5Acであり、該 L3は、 G alであり、該 L4は、 GalNacであり、該 L5は、 Galであり、該 L6は、 Glcであり、ここで Ce r7はリボソームの最近位端に存在する、パターン。 Present in the most proximal end of the over-time, the pattern; ribosome proximal end of the sugar chain glycosylation ribosomes, the following structure: R 1 - F 2 - F 3 - GlcNAc 4 has, wherein said R 1 Is independently hydrogen or any sugar chain, F 2 is a sugar selected from Man, Fuc and Neu5Ac, and F 3 is Ga or GlcNAc. , wherein said GlcNAc 4 is present in the proximal-most end of the ribosome, the pattern; carbohydrate in glycosylation ribosome ribosome proximal end forces the following structure: R 1 - F 2 - F 3 - F 4 - a GlcNAc 5 Wherein F 1 is independently hydrogen or any sugar chain, F 2 is Man, F 3 is Man, and F 4 is , GlcNAc, where GlcNAc 5 is present at the proximal end of the ribosome; the ribosome proximal end of the sugar chain of the sugar chain modified ribosome has the following structure: R 1 — F 2 — F 3 — F 4 — F 5 — GlcNAc 6 , wherein R 1 is independently hydrogen or any sugar chain, F 2 is Man, F 3 is Man, the F 4 is Man, and the F 5 is GlcNAc, where the GlcNAc 6 is present at the proximal end of the ribosome; the sugar of the sugar chain-modified ribosome The ribosome proximal end of the chain has the following structure: R 1 — F 2 — F 3 — F 4 — F 5 — F 6 — GlcNAc 7 , where R 1 is independently hydrogen Or any sugar chain, the F 2 is Man, the F 3 is Man, the F 4 is Man, and F 5 is Man, the F 6 is GlcNAc, where the GlcNAc 7 is present at the proximal end of the ribosome, the pattern; the ribosome proximal end of the sugar chain of the sugar chain modified ribosome is Structure: R 1 —G 2 —Gal 3 where R 1 is independently hydrogen or any sugar chain, and G 2 is Fuc, Gal and GalNac is selected from the group consisting of, wherein G af the present proximal-most end of the ribosome, the pattern; glycosylation ribosomal sugar Li Pozo Ichimu proximal end forces the following structure: I ^ - H 2 - With GalNAc 3 , where R 1 is independently hydrogen or any sugar chain, and the H 2 is Gal, where GalN Ac 3 is the nearest position of the ribosome present in the end, the pattern; glycosylation ribosomes sugar chain re Pozo Ichimu proximal end forces the following structure: R 1 - I 2 - has a Ser 3, wherein said R 1 is German And either are water prime, or any sugar chain, and said I 2 is GalNAc, where Ser 3 is present in the proximal-most end of the liposome, the pattern; glycosylation ribosome sugar The proximal end of the ribosome of the chain has the following structure: R 1 — I 2 — I 3 — Ser 4 where R 1 is independently hydrogen or any sugar chain The I 2 is Neu5Ac and the f is GalNAc, where Ser 4 is present at the proximal end of the ribosome, the pattern; the ribosomal proximal force of the sugar chain of the sugar chain modified liposome It has the following structure: R 1 —J 2 —Glc 3 where R 1 is independently hydrogen or any sugar chain, and 2 is Ga or Fuc There, where Glc 3 is present in the proximal-most end of the ribosome, the pattern; glycosylation Liposomes Ichimu sugar chain ribosome proximal end forces the following structure: R 1 J 2 - J 3 - has a Glc 4, wherein said R 1 is independently a hydrogen, or any sugar chain, and Xie 2, Fuc, the group consisting of GlcN Ac and Neu5Ac Xe 3 is Gal, where Glc 4 is present at the proximal end of the liposome, the pattern; the ribosome proximal end of the sugar chain of the glycosylated ribosome has the following structure:
Figure imgf000026_0001
Where R 1 is independently hydrogen or any sugar chain, and Xie 2 is Fuc or Gal, Xie 3 is GlcNAc, and Word 4 is Gal. Yes, where Glc 5 is present at the proximal end of the ribosome, pattern; the ribosome proximal end of the sugar chain of the glycosylated ribosome has the following structure: R 1 --J 3 — J 4 J 5 — Glc 6 Where R 1 is independently hydrogen or any sugar chain, good 2 is Fuc, good 3 is Gal, and good 4 is GlcN Ac Or GalN Ac, Xie 5 is Gal, where Glc 6 is present at the proximal end of the ribosome, pattern; The ribosome proximal end force of the sugar chain of the sugar chain-modified ribosome has the following structure: R 1 — K 2 — Man 3 where R 1 is independently hydrogen or any sugar chain And the K 2 is Man, where Man 3 is present at the proximal end of the ribosome, the pattern; sugar chain modified ribosome sugar end force of the sugar chain of the modified ribosome The following structure: R 1 — L 2— has Cer 3 , where R 1 is independently hydrogen or any sugar chain, and L 2 is Glc, where Cer 3 is ribosomal The pattern present at the most proximal end; the ribosome proximal end force of the sugar chain of the glycosylated liposome has the following structure: R 1 — L 2 — L 3 — Cer 4 where R 1 is independently, is hydrogen or is any sugar chain, and said L 2 is Gal, said L 3 is Glc, wherein Cer 4 the most proximal of the ribosome Present in the pattern; glycosylation Liposomes ribosome proximal end of the sugar chain Ichimu is the following structure: R 1 - L 2 - L 3 - L 4 - has a Ce r 5, wherein said R 1 Is independently hydrogen or any sugar chain, and the L 2 is GalNAc or Neu5Ac, the L 3 is Gal, and the L 4 is Glc, Here Cer 5 is present at the proximal end of the ribosome, the pattern; the ribosome proximal end force of the sugar chain of the sugar chain modified ribosome The following structure: R 1 — L 2 — L 3 — L 4 — L 5 — Cer 6 Where R 1 is independently hydrogen or any sugar chain, the L 2 is Gal, the L 3 is GalNAc, and the L 4 is , Gal, and L 5 is Glc, where Cer 6 is present at the proximal end of the liposome, the pattern; the ribosome proximal end of the sugar chain of the sugar chain-modified ribosome has the following structure: R 1 L 2 - L 3 - L 4 - L 5 - L 6 - have Cer 7, wherein said R 1 is independently a hydrogen, or any sugar chain, wherein L 2 is Neu5Ac, L 3 is Gal, L 4 is GalNac, L 5 is Gal, L 6 is Glc, where Cer 7 is the most recent ribosome A pattern that exists at the edge.

[0084] 特定の好ましい実施形態において、本発明の糖鎖修飾リボソームは、両端に特定の 糖を有し得る。理論に束縛されないが、特定の糖を有することによって、糖鎖の腸粘 膜に対する親和性が高まり、リボソームの安定性が向上されることも経口吸収性の向 上に寄与して 、るものと考えられる。  [0084] In certain preferred embodiments, the sugar chain-modified ribosome of the present invention may have a specific sugar at both ends. Without being bound by theory, having a specific sugar increases the affinity of the sugar chain for the intestinal mucosa and improves the stability of the ribosome, which also contributes to the improvement of oral absorption. Conceivable.

[0085] 両端に特定の糖を有し得るパターンとしては、例えば、以下が挙げられる力 これら に限定されない： 糖鎖のリボソーム最近位端の糖力 Glcまたは GlcNAcであり、か つ前記糖鎖のリボソーム最遠位端の糖力 SGaほたは Fucである、パターン； 糖鎖のリ 、。VN。IOS'I O[0085] Examples of patterns that may have specific sugars at both ends include, but are not limited to, the following: The sugar power of the most proximal ribosome of the sugar chain is Glc or GlcNAc, and the sugar chain The sugar force at the distal end of the ribosome SGa is Fuc, pattern; ,. VN. IOS'I O

、。VN。IO ' iq。VN。IO iqus^(s' ^UBWS' ^UB^)9' ^UB^(S' ^UB^)9' ^UB^,. VN. IO 'iq. VN. IO iqus ^ (s' ^ UBWS '^ UB ^) 9 ' ^ UB ^ (S '^ UB ^) 9 ' ^ UB ^

、。VN。I09'I 0 ,. VN. I09'I 0

、。VN。IO ' iq。VN。IO iqus^(s' UB^S' ^UBWS' ^UB^)9' ^UB^(S' ^UB^)9' ^UB^ ,. VN. IO 'iq. VN. IO iqus ^ (s 'UB ^ S' ^ UBWS '^ UB ^) 9' ^ UB ^ (S '^ UB ^) 9' ^ UB ^

、。VN。io 'iq。v ,. VN. io 'iq. v

Ν°ΪΟ^' i u^ CS' ΐ^ ζ' ΐ^ ζ' ΐ^ )9' TBUB (S' ΐΏυΏ 2' ΐΏυΏ )9' ΐΏυΏ 2' TBUB Ν ° ΪΟ ^ 'iu ^ CS' ΐ ^ ζ 'ΐ ^ ζ' ΐ ^) 9 'T BUB (S' ΐ ΏυΏ 2 'ΐ ΏυΏ ) 9' ΐ ΏυΏ 2 'T BUB

、。VN。IO i °VNoio^' i u^ Cs' T^ S' T^ S' Ϊ^ )9' ΐΏΥΏ (ε' ΐΏΥΏ )9' ΐΏΥΏ 2' TBUB ,. VN. IO i ° VN o io ^ 'iu ^ Cs' T ^ S 'T ^ S' Ϊ ^) 9 'ΐ ΏΥΏ (ε' ΐ )) 9 'ΐ ΏΥΏ 2' T BUB

^VN^lOCS'T^Wiqpo^eOS-O)-^ ^ VN ^ lOCS'T ^ Wiqpo ^ eOS-O)-^

FO(2'TBont[)S'T∞VNFO FO (2'T Bon t [) S'T∞VNFO

、。VN。 ΐ 0 ,. VN. ΐ 0

、おつ ΐ ' ΐ q。io ' ΐ po(s'2B°ven9N8 ' Z^V ^ )V ι q^vNPos'i qpo , Otsu ΐ 'ΐ q. io 'ΐ po (s'2 B ° ven9N8' Z ^ V ^) V ι q ^ vNPos'i qpo

iq OS' 。 VSnsN

Figure imgf000028_0001
iq OS '. VSnsN
Figure imgf000028_0001

\«"¥P} ^^¾«^¾¾ に)マー fi¾潘讓 ェ、 ¾^暈咪 ½本 [9800]  \ «" ¥ P} ^^ ¾ «^ ¾¾) Ma fi¾ 潘 讓 e, ¾ ^ 暈 咪 ½ [9800]

。ぺ一 ¾^UB ^¾

Figure imgf000028_0002
軎マ一ん . Peichi ¾ ^ UB ^ ¾
Figure imgf000028_0002
Samurai

Z88STC/900Zdf/X3d ιζ Manal,2Man、 Z88STC / 900Zdf / X3d ιζ Manal, 2Man,

Galbl,4(Fucal,3)GlcNAcゝ Galbl, 4 (Fucal, 3) GlcNAc ゝ

Galal,3Gal、 Galal, 3Gal,

Fucal,2Galbl,4Glcゝ Fucal, 2Galbl, 4Glc ゝ

Manal ,6(Manal ,3)Manal ,6Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manal, 6Manbl, 4GlcNAcbl, 4GlcNAc,

Galbl,4(Fucal,3)Glcゝ  Galbl, 4 (Fucal, 3) Glc ゝ

GalNAca 1—O—L— serine、  GalNAca 1—O—L—serine,

Neu5Aca2,3Galbl,4(Fucal,3)GlcNAcゝ  Neu5Aca2,3Galbl, 4 (Fucal, 3) GlcNAc ゝ

Fucal ,2Galbl ,4(Fucal ,3)GlcNAcゝ  Fucal, 2Galbl, 4 (Fucal, 3) GlcNAc ゝ

Galbl,4Glc、  Galbl, 4Glc,

Manal,6Man、  Manal, 6Man,

Neu5Aca2,6GalNAcal— O—L— serineゝ  Neu5Aca2,6GalNAcal— O—L— serine ゝ

Manal ,6(Manal ,3)Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,

Fucal ,2Galbl ,3(Fucal ,4)GlcNAcゝ  Fucal, 2Galbl, 3 (Fucal, 4) GlcNAc ゝ

Manal,4Man^  Manal, 4Man ^

Neu5Ac2 ,6GalNAcaト O-L- serine、  Neu5Ac2, 6GalNAca to O-L-serine,

Neu5Aca2,6Galbl,4Glcゝ Neu5Aca2,6Galbl, 4Glc ゝ

Fucal ,2Galbl ,3(Fucal ,4)GlcNAcbl ,3Galbl ,4Glc,  Fucal, 2Galbl, 3 (Fucal, 4) GlcNAcbl, 3Galbl, 4Glc,

Galb l,3GalNAcb 1 ,4(Neu5Aca2 , 3)Galb 1 ,4Glcb 1 , 1 Cer、  Galb l, 3GalNAcb 1, 4 (Neu5Aca2, 3) Galb 1, 4Glcb 1, 1 Cer,

Manal ,6(Manal ,3)Manal ,6(Manal ,3)Manbl ,4GlcNAcbl ,4GlcNAc,  Manal, 6 (Manal, 3) Manal, 6 (Manal, 3) Manbl, 4GlcNAcbl, 4GlcNAc,

Manal,3Man、  Manal, 3Man,

Neu5Aca2,3Galbl,3(Fucal,4)GlcNAcゝ  Neu5Aca2,3Galbl, 3 (Fucal, 4) GlcNAc ゝ

3'- (O- S03H)Galbl,3(Fucal,4)GlcNAc、 3'- (O- S03H) Galbl, 3 (Fucal, 4) GlcNAc,

Neu5Aca2 ,3Galb 1 ,4GlcNAc、 Neu5Aca2, 3Galb 1, 4GlcNAc,

Galbl,3(Fucal,4)GlcNAcゝ Galbl, 3 (Fucal, 4) GlcNAc ゝ

ならびにそれらの 2つ以上の任意の比率での組み合わせ力 なる群より選択された 糖鎖により修飾されたリボソームが挙げられる。 And a ribosome modified with a sugar chain selected from the group consisting of a combination of two or more in any ratio.

本明細書において使用される場合「リボソーム番号」とは、以下の表 1、表 2、表 3に示 される糖鎖を結合した糖鎖修飾リボソームを参照する番号である。 As used herein, “ribosome number” refers to the following Table 1, Table 2, and Table 3. The number refers to the sugar chain-modified ribosome to which the sugar chain is bound.

[0088] 本明細書において使用される糖鎖修飾リボソームは、例えば、表 1に示される糖鎖が 腸管から血中への移行のために適切な密度で含まれ得る。  [0088] The sugar chain-modified ribosome used in the present specification may contain, for example, the sugar chains shown in Table 1 at a density suitable for transferring from the intestinal tract into the blood.

[0089] 本明細書において使用する場合、「修飾結合密度」とは、糖鎖修飾リボソームを作製 する際に使用される糖鎖の量であり、リボソームの脂質 lmgあたりに結合した糖鎖の 密度 (mg糖鎖 Zmg脂質)として表される。本発明の糖鎖修飾リボソームの結合密度 は、理論に束縛されることを望まないが、経験的に、調製するときに使用した糖鎖の 量は、リボソームに結合した糖鎖の密度にほぼ比例していることが分力つている。従 つて、本明細書では、特に言及しない限り、調製時に使用した量によって結合密度が 確定される。インビト口において、例えば、 E—セレクチンを用いて間接的に決定する ことができる。本発明の糖鎖修飾リボソームは、リボソームに結合される糖鎖の種類と 結合密度を選択することにより、目的の送達部位に対する指向性を制御することがで きる。以下、表 1にリボソーム番号、糖鎖の構造、修飾結合密度およびその経口投与 (経腸)指向性を示す。  [0089] As used herein, "modified bond density" is the amount of sugar chains used in preparing sugar chain-modified ribosomes, and the density of sugar chains bound per mg of lipid in the ribosome. It is expressed as (mg sugar chain Zmg lipid). Although the binding density of the sugar chain-modified ribosome of the present invention is not desired to be bound by theory, empirically, the amount of sugar chain used in the preparation is almost proportional to the density of sugar chains bound to the ribosome. What you are doing is divided. Therefore, in this specification, unless otherwise stated, the bond density is determined by the amount used during preparation. In the in vitro mouth, for example, it can be determined indirectly using E-selectin. The sugar chain-modified ribosome of the present invention can control the directivity with respect to the intended delivery site by selecting the type of sugar chain to be bound to the ribosome and the binding density. Table 1 below shows the ribosome number, sugar chain structure, modified bond density, and oral administration (enteral) directivity.

[0090] [表 1] [0090] [Table 1]

Figure imgf000031_0001
Figure imgf000031_0001

[0091] 「 + +」は、糖鎖の代わりにトリス (ヒドロキシメチル)ァミノメタンを結合させたリボソーム  [0091] “++” is a ribosome in which tris (hydroxymethyl) aminomethane is bound instead of a sugar chain

(基準リボソーム)を経口投与した場合、投与 10分後に腸管により吸収されたリポソ一 ムの平均値が基準リボソームの平均値の 4〜6倍になることを表す。  When (reference ribosome) is administered orally, the average value of liposomes absorbed by the intestinal tract 10 minutes after administration is 4 to 6 times the average value of reference ribosome.

[0092] 「 +」は、糖鎖の代わりにトリス (ヒドロキシメチル)ァミノメタンを結合させたリボソーム（ 基準リボソーム)を経口投与した場合、投与 10分後に腸管により吸収されたリポソ一 ムの平均値が基準リボソームの平均値の 3〜4倍になることを表す。  [0092] “+” indicates the average value of the liposome absorbed by the intestinal tract 10 minutes after administration when ribosome (reference ribosome) conjugated with tris (hydroxymethyl) aminomethane instead of sugar chain was orally administered. Represents 3-4 times the average value of the reference ribosome.

[0093] 好ましくは、本発明の経口投与に適する糖鎖修飾リボソームは、上記の表 1に示され る種類の糖鎖および修飾結合密度ならびにそれらの組み合わせを用いて調製され 得る。理論に束縛されないが、ー且標的指向性が +または + +であることがわかれ ば、 2種以上の糖鎖を組み合せても同様の効果が期待できる力もである。なぜなら、 標的組織または標的細胞のレクチンが好まし ヽと認識する糖鎖は、組み合せても同 様に好ま ヽと認識されるからである。 [0093] Preferably, the sugar chain-modified ribosome suitable for oral administration of the present invention is prepared using the sugar chain of the type shown in Table 1 above and the modified bond density and combinations thereof. obtain. Without being bound by theory, and if it is found that the target directivity is + or ++, it is the power that can be expected to have the same effect even if two or more sugar chains are combined. This is because sugar chains that are recognized as preferred by lectins of target tissues or target cells are recognized as preferred when combined.

[0094] 本発明において使用される経口投与に適する糖鎖修飾リボソームは、好ましくは、リ ポソーム番号 27、 29、 40、 45、 50、 53、 56、 67、 68、 69、 70、 71、 87、 105、 117 、 120、 125、 139、 142、 150、 152、 153、 154、 175、 184、 186、 197、 204、 22 4、 225、 230、 236、 237、 240、 273、 285、 288または 290であり得る。  [0094] The sugar chain-modified ribosome suitable for oral administration used in the present invention is preferably liposomal numbers 27, 29, 40, 45, 50, 53, 56, 67, 68, 69, 70, 71, 87. , 105, 117, 120, 125, 139, 142, 150, 152, 153, 154, 175, 184, 186, 197, 204, 22 4, 225, 230, 236, 237, 240, 273, 285, 288 or It can be 290.

[0095] 本明細書において使用される糖鎖修飾リボソームは、例えば表 2に示される糖鎖が 腫瘍への送達のために適切な密度で含まれ得る。  [0095] The sugar chain-modified ribosome used in the present specification may contain, for example, the sugar chains shown in Table 2 at a density suitable for delivery to a tumor.

[0096] 本明細書で使用される場合、腫瘍への送達とは、線維肉腫、筋肉腫、脂肪肉腫、 軟骨肉腫、骨原性肉腫、脊索腫、血管肉腫、リンパ管肉腫、骨膜腫、中皮腫、平滑 筋肉腫、横紋筋肉腫、胃癌、食道癌、直腸癌、脾臓癌、卵巣癌、前立腺癌、子宮癌 、頭部および頸部の癌、皮膚癌、脳の癌、扁平上皮癌、脂腺癌腫、乳頭状癌、嚢胞 腺癌、髄様癌、気管支原生癌、腎細胞癌、肝細胞癌、胆管癌腫、絨毛上皮癌、セミノ 一マ、胎生期癌、ウィルムス腫瘍、子宮頸癌、精巣癌、小細胞性肺癌腫、非小細胞 性肺癌種、膀胱癌腫、上皮細胞癌腫、ダリオ一マ、星状細胞腫、髄芽腫、頭蓋咽頭 腫、脳室上衣腫、松果体腫、血管芽腫、聴神経腫、乏突起神経膠腫、髄膜腫、黒色 腫、神経芽腫、網膜芽腫、白血病、リンパ腫、力ポジ肉腫からなる群より選択される腫 瘍への送達をいう。  [0096] As used herein, delivery to a tumor includes fibrosarcoma, sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, lymphangiosarcoma, periosteum, medium Skin tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, rectal cancer, spleen cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, brain cancer, squamous cell carcinoma , Sebaceous carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, primary bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, cervical cancer , Testicular cancer, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelial cell carcinoma, Dariooma, astrocytoma, medulloblastoma, craniopharyngioma, ventricular ependymoma, pineal gland tumor , Hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, force positive sarcoma It refers to the delivery to the selected are tumor.

[0097] 本明細書において使用する場合、「修飾結合密度」とは、糖鎖修飾リボソームを作 製する際に使用される糖鎖の量であり、リボソームの脂質 lmgあたりに結合した糖鎖 の密度 (mg糖鎖 Zmg脂質)として表される。本発明の糖鎖修飾リボソームの結合密 度は、理論に束縛されることを望まないが、経験的に、調製するときに使用した糖鎖 の量は、リボソームに結合した糖鎖の密度にほぼ比例していることが分力つている。 従って、本明細書では、特に言及しない限り、調製時に使用した量によって結合密 度が確定される。インビト口において、例えば、 E—セレクチンを用いて間接的に決定 することができる。本発明の糖鎖修飾リボソームは、リボソームに結合される糖鎖の種 類と結合密度を選択することにより、目的の送達部位に対する指向性を制御すること ができる。以下、表 2にリボソーム番号、糖鎖の構造、修飾結合密度およびその腫瘍 指向性を示す。 [0097] As used herein, "modified bond density" is the amount of sugar chain used in producing a sugar chain-modified ribosome, and is the number of sugar chains bound per mg of lipid in the ribosome. Expressed as density (mg sugar chain Zmg lipid). Although the binding density of the sugar chain-modified ribosome of the present invention is not desired to be bound by theory, empirically, the amount of sugar chain used in the preparation is almost equal to the density of sugar chains bound to the ribosome. Proportionalness is a component. Therefore, in the present specification, unless otherwise stated, the binding density is determined by the amount used at the time of preparation. In the in vitro mouth, for example, it can be determined indirectly using E-selectin. The sugar chain-modified ribosome of the present invention is a kind of sugar chain that is bound to the ribosome. By selecting the type and binding density, the directivity to the intended delivery site can be controlled. Table 2 below shows the ribosome number, sugar chain structure, modified bond density, and tumor directionality.

[表 2] [Table 2]

Figure imgf000034_0001
Figure imgf000034_0001

「 + +」は、糖鎖の代わりに Gal β 1 , 3GalNAc β ΐ, 4 (Neu5Ac a 2, 3)Galj81,G1C J81, lCerを結合させたリボソーム (基準リボソーム）を静脈注射した場合、静脈 注射 5分後に腫瘍に送達されたリボソームの平均値が基準リボソームの平均値の 2〜 4倍になることを表す。 “+ +” Means that when a ribosome (reference ribosome) conjugated with Gal β 1, 3GalNAc β ΐ, 4 (Neu5Ac a 2, 3) Galj81, G1 CJ 81, lCer is injected intravenously instead of a sugar chain, It represents that the mean value of ribosome delivered to the tumor 5 minutes after injection is 2 to 4 times the mean value of the reference ribosome.

[0100] 「 +」は、糖鎖の代わりに Gal jS 1, 3GalNAC j8 1, 4 (Neu5Ac a 2, 3) Gal j8 1, 4 G1C J8 1, ICerを結合させたリボソーム (基準リボソーム）を静脈注射した場合、静脈 注射 5分後に腫瘍に送達されたリボソームの平均値が基準リボソームの平均値の 1〜 2倍になることを表す。 [0100] “+” indicates a ribosome in which Gal jS 1, 3GalNA C j 8 1, 4 (Neu5Ac a 2, 3) Gal j8 1, 4 G1 CJ 8 1, ICer is bound instead of a sugar chain (reference ribosome ), The average value of ribosomes delivered to the tumor 5 minutes after intravenous injection is 1 to 2 times the average value of the reference ribosome.

[0101] トリス (ヒドロキシメチル)ァミノメタンを結合させたリボソームを基準リボソームとする場 合、「+ +」は、静脈注射 5分後に腫瘍に送達されたリボソームの平均値が基準リポソ ームの平均値の 1. 5〜2. 5倍になることを表す。  [0101] When the ribosome bound to tris (hydroxymethyl) aminomethane is used as the reference ribosome, “++” means that the average value of the ribosome delivered to the tumor 5 minutes after intravenous injection is the average value of the reference liposome. 1.5 to 2.5 times greater than

[0102] トリス (ヒドロキシメチル)ァミノメタンを結合させたリボソームを基準リボソームとする場 合、「 +」は、静脈注射 5分後に腫瘍に送達されたリボソームの平均値が基準リポソ一 ムの平均値の 1. 1〜1. 4倍になることを表す。  [0102] When the reference ribosome is a ribosome bound to tris (hydroxymethyl) aminomethane, “+” means that the average value of the ribosome delivered to the tumor 5 minutes after intravenous injection is the average value of the reference liposome. 1. 1 to 1.4 means that it will be 4 times.

[0103] トリス (ヒドロキシメチル)ァミノメタンを結合させたリボソームは腫瘍指向性をわずか に有するので、基準リボソームとして Gal j8 1, 3GalNAC j8 1, 4 (Neu5Ac a 2, 3) G al j8 1, 4G1C J8 1, ICerを使用した。 [0103] Since the ribosome bound to tris (hydroxymethyl) aminomethane has a slight tumor tropism, Gal j8 1, 3GalNA C j 8 1, 4 (Neu5Ac a 2, 3) G al j8 1, 4G1 CJ 8 1, ICer was used.

[0104] 好ましくは、本発明の腫瘍への送達に適する糖鎖修飾リボソームは、上記の表 2に 示される種類の糖鎖および修飾結合密度ならびにそれらの組み合わせを用いて調 製され得る。理論に束縛されないが、一旦標的指向性が +または + +であることが わかれば、 2種以上の糖鎖を組み合せても同様の効果が期待できるからである。なぜ なら、標的組織または標的細胞のレクチンが好ましいと認識する糖鎖は、組み合せて も同様に好ま 、と認識されるからである。  [0104] Preferably, a sugar chain-modified ribosome suitable for delivery to a tumor of the present invention can be prepared using a sugar chain of the type shown in Table 2 above and a modified bond density, and combinations thereof. Without being bound by theory, once the target directivity is found to be + or ++, the same effect can be expected by combining two or more sugar chains. This is because it is recognized that sugar chains that recognize lectins of target tissues or target cells are preferable as well.

[0105] 本発明において使用される腫瘍への送達に適する糖鎖修飾リボソームは、好ましく は、リボソーム番号 22、 27、 29、 38、 40、 41、 45、 53、 60、 68、 69、 71、 87、 91、 93、 96、 105、 106、 111、 116、 117、 120、 125、 139、 150、 151、 152、 153、 1 54、 155、 184、 186、 189、 191、 195、 197、 204、 209、 213、 218、 220、 224、 225、 229、 230、 233、 234、 235、 236、 237、 240、 263、 285、 288、 290、 292 、または 295であり得る。  [0105] The sugar chain-modified ribosome suitable for delivery to the tumor used in the present invention is preferably ribosome number 22, 27, 29, 38, 40, 41, 45, 53, 60, 68, 69, 71, 87, 91, 93, 96, 105, 106, 111, 116, 117, 120, 125, 139, 150, 151, 152, 153, 1 54, 155, 184, 186, 189, 191, 195, 197, 204 , 209, 213, 218, 220, 224, 225, 229, 230, 233, 234, 235, 236, 237, 240, 263, 285, 288, 290, 292, or 295.

[0106] 本明細書において使用される糖鎖修飾リボソームは、例えば表 3に示される糖鎖が 炎症部位への送達のために適切な密度で含まれ得る。 [0106] The sugar chain-modified ribosome used in the present specification has, for example, the sugar chains shown in Table 3. It may be included at an appropriate density for delivery to the site of inflammation.

[0107] 本明細書で使用される場合、炎症部位への送達とは、物理的、化学的、または生物 学的作用物質による損傷や異常刺激によって罹患した血管および隣接する組織に 起こる細胞学的，組織学的反応の動的な複合体力 なる基本的な病理学上の過程 の生じている領域への送達をいう。炎症部位であるかどうかは、炎症性物質 (プロスタ グランジン類、ロイコトリェン類等)を検出することによって確認することができる。  [0107] As used herein, delivery to a site of inflammation refers to cytology that occurs in blood vessels and adjacent tissues affected by physical or chemical or biological agent damage or abnormal stimulation. This refers to the delivery to the area where the basic pathological process occurs, which is the dynamic complex force of histological reaction. Whether it is an inflammatory site can be confirmed by detecting an inflammatory substance (prostaglandins, leukotrienes, etc.).

[0108] 本明細書において使用する場合、「修飾結合密度」とは、糖鎖修飾リボソームを作製 する際に使用される糖鎖の量であり、リボソームの脂質 lmgあたりに結合した糖鎖の 密度 (mg糖鎖 Zmg脂質)として表される。本発明の糖鎖修飾リボソームの結合密度 は、理論に束縛されることを望まないが、経験的に、調製するときに使用した糖鎖の 量は、リボソームに結合した糖鎖の密度にほぼ比例していることが分力つている。従 つて、本明細書では、特に言及しない限り、調製時に使用した量によって結合密度が 確定される。インビト口において、例えば、 E—セレクチンを用いて間接的に決定する ことができる。本発明の糖鎖修飾リボソームは、リボソームに結合される糖鎖の種類と 結合密度を選択することにより、目的の送達部位に対する指向性を制御することがで きる。以下、表 3にリボソーム番号、糖鎖の構造、修飾結合密度およびその炎症部位 への指向性を示す。  [0108] As used herein, "modified bond density" is the amount of sugar chains used in preparing sugar chain-modified ribosomes, and the density of sugar chains bound per mg of lipid in the ribosome. It is expressed as (mg sugar chain Zmg lipid). The binding density of the sugar chain-modified ribosome of the present invention is not desired to be bound by theory, but empirically, the amount of sugar chain used for preparation is almost proportional to the density of sugar chains bound to the ribosome. What you are doing is divided. Therefore, in this specification, unless otherwise stated, the bond density is determined by the amount used at the time of preparation. In the in vitro mouth, for example, it can be determined indirectly using E-selectin. The sugar chain-modified ribosome of the present invention can control the directivity with respect to the intended delivery site by selecting the type of sugar chain to be bound to the ribosome and the binding density. Table 3 below shows the ribosome number, sugar chain structure, modified bond density, and directivity to the inflammatory site.

[0109] [表 3] [0109] [Table 3]

修飾結合密 Modified bond

リボソーム 炎症部位  Ribosome Inflamed site

糖鎖の構造 度（ 糖銀  Sugar chain structure (sugar silver

番号 指向性  Number Directionality

ノ 脂  Fat

++  ++

++  ++

++  ++

+  +

+  +

+  +

+  +

+  +

++  ++

+  +

++  ++

++  ++

+  +

+  +

++  ++

++  ++

++  ++

++  ++

++  ++

++  ++

+  +

+  +

+  +

++  ++

+  +

++  ++

++  ++

++  ++

+  +

++  ++

++  ++

++  ++

++  ++

+  +

++  ++

+  +

++  ++

+  +

++  ++

+  +

++  ++

++  ++

+  +

++  ++

++  ++

++  ++

++  ++

++  ++

++  ++

++  ++

++  ++

++  ++

+  +

++  ++

+  +

++  ++

レ ++  Les ++

+  +

「 + +」は、糖鎖の代わりに Gal β 1 , 3GalNAc β ΐ, 4 (Neu5Ac α 2, 3) Gal j8 1 ,Glc ^ l , lCerを結合させたリボソーム (基準リボソーム）を静脈注射した場合、静脈 注射 5分後に炎症部位に送達されたリボソームの平均値が基準リボソームの平均値 の 2〜8倍になることを表す。 “+ +” Means that ribosomes (reference ribosomes) bound with Gal β 1, 3GalNAc β ΐ, 4 (Neu5Ac α 2, 3) Gal j8 1, Glc ^ l, lCer instead of sugar chains are injected intravenously ,vein This means that the mean value of the ribosome delivered to the inflamed site 5 minutes after the injection is 2 to 8 times the mean value of the reference ribosome.

[0110] 「 +」は、糖鎖の代わりに Gal jS 1 , 3GalNAC j8 1 , 4 (Neu5Ac a 2, 3) Gal j8 1 , 4G1 ο β ΐ , ICerを結合させたリボソーム (基準リボソーム）を静脈注射した場合、静脈注 射 5分後に炎症部位に送達されたリボソームの平均値が基準リボソームの平均値の 1[0110] "+" is a ribosome (standard ribosome) in which Gal jS 1, 3GalNA C j 8 1, 4 (Neu5Ac a 2, 3) Gal j8 1, 4G1 ο β ΐ, ICer is bound instead of the sugar chain Intravenous injection of ribosome delivered to the inflamed site 5 minutes after intravenous injection is 1

〜2倍になることを表す。 Represents doubling.

[0111] トリス (ヒドロキシメチル)ァミノメタンを結合させたリボソームを基準リボソームとする場 合、「+ +」は、静脈注射 5分後に炎症部位に送達されたリボソームの平均値が基準 リボソームの平均値の 1. 5〜4. 9倍になることを表す。 [0111] When the reference ribosome is a ribosome coupled with tris (hydroxymethyl) aminomethane, “++” is the average value of the reference ribosome delivered to the inflammatory site 5 minutes after intravenous injection. 1. Indicates 5 to 4.9 times.

[0112] トリス (ヒドロキシメチル)ァミノメタンを結合させたリボソームを基準リボソームとする場 合、「 +」は、静脈注射 5分後に炎症部位に送達されたリボソームの平均値が基準リ ポソームの平均値の 1. 2〜1. 5倍になることを表す。 [0112] When the ribosome bound with tris (hydroxymethyl) aminomethane is used as the reference ribosome, “+” means that the average value of the ribosome delivered to the inflammatory site 5 minutes after intravenous injection is the average value of the reference liposome. 1. Represents 2 to 1.5 times.

[0113] トリス (ヒドロキシメチル)ァミノメタンを結合させたリボソームは炎症部位への指向性を わずかに有するので、基準リボソームとして Gal j8 1 , 3GalNAC j8 1 , 4 (Neu5Ac a[0113] Since the ribosome bound to tris (hydroxymethyl) aminomethane has a slight directivity to the inflammatory site, Gal j8 1, 3GalNA C j 8 1, 4 (Neu5Ac a

2, 3) Gal j8 1 , 4GlC j8 1 , ICerを使用した。 2, 3) Gal j8 1, 4Gl C j 8 1, ICer was used.

[0114] 好ましくは、本発明の炎症部位への送達に適する糖鎖修飾リボソームは、上記の表 3 に示される種類の糖鎖および修飾結合密度ならびにそれらの組み合わせを用いて 調製され得る。理論に束縛されないが、一旦標的指向性が +または + +であること がわかれば、 2種以上の糖鎖を組み合せても同様の効果が期待できるからである。な ぜなら、標的組織または標的細胞のレクチンが好ましいと認識する糖鎖は、組み合 せても同様に好ましいと認識されるからである。  [0114] Preferably, sugar chain-modified ribosomes suitable for delivery to the inflammatory site of the present invention can be prepared using the types of sugar chains and modified bond densities shown in Table 3 above and combinations thereof. Without being bound by theory, once the target directivity is found to be + or ++, the same effect can be expected by combining two or more sugar chains. This is because it is recognized that a sugar chain that recognizes a lectin of a target tissue or a target cell is preferable even if it is combined.

[0115] 本発明において使用される炎症部位への送達に適する糖鎖修飾リボソームは、好 ましくは、リボソーム番号 22、 27、 38、 40、 41、 50、 53、 56、 60、 68、 69、 70、 71、 76、 87、 91、 93、 96、 105、 106、 111、 116、 1 17、 120、 125、 137、 139、 146、 150、 151、 152、 153、 154、 155、 183、 184、 186、 189、 191、 195、 197、 199 、 204、 209、 213、 218、 220、 224、 229、 230、 233、 234、 235、 237、 240、 26 [0115] The sugar chain-modified ribosome suitable for delivery to the inflammatory site used in the present invention is preferably ribosome number 22, 27, 38, 40, 41, 50, 53, 56, 60, 68, 69. , 70, 71, 76, 87, 91, 93, 96, 105, 106, 111, 116, 1 17, 120, 125, 137, 139, 146, 150, 151, 152, 153, 154, 155, 183, 184, 186, 189, 191, 195, 197, 199, 204, 209, 213, 218, 220, 224, 229, 230, 233, 234, 235, 237, 240, 26

3、 288、 290、 292、または 295であり得る。 It can be 3, 288, 290, 292, or 295.

[0116] 上記の表に記載されるような本発明の好ましい糖鎖修飾リボソームは、以下の方法に よって製造され得る。具体的には、この方法は、（a)リボソームを提供する工程； (b) 該リボソームを親水性化処理する工程；（c)必要に応じて、該親水性化処理されたリ ポソームにリンカ一を結合させて、リンカ一結合リボソームを生成する工程;および (d )該リボソームに、上記表 3に記載される糖鎖を結合させて糖鎖修飾リボソームを生成 する工程を包含する。 [0116] The preferred sugar chain-modified ribosome of the present invention as described in the above table is obtained by the following method. Thus, it can be manufactured. Specifically, this method comprises (a) a step of providing a ribosome; (b) a step of hydrophilizing the ribosome; (c) a linker on the hydrophilized liposome as necessary. And (d) binding a sugar chain described in Table 3 above to produce a sugar chain-modified ribosome.

[0117] 好ましくは、この方法において、工程 (b)のリボソームを親水性ィ匕処理する工程は、リ ポソームの脂質膜上またはリンカ一上に、直接または間接的に低分子量の親水性ィ匕 合物を結合することによって実施され、工程 (c)において使用されるリンカ一は、ヒト 由来のタンパク質であり、かつ工程 (d)において、該リボソームに、直接または間接的 に糖鎖を結合させる条件下で、糖鎖を結合させて糖鎖修飾リボソームを生成する。  [0117] Preferably, in this method, the step of treating the ribosome in step (b) with hydrophilic property directly or indirectly on the lipid membrane or linker of the liposome is performed directly or indirectly. The linker used in step (c) is a human-derived protein, and a sugar chain is directly or indirectly bound to the ribosome in step (d). Under conditions, sugar chains are bound to produce sugar chain-modified ribosomes.

[0118] リボソームとリンカ一、リンカ一と糖鎖とは、二官能性架橋剤（例えば、 DTSSP)など を利用して結合されることが好ましい。  [0118] The ribosome and the linker, and the linker and the sugar chain are preferably bound using a bifunctional crosslinking agent (for example, DTSSP).

[0119] 本発明の糖鎖修飾リボソームは、薬剤または遺伝子を封入または結合し得る薬剤と しては、例えば、バイオ医薬品またはバイオ治療用物質 (例えば、 siRNA、 shRNA、 si RNA誘導体、 shRNA誘導体、 RNA、 RNA誘導体、 DNA、 DNA誘導体、モノクローナル 抗体、ワクチン、インターフェロン、ホルモン、プロスタグランジン、転写因子、組換え タンパク質、抗体医薬、核酸〉医薬、遺伝子治療薬)、アルキル化系抗癌剤、代謝拮 抗剤、植物由来抗癌剤、抗癌性抗生物質、生物学的応答調節剤 (biological resp onse modifiers : BRM) 'サイト力イン類、白金錯体系抗癌剤、免疫療法剤、ホルモ ン系抗癌剤、モノクローナル抗体等の腫瘍用薬剤、中枢神経用薬剤、末梢神経系- 感覚器官用薬剤、呼吸器疾患治療薬剤、循環器用薬剤、消化器官用薬剤、ホルモ ン系用薬剤、泌尿器'生殖器用薬剤、ビタミン '滋養強壮剤、代謝性医薬品、抗生物 質，化学療法薬剤、検査用薬剤、抗炎症剤、眼疾患薬剤、中枢神経系薬剤、自己免 疫系薬剤、循環器系薬剤、糖尿病、高脂血症のような生活習慣病薬剤、副腎皮質ホ ルモン、免疫抑制剤、抗菌薬、抗ウィルス薬、血管新生抑制剤、サイト力イン、ケモカ イン、抗サイト力イン抗体、抗ケモカイン抗体、抗サイト力イン'ケモカイン受容体抗体 、 siRNA、 shRNA、 miRNA、 smRNA、アンチセンス RNAまたは ODNまたは DN Aのような遺伝子治療関連の核酸製剤、神経保護因子、抗体医薬、分子標的薬、骨 粗鬆症 ·骨代謝改善薬、神経ペプチド、生理活性ペプチド ·蛋白質が挙げられるが、 これらに限定されない。 [0119] The sugar chain-modified ribosome of the present invention is, for example, a biopharmaceutical or a biotherapeutic substance (for example, siRNA, shRNA, siRNA derivative, shRNA derivative, RNA, RNA derivative, DNA, DNA derivative, monoclonal antibody, vaccine, interferon, hormone, prostaglandin, transcription factor, recombinant protein, antibody drug, nucleic acid> drug, gene therapy drug), alkylated anticancer drug, metabolic antagonist Agents, plant-derived anticancer agents, anticancer antibiotics, biological response modifiers (BRM) 'site force ins, platinum complex anticancer agents, immunotherapeutic agents, hormone anticancer agents, monoclonal antibodies, etc. Oncology drugs, central nervous system drugs, peripheral nervous system-sensory organ drugs, respiratory disease drugs, cardiovascular drugs, gastrointestinal drugs, hormone drugs Drugs, urological 'genital agents, vitamins' nourishing tonics, metabolic drugs, antibiotics, chemotherapeutic drugs, test drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, self-immune drugs, circulation Systemic drugs, lifestyle-related diseases such as diabetes and hyperlipidemia, corticosteroids, immunosuppressive agents, antibacterial agents, antiviral agents, angiogenesis inhibitors, cytoforce-in, chemokines, anti-site-forced in Antibodies, anti-chemokine antibodies, anti-site force-in chemokine receptor antibodies, siRNA, shRNA, miRNA, smRNA, antisense RNA or gene therapy-related nucleic acid preparations such as ODN or DN A, neuroprotective factors, antibody drugs, molecules Target drug, bone Examples include, but are not limited to, osteoporosis, bone metabolism-improving drugs, neuropeptides, bioactive peptides, and proteins.

[0120] 本明細書において使用される場合、「リンカ一」とは、糖鎖とリボソーム表面との結合 を介在する分子である。本発明の糖鎖修飾リボソームにおいて、糖鎖はリンカ一を介 してリボソーム表面に結合してもよい。リンカ一は、当業者が適宜選択することができ るが、生体適合性であるものが好ましぐより好ましくは、薬学的に受容可能である。 本明細書において使用されるリンカ一としては、例えば、生体由来蛋白質、好ましく は、ヒト由来蛋白質、より好ましくは、ヒト由来血清蛋白質、さらにより好ましくは、ヒト血 清アルブミンまたはゥシ血清アルブミンであり得る。特に、ヒト血清アルブミンを使用す る場合は、各組織に対する取り込みが多いことがマウスについての実験により確かめ られている。  [0120] As used herein, "linker" is a molecule that mediates the binding between a sugar chain and the ribosome surface. In the sugar chain-modified ribosome of the present invention, the sugar chain may be bound to the ribosome surface via a linker. The linker can be appropriately selected by those skilled in the art, but those that are biocompatible are preferred, and are preferably pharmaceutically acceptable. The linker used in the present specification is, for example, a biological protein, preferably a human-derived protein, more preferably a human-derived serum protein, and still more preferably human serum albumin or ushi serum albumin. obtain. In particular, when human serum albumin is used, it has been confirmed by experiments on mice that the uptake into each tissue is large.

[0121] 本明細書において「架橋剤」とは、橋をかけるように，鎖式高分子の分子間で化学結 合を形成させることをいう。代表的には、脂質、タンパク質、ペプチド、糖鎖などの高 分子と他の分子 (例えば、脂質、タンパク質、ペプチド、糖鎖)との間に作用し、分子 内または分子間で， 共有結合のな力つたところを結ぶ共有結合を形成させる薬剤を いう。本明細書においては、リボソームと糖鎖とはこの架橋剤によって共有結合が形 成されていてもよぐあるいは、リンカ一を介し、かつ、そのリンカ一と糖鎖との間、およ びリンカ一とリボソームとの間が架橋剤によって結合されていてもよい。架橋剤は、架 橋を目的とする標的によって変動し、例えば、アルデヒド類 (例えば、ダルタルアルデ ヒド）、カルポジイミド類、イミドエステル類など挙げることができるがそれらに限定され ない。アミノ基含有物質を架橋する場合、アルデヒド含有基、例えば、ダルタルアル デヒドを用いることができる。具体的には、例えば、ビススルホスクシ-ミジルスべラー ト、ジスクシ-ミジルグルタレート、ジチオビススクシ-ミジルプロピオネート、ジスクシ -ミジルスべラート、 3, 3，一ジチォビス（スルホスクシ-ミジルプロピオネート）、ェチ レングリコ一ルビススクシ二ミジノレスクシネート、エチレングリコ一ルビススノレホスタシニ ミジルスクシネート等の 2価試薬などを使用することができる。  In the present specification, the “crosslinking agent” means that a chemical bond is formed between molecules of a chain polymer so as to form a bridge. Typically, it acts between high molecules such as lipids, proteins, peptides, and sugar chains and other molecules (for example, lipids, proteins, peptides, and sugar chains), and is covalently bound within or between molecules. A drug that forms a covalent bond that connects strong forces. In the present specification, a ribosome and a sugar chain may be covalently formed by this cross-linking agent, or through a linker, between the linker and the sugar chain, and the linker. One and the ribosome may be bound by a cross-linking agent. The cross-linking agent varies depending on the target for crosslinking, and examples thereof include, but are not limited to, aldehydes (for example, dartal aldehyde), carpositimides, imide esters and the like. When the amino group-containing substance is cross-linked, an aldehyde-containing group such as dartaldehyde can be used. Specifically, for example, bissulfosuccimidyl suberate, disucci midyl glutarate, dithiobis succimidyl propionate, disucci midyl suberate, 3, 3, 1 dithiobis (sulfosuccimidyl propionate) Bivalent reagents such as ethylene glycol bisbissuccinimidinoresuccinate and ethylene glycol bissunorefostasinimidyl succinate can be used.

[0122] 本明細書において使用される用語「蛋白質」、「ポリペプチド」、「オリゴペプチド」およ び「ペプチド」は、本明細書において同じ意味で使用され、任意の長さのアミノ酸のポ リマーをいう。このポリマーは、直鎖であっても分岐していてもよぐ環状であってもよ い。アミノ酸は、天然のものであっても非天然のものであってもよぐ改変されたァミノ 酸であってもよい。この用語はまた、複数のポリペプチド鎖の複合体へとアセンブルさ れたものを包含し得る。この用語はまた、天然または人工的に改変されたアミノ酸ポリ マーも包含する。そのような改変としては、例えば、ジスルフイド結合形成、グリコシル ィ匕、脂質化、ァセチル化、リン酸ィ匕または任意の他の操作もしくは改変 (例えば、標 識成分との結合体化)。この定義にはまた、例えば、アミノ酸の 1または 2以上のアナ ログを含むポリペプチド (例えば、非天然のアミノ酸などを含む）、ペプチド様ィ匕合物（ 例えば、ぺプトイド）および当該分野において公知の他の改変が包含される。 [0122] As used herein, the terms "protein", "polypeptide", "oligopeptide" and "peptide" are used interchangeably in this specification, and are amino acid residues of any length. A remer. This polymer may be linear, branched or cyclic. The amino acid may be a modified amino acid, which may be natural or non-natural. The term can also encompass one assembled into a complex of multiple polypeptide chains. The term also encompasses amino acid polymers that are naturally or artificially modified. Such modifications include, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphate, or any other manipulation or modification (eg, conjugation with a labeling component). This definition also includes, for example, polypeptides containing one or more analogs of amino acids (eg, including unnatural amino acids, etc.), peptidomimetics (eg, peptoids), and known in the art. Other modifications are included.

[0123] 本明細書では、特に言及するときは、「蛋白質」は、比較的大きな分子量を有するアミ ノ酸のポリマーまたはその改変体を指し、「ペプチド」というときは、比較的小さな分子 量を有するアミノ酸のポリマーまたはその改変体を指すことがあることが理解されるべ きである。そのような分子量としては、たとえば、約 30kDa、好ましくは約 20kDa、より 好ましくは約 lOkDaなどを挙げることができるがそれらに限定されない。  [0123] In this specification, “protein” refers to a polymer of amino acid having a relatively large molecular weight or a modification thereof, and “peptide” refers to a relatively small molecular weight. It should be understood that it may refer to a polymer of amino acids having or modifications thereof. Examples of such molecular weight include, but are not limited to, about 30 kDa, preferably about 20 kDa, more preferably about 10 kDa.

[0124] 本明細書中で使用される場合、「生体由来蛋白質」とは、生物に由来する蛋白質を いい、どの生物（たとえば、任意の種類の多細胞生物（例えば、動物（たとえば、脊椎 動物、無脊椎動物）、植物 (たとえば、単子葉植物、双子葉植物など)など)）由来の 蛋白質でもよい。好ましくは、脊椎動物 (たとえば、メタラウナギ類、ャッメゥナギ類、軟 骨魚類、硬骨魚類、両生類、爬虫類、鳥類、哺乳動物など）由来の蛋白質、より好ま しくは、哺乳動物 (例えば、単孔類、有袋類、貧歯類、皮翼類、翼手類、食肉類、食 虫類、長鼻類、奇蹄類、偶蹄類、管歯類、有鱗類、海牛類、クジラ目、霊長類、齧歯 類、ゥサギ目など）由来の蛋白質が用いられる。さらに好ましくは、霊長類 (たとえば、 チンパンジー、二ホンザル、ヒト）由来の蛋白質が用いられる。最も好ましくは投与を 目的とする生体由来の蛋白質が用いられる。  [0124] As used herein, "biological protein" refers to a protein derived from an organism, including any organism (eg, any type of multicellular organism (eg, animal (eg, vertebrate)). , Invertebrates), plants (eg monocotyledonous plants, dicotyledonous plants, etc.))). Preferably, the protein is derived from a vertebrate (e.g., metaraunagi, shark eels, teleosts, teleosts, amphibians, reptiles, birds, mammals, etc.), more preferably a mammal (e.g. Pouches, rodents, crustaceans, wings, carnivores, carnivores, long noses, odd-hoofed animals, cloven-hoofed animals, rodents, scales, sea cattle, cetaceans, primates, Proteins from rodents, maggots, etc.) are used. More preferably, a protein derived from a primate (for example, chimpanzee, second monkey, human) is used. Most preferably, a biological protein intended for administration is used.

[0125] 本明細書で使用される場合「ヒト由来血清蛋白質」は、ヒトの血液が自然に凝固したと きに残る液体部分に含まれる蛋白質をいう。  [0125] As used herein, "human serum protein" refers to a protein contained in a liquid portion that remains when human blood naturally coagulates.

[0126] 本明細書で使用される場合、「ヒト血清アルブミン」は、ヒトの血清中に含まれるアルブ ミンを 、 、、「ゥシ血清アルブミン」は、ゥシの血清中に含まれるアルブミンを!、う。 [0127] 本発明における糖鎖修飾リボソームは、リボソーム膜またはリンカ一の少なくとも一方 が親水性化合物、好ましくは、トリス (ヒドロキシアルキル)アミノアルカンを結合させる ことにより親水性ィ匕されて 、てもよ 、。 [0126] As used herein, "human serum albumin" refers to albumin contained in human serum,,, "ushi serum albumin" refers to albumin contained in serum of ushi. ! [0127] In the sugar chain-modified ribosome in the present invention, at least one of the ribosome membrane and the linker may be made hydrophilic by binding a hydrophilic compound, preferably a tris (hydroxyalkyl) aminoalkane. ,.

[0128] 本明細書中で使用される場合、「親水性化」は、リボソーム表面に親水性ィ匕合物を結 合させることをいう。親水性ィ匕に用いる化合物としては、低分子の親水性化合物、好 ましくは少なくとも 1つの OH基を有する低分子の親水性化合物、さらに好ましくは、 少なくとも 2つの OH基を有する低分子の親水性化合物が挙げられる。また、さらに少 なくとも 1つのアミノ基を有する低分子の親水性ィ匕合物、すなわち分子中に少なくとも 1つの OH基と少なくとも 1つのアミノ基を有する親水性ィ匕合物が挙げられる。親水性 化合物は、低分子なので、糖鎖に対する立体障害となりに《標的細胞膜面上のレク チンによる糖鎖分子認識反応の進行を妨げることはない。また、親水性ィ匕合物には、 本発明の糖鎖修飾リボソームにおいて、レクチン等の特定の標的を指向するために 用いられるレクチンが結合し得る糖鎖は含まれな 、。このような親水性ィ匕合物として、 例えば、トリス (ヒドロキシメチル)ァミノメタンなどを含むトリス (ヒドロキシアルキル)アミ ノアルカン等のァミノアルコール類等が挙げられ、さらに具体的には、トリス（ヒドロキシ メチノレ）アミノエタン、トリス（ヒドロキシェチル）アミノエタン、トリス（ヒドロキシプロピル） アミノエタン、トリス（ヒドロキシメチル)ァミノメタン、トリス（ヒドロキシェチル)ァミノメタン 、トリス（ヒドロキシプロピル)ァミノメタン、トリス（ヒドロキシメチル）ァミノプロパン、トリス（ ヒドロキシェチル)ァミノプロパン、トリス（ヒドロキシプロピル)ァミノプロパン等が挙げら れる。さら〖こ、 OH基を有する低分子化合物にアミノ基を導入した化合物も本発明の 親水性ィ匕合物として用いることができる。該化合物は限定されないが、例えば、セロ ビオース等のレクチンが結合しない糖鎖にアミノ基を導入したィ匕合物が挙げられる。 例えば、リボソーム膜の脂質ホスファチジルエタノールァミン上に架橋用の 2価試薬と トリス (ヒドロキシメチル)ァミノメタンとを用いてリボソーム表面を親水性ィ匕する。親水 性化合物の一般式は、下記式（1)、式 (2)、式 (3)等で示される。  [0128] As used herein, "hydrophilization" refers to binding of a hydrophilic compound to the ribosome surface. The compound used for the hydrophilic property is a low molecular weight hydrophilic compound, preferably a low molecular weight hydrophilic compound having at least one OH group, and more preferably a low molecular weight hydrophilic compound having at least two OH groups. Compound. Further, a low molecular weight hydrophilic compound having at least one amino group, that is, a hydrophilic compound having at least one OH group and at least one amino group in the molecule can be mentioned. Since the hydrophilic compound is a small molecule, it does not hinder the progress of the sugar chain molecule recognition reaction by the lectin on the surface of the target cell membrane due to steric hindrance to the sugar chain. In addition, the hydrophilic compound does not include a sugar chain to which a lectin used for directing a specific target such as a lectin can be bound in the sugar chain-modified ribosome of the present invention. Examples of such hydrophilic compounds include amino alcohols such as tris (hydroxyalkyl) aminoalkane including tris (hydroxymethyl) aminomethane, and more specifically, tris (hydroxymethylol). ) Aminoethane, Tris (hydroxyethyl) aminoethane, Tris (hydroxypropyl) Aminoethane, Tris (hydroxymethyl) aminomethane, Tris (hydroxyethyl) aminomethane, Tris (hydroxypropyl) aminomethane, Tris (hydroxymethyl) aminopropane, Tris (hydroxy) Ethyl) aminopropane, tris (hydroxypropyl) aminopropane and the like. Furthermore, a compound in which an amino group is introduced into a low molecular weight compound having an OH group can also be used as the hydrophilic compound of the present invention. The compound is not limited, and examples thereof include compounds in which an amino group is introduced into a sugar chain to which a lectin such as cellobiose does not bind. For example, the ribosome surface is rendered hydrophilic using a divalent reagent for crosslinking and tris (hydroxymethyl) aminomethane on the lipid phosphatidylethanolamine of the ribosome membrane. The general formula of the hydrophilic compound is represented by the following formula (1), formula (2), formula (3) and the like.

[0129] X-R1 (R2OH) 式（1) H N—R3—(R4OH) 式（2) H N—R5 (OH) 式（3) ここで、 力

Figure imgf000042_0001
[0129] XR 1 (R 2 OH) Formula (1) HN—R 3 — (R 4 OH) Formula (2) HN—R 5 (OH) Formula (3) where
Figure imgf000042_0001

ら C の直鎖または分岐鎖の炭化水素鎖を示し、 R2、 R4は存在しないかもしくは Cか ら C 、好ましくは C力 C 、さらに好ましくは C力 C の直鎖または分岐鎖の炭化Represents a straight or branched hydrocarbon chain of C, and R 2 and R 4 are absent or C C, preferably C-force C, more preferably C-force C linear or branched carbonization

40 1 20 1 10 40 1 20 1 10

水素鎖を示す。 Xはリボソーム脂質と直接または架橋用の二価試薬と結合する反応 性官能基を示し、例えば、 COOH、 NH、 NH Indicates a hydrogen chain. X represents a reactive functional group that binds to the ribosomal lipid directly or to a divalent reagent for crosslinking, such as COOH, NH, NH

2、 CHO、 SH、 NHS エステル、マレ イミド、イミドエステル、活性ハロゲン、 EDC、ピリジルジスルフイド、アジドフヱ-ル、ヒ ドラジド等が挙げられる。 nは自然数を示す。このような親水性化合物で親水性化を 行ったリボソームの表面は、薄く親水性ィ匕合物で覆われている。但し、その親水性ィ匕 合物の覆いの厚みは小さいので、リボソームに糖鎖を結合させた場合であっても、糖 鎖等の反応性を抑制することはな 、。  2, CHO, SH, NHS ester, maleimide, imide ester, active halogen, EDC, pyridyl disulfide, azido file, hydrazide and the like. n represents a natural number. The surface of the ribosome that has been rendered hydrophilic with such a hydrophilic compound is thinly covered with a hydrophilic compound. However, since the thickness of the cover of the hydrophilic compound is small, even when sugar chains are bound to ribosomes, the reactivity of sugar chains and the like cannot be suppressed.

リボソームの親水性ィ匕は、従来公知の方法、例えば、ポリエチレングリコール、ポリビ ニルアルコール、無水マレイン酸共重合体等を共有結合により結合させたリン脂質を 用いてリボソームを作成する方法 (特開 2000— 302685号 (例えば、 CNDAC含有 リボソーム製剤ジラウロイルホスファチジルコリン、ジミリストイルホスファチジルコリン、 ジパ ルミトイルホスファチジルコリン、ジステアロイルホスファチジルコリン；ジパルミト ィルホスファチジルグリセロール、ジステアロイルホスファチジルグリセ ロール；スフィ ンゴミエリン；コレステロ一ノレ； The hydrophilicity of the ribosome can be determined by a conventionally known method, for example, a method for producing a ribosome using a phospholipid obtained by covalently binding polyethylene glycol, polyvinyl alcohol, maleic anhydride copolymer, etc. — 302685 (eg, CNDAC-containing ribosomal formulations dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine; dipalmitoylphosphatidylglycerol, distearoyl phosphatidylglycerol; sphingomyelin; cholesterol

ポリエチレングリコール部分の分子量が約 2000である N モノメトキシポリエチレング リコールサクシ-ル ジステアロイルホスファチジルエタノールァミン（以下、 PEG2 000— DSPEとする。）； CNDAC塩酸塩、グルコース水溶液及びトレハロース水溶 液を使用し、 Banghamら (J. Mol. Biol. 8、 660— 668 (1964)参照。）の方法 により、多重層リボソームの粗分散液を得た。」と記載されている。；)）等の方法を採用 すること〖こよっても行うことができる。このうち、トリス (ヒドロキシメチル)ァミノメタンを用 いてリボソーム表面を親水性ィ匕することが特に好ましい。本発明のトリス (ヒドロキシメ チル)ァミノメタンを用いる手法は、ポリエチレングリコールなどを用いる従来の親水性 化方法と比較していくつかの点で好ましい。例えば、本発明のように糖鎖をリボソーム 上に結合してその分子認識機能を標的指向性に利用するものでは、トリス (ヒドロキシ メチル)ァミノメタンは低分子量物質であるので従来のポリエチレングリコールなどの 高分子量物質を用いる方法に比べて、糖鎖に対する立体障害となりにくく標的細胞 膜面上のレクチン (糖鎖認識蛋白質）による糖鎖分子認識反応の進行を妨げないの で特に好ましい。 N monomethoxypolyethylene glycol succinyl distearoyl phosphatidylethanolamine (hereinafter referred to as PEG2000-DSPE) with a molecular weight of polyethylene glycol moiety of about 2000; CNDAC hydrochloride, glucose aqueous solution and trehalose aqueous solution are used. , Bangham et al. (See J. Mol. Biol. 8, 660-668 (1964)), a crude dispersion of multilayer ribosomes was obtained. Is described. ))) Etc. can be used. Among these, it is particularly preferable to make the ribosome surface hydrophilic using tris (hydroxymethyl) aminomethane. The method using tris (hydroxymethyl) aminomethane of the present invention is preferable in several respects as compared with the conventional hydrophilization method using polyethylene glycol or the like. For example, in the case where a sugar chain is bound on a ribosome and its molecular recognition function is used for target orientation as in the present invention, tris (hydroxymethyl) aminomethane is a low molecular weight substance, so that it has a high molecular weight such as conventional polyethylene glycol. Compared with methods using molecular weight substances, it is less likely to cause steric hindrance to sugar chains, and does not interfere with the progress of sugar chain molecule recognition reactions by lectins (sugar chain recognition proteins) on the surface of target cells. Is particularly preferable.

[0131] また、本発明によるリボソームは該親水化処理後においても粒径分布や成分組成、 分散特性が良好であり、長時間の保存性や生体内安定性も優れて!ヽるのでリポソ一 ム製剤化して利用するために好まし ヽ。トリス (ヒドロキシメチル)ァミノメタンを用いてリ ポソーム表面を親水性ィ匕するには、例えばジミリストイルホスファチジルエタノールァ ミン、ジパルミトイルホスファチジルエタノールァミン、ジステアロイルホスファチジルェ タノールァミン等の脂質を用いて、常法により得たリボソーム溶液にビススルホスクシ -ミジルスべラート、ジスクシ-ミジルグルタレート、ジチオビススクシ-ミジルプロピオ ネート、ジスクシ二ミジルスべラート、 3, 3，一ジチオピス（スルホスクシ-ミジルプロピ ォネート）、エチレングリコーノレビススクシ-ミジノレスクシネート、エチレングリコールビ ススルホスクシ-ミジルスクシネート等の 2価試薬をカ卩えて反応させることにより、リポソ ーム膜上のジパルミトイルホスファチジルエタノールァミン等の脂質に 2価試薬を結合 させ、次いでトリス (ヒドロキシメチル)ァミノメタンを、該 2価試薬の—方の結合手と反 応させることにより、リボソーム表面にトリス (ヒドロキシメチル)ァミノメタンを結合せしめ る。  [0131] Further, the ribosome according to the present invention has good particle size distribution, component composition, and dispersion characteristics even after the hydrophilization treatment, and has excellent long-term storage and in vivo stability. It is preferable for use as a pharmaceutical preparation. In order to make the liposomal surface hydrophilic using tris (hydroxymethyl) aminomethane, for example, using lipids such as dimyristoyl phosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, etc. Bissulfosuccimidyl subtilate, disucci-midyl glutarate, dithiobissuccinimidyl propionate, disuccinimidyl subionate, 3,3,1 dithiopis (sulfosucci-midyl propionate), ethylene glyconorebissucci Dipalmitoyl phosphatidyl ethanol on the liposomal membrane is prepared by reacting with a bivalent reagent such as midinoresuccinate or ethylene glycol bissulfosucci-midyl succinate. A trivalent (hydroxymethyl) aminomethane is bound to the surface of the ribosome by binding a divalent reagent to a lipid such as glucose, and then reacting tris (hydroxymethyl) aminomethane with the other side of the divalent reagent. The

[0132] このように、リボソームを親水性化処理したリボソームは、生体内で極めて安定であり 、後述のように標的指向性を有する糖鎖を結合しなくても、生体内での半減期が長い ためドラッグデリバリーシステムにおけるドラッグ担体として好適に用いることができる 。本発明は、表面を低分子化合物で親水性化したリボソームをも包含する。  [0132] Thus, a ribosome obtained by hydrophilizing a ribosome is extremely stable in vivo, and has a half-life in vivo without binding a target-directed sugar chain as described later. Since it is long, it can be suitably used as a drug carrier in a drug delivery system. The present invention also includes a ribosome whose surface is made hydrophilic with a low molecular weight compound.

[0133] 本明細書にぉ 、て「送達媒体」は、所望の物質の送達を媒介する担体 (ビヒクル)を いう。送達される物質が薬物であれば、「薬物送達媒体」という。薬物送達システム (D rug Delivery System, DDS)とは、ドラッグデリバリーシステムとも呼ばれ、吸収 制御型 DDS、放出制御型 DDS、標的指向型 DDSに分類することもある。理想的な DDSは、薬物を「体内の必要な部位に」、「必要な量を」、「必要な時間だけ」送り込 むシステムである。ターゲティング DDS (Targeting DDSと書き、和訳は標的指向 性 DDSである。）は、ノ ッシブ 'ターゲティング (受動的 ·標的指向性) DDSとァクティ ブ 'ターゲティング (能動的'標的指向性) DDSとに分類される。前者はキャリアー (薬 物運搬体)の粒子径ゃ親水性など物理化学的性質を利用して体内挙動を制御する 方法である。後者はこれらに特殊な仕組みを付け加えて積極的に標的組織への指 向性を制御しょうとする方法であり、例えば標的組織を構成する特定細胞の標的分 子への特異的分子認識機能を有する抗体や糖鎖などを結合したキャリアーを利用す る方法があり"ミサイルドラッグ"と呼ばれることもある。 [0133] As used herein, "delivery vehicle" refers to a carrier (vehicle) that mediates delivery of a desired substance. If the substance to be delivered is a drug, it is referred to as a “drug delivery vehicle”. The drug delivery system (DDS) is also called a drug delivery system, and is sometimes classified into an absorption-controlled DDS, a controlled-release DDS, and a target-oriented DDS. The ideal DDS is a system that delivers a drug “to the necessary part of the body”, “a necessary amount”, and “for the required time”. Targeting DDS (written as Targeting DDS, translated into target-oriented DDS) is categorized as noisy 'targeting (passive / target-oriented) DDS and active' targeting (active 'target-oriented) DDS. Is done. The former controls the behavior in the body using physicochemical properties such as carrier particle size and hydrophilicity. Is the method. The latter is a method in which a special mechanism is added to these to actively control the direction to the target tissue.For example, it has a specific molecular recognition function for the target molecules of specific cells that constitute the target tissue. There is a method using a carrier to which an antibody or a sugar chain is bound, and it is sometimes called a “missile drug”.

[0134] 本明細書にぉ 、て「薬物送達媒体」は、所望の薬物を送達するためのビヒクルを 、う  [0134] As used herein, "drug delivery vehicle" refers to a vehicle for delivering a desired drug.

[0135] 別の局面において、本発明は、経口投与用薬物送達媒体に関する。この経口投与 用薬物送達媒体は、薬学的に受容可能なキャリアなどをさらに含み得る。薬学的に 受容可能なキャリアとしては、例えば、抗酸化剤、保存剤、着色料、風味料、および 希釈剤、乳化剤、懸濁化剤、溶媒、フィラー、増量剤、緩衝剤、送達ビヒクル、希釈剤 、賦形剤および Zまたは薬学的アジュバントが挙げられるがそれらに限定されな 、。 代表的には、本発明の経口投与用薬物送達媒体は、糖鎖修飾リボソームを、 1っ以 上の生理的に受容可能なキャリア、賦形剤または希釈剤とともに含む組成物の形態 で投与される。例えば、適切なビヒクルは、注射用水、生理的溶液、または人工脳脊 髄液であり得る。 [0135] In another aspect, the present invention relates to a drug delivery vehicle for oral administration. The drug delivery vehicle for oral administration can further comprise a pharmaceutically acceptable carrier and the like. Pharmaceutically acceptable carriers include, for example, antioxidants, preservatives, colorants, flavors, and diluents, emulsifiers, suspending agents, solvents, fillers, extenders, buffers, delivery vehicles, dilutions Agents, excipients and Z or pharmaceutical adjuvants, including but not limited to. Typically, the drug delivery vehicle for oral administration of the present invention is administered in the form of a composition comprising a glycosylated ribosome together with one or more physiologically acceptable carriers, excipients or diluents. The For example, a suitable vehicle can be water for injection, physiological solution, or artificial cerebrospinal fluid.

[0136] 本明細書で使用される受容可能なキャリア、賦形剤または安定化剤は、レシピエント に対して非毒性であり、そして好ましくは、使用される投薬量および濃度において不 活性である。そのような非毒性および不活性のキャリアとしては、例えば、リン酸塩、ク ェン酸塩、または他の有機酸；ァスコルビン酸、 α—トコフエロール；低分子量ポリべ プチド;蛋白質 (例えば、血清アルブミン、ゼラチンまたは免疫グロブリン）；親水性ポ リマー（例えば、ポリビニルピロリドン）；アミノ酸 (例えば、グリシン、グルタミン、ァスパ ラギン、アルギニンまたはリジン）；モノサッカリド、ジサッカリドおよび他の炭水化物（グ ルコース、マンノース、またはデキストリンを含む）；キレート剤（例えば、 EDTA)；糖ァ ルコール (例えば、マン-トールまたはソルビトール）；塩形成対イオン (例えば、ナトリ ゥム）；ならびに Ζあるいは非イオン性表面活性化剤（例えば、 Tween、プル口ニック (pluronic)またはポリエチレングリコール (PEG) )などが挙げられるがそれらに限定 されない。  [0136] Acceptable carriers, excipients or stabilizers used herein are non-toxic to the recipient and are preferably inert at the dosages and concentrations used. . Such non-toxic and inert carriers include, for example, phosphate, citrate, or other organic acids; ascorbic acid, α-tocopherol; low molecular weight polypeptides; proteins (eg, serum albumin Hydrophilic polymers (eg polyvinylpyrrolidone); amino acids (eg glycine, glutamine, asparagine, arginine or lysine); monosaccharides, disaccharides and other carbohydrates (glucose, mannose or dextrin); Chelating agents (eg, EDTA); sugar alcohols (eg, mantol or sorbitol); salt-forming counterions (eg, sodium); and moth or non-ionic surfactants (eg, Tween, pulluric or polyethylene glycol (PEG)), but is not limited thereto.

[0137] 例示の適切なキャリアとしては、中性緩衝化生理食塩水、または血清アルブミンと混 合された生理食塩水が挙げられる。好ましくは、その生成物は、適切な賦形剤 (例え ば、スクロース）を用いて凍結乾燥剤として処方される。他の標準的なキャリア、希釈 剤および賦形剤は所望に応じて含まれ得る。他の例示的な組成物は、 pH7. 0〜8. 5の Tris緩衝剤または pH4. 0〜5. 5の酢酸緩衝剤を含み、これらは、さら〖こ、ソルビ トールまたはその適切な代替物を含み得る。 [0137] Exemplary suitable carriers include neutral buffered saline or serum albumin. Combined saline is mentioned. Preferably, the product is formulated as a lyophilizer using a suitable excipient (eg, sucrose). Other standard carriers, diluents and excipients may be included as desired. Other exemplary compositions include Tris buffer at pH 7.0-8.5 or acetate buffer at pH 4.0-5.5, which are sardine, sorbitol or suitable substitutes thereof. Can be included.

[0138] 1つの局面において、本発明は、糖鎖修飾リボソームを含む経口投与用薬物送達媒 体を提供する。本発明の薬物送達媒体は、 Gal, GalNAc、 Man, Glc、 GlcNAc、 F ucおよび Neu5Ac力もなる群より選択される少なくとも 1つの構造を有する糖鎖、好ま しくは、上記表 1に示される糖鎖を結合した糖鎖修飾リボソームを含む。この糖鎖修 飾リボソームは、薬剤または遺伝子を封入していても、結合していてもよい。  [0138] In one aspect, the present invention provides a drug delivery vehicle for oral administration containing a sugar chain-modified ribosome. The drug delivery vehicle of the present invention comprises a sugar chain having at least one structure selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc, Fuc and Neu5Ac, preferably the sugar chains shown in Table 1 above. Including a sugar chain-modified ribosome linked with The sugar chain-modified ribosome may encapsulate or bind a drug or gene.

[0139] 本発明の糖鎖修飾リボソームに、封入または結合される薬剤としては、例えば、以 下が挙げられるが、これらに限定されない:バイオ医薬品またはバイオ治療用物質（ 例えば、 siRNA、 shRNA、 siRNA誘導体、 shRNA誘導体、 RNA、 RNA誘導体、 DNA、 D NA誘導体、モノクローナル抗体、ワクチン、インターフェロン、ホルモン、プロスタグラ ンジン、転写因子、組換えタンパク質、抗体医薬、核酸〉  [0139] Examples of the drug encapsulated or bound to the sugar chain-modified ribosome of the present invention include, but are not limited to, the following: biopharmaceuticals or biotherapeutic substances (eg, siRNA, shRNA, siRNA) Derivatives, shRNA derivatives, RNA, RNA derivatives, DNA, DNA derivatives, monoclonal antibodies, vaccines, interferons, hormones, prostaglandins, transcription factors, recombinant proteins, antibody drugs, nucleic acids>

医薬、遺伝子治療薬)、  Drugs, gene therapy drugs),

アルキル化系抗癌剤、代謝拮抗剤、植物由来抗癌剤、抗癌性抗生物質、 BRM，サ イト力イン類、白金錯体系抗癌剤、免疫療法剤、ホルモン系抗癌剤、モノクローナル 抗体等の腫瘍用薬剤、中枢神経用薬剤、末梢神経系，感覚器官用薬剤、呼吸器疾 患治療薬剤、循環器用薬剤、消化器官用薬剤、ホルモン系用薬剤、泌尿器'生殖器 用薬剤、ビタミン ·滋養強壮剤、代謝性医薬品、抗生物質 ·化学療法薬剤、検査用薬 剤、抗炎症剤、眼疾患薬剤、中枢神経系薬剤、自己免疫系薬剤、循環器系薬剤、 糖尿病、高脂血症のような生活習慣病薬剤、副腎皮質ホルモン、免疫抑制剤、抗菌 薬、抗ウィルス薬、血管新生抑制剤、サイト力イン、ケモカイン、抗サイト力イン抗体、 抗ケモカイン抗体、抗サイト力イン.ケモカイン受容体抗体、 siRNA、 shRNA、 miR NA、 smRNA、アンチセンス RNAまたは ODNまたは DNAのような遺伝子治療関連 の核酸製剤、神経保護因子、抗体医薬、分子標的薬、骨粗鬆症，骨代謝改善薬、神 経ペプチド、生理活性ペプチド '蛋白質のような薬剤。 [0140] 本発明の経口投与用薬物送達媒体は、生物学的因子を必要とする被験体へ生物学 的因子の経口投与するため、および呼吸器系、循環器系、消化器系、泌尿器'生殖 器系、中枢神経系または末梢神経系の障害を有する哺乳動物を処置するためにも 使用され得る。 Alkylating anticancer drugs, antimetabolites, plant-derived anticancer drugs, anticancer antibiotics, BRM, site force-ins, platinum complex anticancer drugs, immunotherapy drugs, hormone anticancer drugs, tumor drugs such as monoclonal antibodies, central nervous system Drugs, peripheral nervous system, sensory organ drugs, respiratory disease drugs, cardiovascular drugs, gastrointestinal drugs, hormonal drugs, genitourinary drugs, vitamins, nourishing tonics, metabolic drugs, antibiotics Substances ・ Chemotherapeutic drugs, testing drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, autoimmune drugs, cardiovascular drugs, lifestyle-related drugs such as diabetes and hyperlipidemia, adrenal cortex Hormone, immunosuppressive agent, antibacterial agent, antiviral agent, angiogenesis inhibitor, cyto force in, chemokine, anti cyto force in antibody, anti chemokine antibody, anti cyto force in. Chemokine receptor antibody, siRNA, shRNA, m Gene therapy-related nucleic acid preparations such as iRNA, smRNA, antisense RNA or ODN or DNA, neuroprotective factors, antibody drugs, molecular targeting drugs, osteoporosis, bone metabolism improving drugs, neuropeptides, bioactive peptides Such drugs. [0140] The drug delivery vehicle for oral administration of the present invention is used for oral administration of a biological agent to a subject in need of the biological agent, and for the respiratory system, circulatory system, digestive system, urinary ' It can also be used to treat mammals with genital, central or peripheral nervous system disorders.

[0141] 本発明の経口投与用薬物送達媒体は、糖鎖修飾リボソームの糖鎖の種類と結合密 度を調節することによって、腸管での吸収制御性を高めることもできる。腸管吸収制 御性を高める糖鎖と特定の組織または器官への指向性を有する糖鎖の両方をリポソ ームに結合させることにより、特定組織または器官への指向性と腸管吸収制御性の 両方の特性を併せ持ったリボソームを作製することも可能である。  [0141] The drug delivery vehicle for oral administration of the present invention can also enhance the absorption controllability in the intestinal tract by adjusting the type of sugar chain and the binding density of the sugar chain-modified ribosome. By binding to the liposome both sugar chains that enhance intestinal absorption control and sugar chains that have directivity to specific tissues or organs, both directivity to specific tissues or organs and intestinal absorption control are achieved. It is also possible to produce ribosomes with the above characteristics.

[0142] 本発明の経口投与用薬物送達媒体の調製は、 pH、等張性、安定性などを考慮する ことにより、当業者は、容易に行うことができる。本発明の経口投与用薬物送達媒体 は、薬学的に受容可能なキャリアと配合し、錠剤、カプセル剤、顆粒剤、散剤、粉剤 等の固形製剤、シロップ剤、懸濁剤、溶液剤等の液状製剤として経口的に投与する ことができる。  [0142] The drug delivery vehicle for oral administration of the present invention can be easily prepared by those skilled in the art by considering pH, isotonicity, stability, and the like. The drug delivery vehicle for oral administration of the present invention is mixed with a pharmaceutically acceptable carrier, and is a liquid such as a solid preparation such as a tablet, capsule, granule, powder or powder, syrup, suspension or solution. It can be administered orally as a formulation.

[0143] 本発明の経口投与用薬物送達媒体は、必要に応じて生理学的に受容可能なキヤリ ァ、賦型剤または安定化剤 (日本薬局方第 14版またはその最新版、 Remington' s Pharmaceutical sciences, 18th Edition, A. R. Gennaro, ed. , Mack P ublishing Company, 1990などを参照）と、所望の程度の純度を有する糖鎖組成 物とを混合することによって、凍結乾燥されたケーキまたは水溶液の形態で調製され 保存され得る。  [0143] The drug delivery vehicle for oral administration of the present invention comprises a physiologically acceptable carrier, excipient or stabilizer as necessary (Japanese Pharmacopoeia 14th edition or the latest edition, Remington's Pharmaceutical sciences, 18th Edition, AR Gennaro, ed., Mack Publishing Company, 1990, etc.) and a glycan composition having the desired degree of purity, by mixing it in the form of a lyophilized cake or aqueous solution Can be prepared and stored.

[0144] 本発明の処置方法において使用される経口投与用薬物送達媒体の量は、使用目的 、対象疾患 (種類、重篤度など)、患者の年齢、体重、性別、既往歴、細胞の形態ま たは種類などを考慮して、当業者が容易に決定することができる。本発明の処置方 法を被検体 (または患者)に対して施す頻度もまた、使用目的、対象疾患 (種類、重 篤度など)、患者の年齢、体重、性別、既往歴、および治療経過などを考慮して、当 業者が容易に決定することができる。頻度としては、例えば、毎日—数ケ月に 1回（例 えば、 1週間に 1回 1ヶ月に 1回）の投与が挙げられる。 1週間 1ヶ月に 1回の投与 を、経過を見ながら施すことが好ましい。 [0145] 経口投与用薬物送達媒体は、投与に適した投与形において当該分野で周知の薬学 的に受容可能なキャリアを用いて処方され得る。このようなキャリアは、薬物送達媒体 が患者による摂取に適した液体、ゲル、シロップ、スラリー、懸濁物などに処方される ことを可能とする。 [0144] The amount of the drug delivery vehicle for oral administration used in the treatment method of the present invention depends on the purpose of use, target disease (type, severity, etc.), patient age, weight, sex, medical history, cell morphology. Or it can be easily determined by those skilled in the art in consideration of the type and the like. The frequency with which the treatment method of the present invention is applied to a subject (or patient) also depends on the purpose of use, target disease (type, severity, etc.), patient age, weight, gender, medical history, treatment course, etc. Can be easily determined by those skilled in the art. The frequency may be, for example, administered daily—once every several months (eg once a week, once a month). It is preferable to administer once a week, once a month, while monitoring the course. [0145] Drug delivery vehicles for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosage forms suitable for administration. Such carriers allow drug delivery vehicles to be formulated into liquids, gels, syrups, slurries, suspensions, etc. suitable for consumption by the patient.

[0146] 本発明の薬物送達媒体は、薬剤または生物学的因子が意図される目的を達成する のに有効な量で、糖鎖修飾リボソーム中に含有される組成物を含む。「処置するのに 有効な量」は当業者に十分に認識される用語であり、意図される薬理学的結果 (例え ば、予防、治療、再発防止など)を生じるために有効な薬剤の量をいう。従って、処置 有効量は、処置されるべき疾患の徴候を軽減するのに十分な量である。所定の適用 のための有効量 (例えば、処置有効量)を確認する 1つの有用なアツセィは、標的疾 患の回復の程度を測定することである。実際に投与される量は、処置が適用されるべ き個体に依存し、好ましくは、所望の効果が顕著な副作用をともなうことなく達成され るように最適化された量である。有効用量の決定は十分に当業者の能力内にある。  [0146] The drug delivery vehicle of the present invention comprises a composition contained in a sugar chain-modified ribosome in an amount effective to achieve the intended purpose of the drug or biological agent. An “effective amount to treat” is a term well recognized by those skilled in the art and is an amount of a drug effective to produce the intended pharmacological result (eg, prevention, treatment, prevention of recurrence, etc.). Say. Thus, a treatment effective amount is an amount sufficient to reduce symptoms of the disease to be treated. One useful approach to ascertaining an effective amount (eg, a therapeutically effective amount) for a given application is to measure the extent of recovery of the target disease. The amount actually administered will depend on the individual to whom the treatment is to be applied, and is preferably an amount optimized to achieve the desired effect without significant side effects. The determination of an effective dose is well within the ability of those skilled in the art.

[0147] 治療有効量、予防有効量などおよび毒性は、細胞培養または実験動物における標 準的な薬学的手順 (例えば、 ED 、集団の 50%において治療的に有効な用量;お  [0147] Therapeutically effective doses, prophylactically effective doses, and the like and toxicity are standard pharmaceutical procedures in cell cultures or laboratory animals (e.g. ED, doses therapeutically effective in 50% of the population; and

50  50

よび LD 、集団の 50%に対して致死的である用量）によって決定され得る。治療効 And LD, doses that are lethal to 50% of the population). Therapeutic effect

50 50

果と毒性効果との間の用量比は治療係数であり、それは比率 ED ZLD  The dose ratio between fruit and toxic effects is the therapeutic index, which is the ratio ED ZLD

50 50として表さ れ得る。大きな治療係数を呈する薬物送達媒体が好ましい。細胞培養アツセィおよ び動物実験力 得られたデータ力 ヒトでの使用のための量の範囲を公式ィ匕するの に使用される。このような化合物の用量は、好ましくは、毒性をほとんどまたは全くとも なわな 、ED を含む循環濃度の範囲内にある。この用量は、使用される投与形態、  50 can be expressed as 50. Drug delivery vehicles that exhibit large therapeutic indices are preferred. Cell culture and animal experimentation power obtained Data used to formulate a range of quantities for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED with little or no toxicity. This dosage is the dosage form used,

50  50

患者の感受性、および投与経路に依存してこの範囲内で変化する。一例として、投 与量は、年齢その他の患者の条件、疾患の種類、使用する細胞の種類等により適宜 選択される。  It will vary within this range depending on the sensitivity of the patient and the route of administration. As an example, the dose is appropriately selected depending on age and other patient conditions, the type of disease, the type of cells used, and the like.

[0148] 本発明の薬物送達媒体は、当該分野で公知の様式と同様の様式 (例えば、混合、溶 解など)で製造され得る。  [0148] The drug delivery vehicle of the present invention can be manufactured in a manner similar to that known in the art (eg, mixing, dissolving, etc.).

[0149] 本明細書において「指示書」は、本発明の糖鎖修飾リボソームまたは経口投与用薬 物送達媒体などを投与する方法などを医師、患者など投与を行う人、診断する人 (患 者本人であり得る）に対して記載したものである。この指示書は、本発明の糖鎖修飾リ ポソームまたは経口投与用薬物送達媒体などを投与する手順を指示する文言が記 載されている。この指示書は、本発明が実施される国の監督官庁 (例えば、日本であ れば厚生労働省、米国であれば食品医薬品局 (FDA)など)が規定した様式に従つ て作成され、その監督官庁により承認を受けた旨が明記される。指示書は、いわゆる 添付文書 (package insert)であり、通常は紙媒体で提供されるが、それに限定さ れず、例えば、電子媒体 (例えば、インターネットで提供されるホームページ (ウェブ サイト）、電子メール)のような形態でも提供され得る。 In the present specification, the “instruction” refers to a method for administering the sugar chain-modified ribosome of the present invention or a drug delivery vehicle for oral administration, etc. The person who can be the person himself / herself). This instruction manual includes a word indicating a procedure for administering the sugar chain-modified liposome of the present invention or a drug delivery vehicle for oral administration. This instruction is prepared according to a format prescribed by the national supervisory authority in which the present invention is implemented (for example, the Ministry of Health, Labor and Welfare in Japan and the Food and Drug Administration (FDA) in the United States). It is clearly stated that it has been approved by the supervisory authority. Instructions are so-called package inserts, usually provided in paper form, but not limited to it, for example, electronic media (eg homepage (website) provided by the Internet, e-mail) It can also be provided in such a form.

[0150] 本明細書において「被験体」とは、本発明の処置が適用される生物をいい、「患者」と もいわれる。患者または被験体は好ましくは、ヒトであり得る。  [0150] As used herein, "subject" refers to an organism to which the treatment of the present invention is applied, and is also referred to as "patient". The patient or subject may preferably be a human.

[0151] (糖鎖修飾リボソームの医薬としての使用） 他の局面において、本発明は、呼吸器 系、循環器系、消化器系、泌尿器，生殖器系、中枢神経系、または末梢神経系の障 害を処置するための医薬の製造のための、糖鎖修飾リボソームの使用を提供する。 ここで糖鎖修飾リボソームは、上述の (糖鎖修飾リボソーム）に記載される任意の形態 が使用され得る。  [0151] (Use of glycosylated ribosome as a medicine) In another aspect, the present invention relates to a disorder of the respiratory system, circulatory system, digestive system, urinary system, genital system, central nervous system, or peripheral nervous system. The use of a sugar chain-modified ribosome for the manufacture of a medicament for treating harm is provided. Here, as the sugar chain-modified ribosome, any form described in the above (Sugar chain-modified ribosome) can be used.

[0152] (処置方法） 別の局面において、本発明は、呼吸器系、循環器系、消化器系、泌尿 器'生殖器系、中枢神経系、または末梢神経系の障害を有する被験体を処置するた めの方法を提供する。この方法は、被験体に、障害を処置するための経口投与用薬 物送達媒体を投与する工程を包含し、該経口投与用薬物送達媒体は糖鎖修飾リポ ソームおよび薬学的受容可能なキャリアを含み、該糖鎖修飾リボソームは該障害を 処置するのに有効な量の薬剤を含有する。ここで糖鎖修飾リボソームは、上述の (糖 鎖修飾リボソーム）に記載される任意の形態が使用され得る。  [0152] (Treatment Method) In another aspect, the present invention treats a subject having a disorder of the respiratory system, circulatory system, digestive system, urinary 'genital system, central nervous system, or peripheral nervous system. Provide a way to do this. This method comprises the step of administering to a subject an orally administered drug delivery vehicle for treating a disorder, wherein the orally administered drug delivery vehicle comprises a glycosylated liposome and a pharmaceutically acceptable carrier. And the glycosylated ribosome contains an amount of the drug effective to treat the disorder. Here, as the sugar chain-modified ribosome, any form described in the above (Sugar-modified ribosome) can be used.

[0153] (送達方法） 別の局面において、本発明は、生物学的因子を必要とする被験体に おいて、標的部位に該生物学的因子を送達するための方法を提供する。この方法は 、本発明の糖鎖修飾リボソームを経口投与する工程を包含し、該糖鎖修飾リボソーム は該生物学的因子の有効量を含有する。ここで糖鎖修飾リボソームは、上述の (糖鎖 修飾リボソーム）に記載される任意の形態が使用され得る。  [0153] (Delivery Method) In another aspect, the present invention provides a method for delivering a biological agent to a target site in a subject in need of the biological agent. This method includes the step of orally administering the sugar chain-modified ribosome of the present invention, wherein the sugar chain-modified ribosome contains an effective amount of the biological factor. Here, as the sugar chain-modified ribosome, any form described in the above (Sugar chain-modified ribosome) can be used.

[0154] (製造方法） 別の局面において、本発明は、糖鎖修飾リボソームを製造する方法を 提供する。この方法は、（a)リボソームを提供する工程；（b)該リボソームを親水性ィ匕 処理する工程；（c)必要に応じて、該親水性ィ匕処理されたリボソームにリンカ一を結 合させて、リンカ一結合リボソームを生成する工程;および (d)該リボソームに、糖鎖を 結合させて糖鎖修飾リボソームを生成する工程を包含する。好ましくは、この方法に おいて、工程 (b)のリボソームを親水性ィ匕処理する工程は、リボソームの脂質膜上ま たはリンカ一上に、直接または間接的に低分子量の親水性ィ匕合物 (例えば、トリス (ヒ ドロキシアルキル)アミノアルカンなど）を結合することによって実施され、工程 (c)に おいて使用されるリンカ一は、ヒト由来の蛋白質 (例えば、ヒト血清アルブミンなど)で あり、そして工程 (d)において、該リボソームに、直接または間接的に糖鎖を結合させ る条件下で、糖鎖を結合させて糖鎖修飾リボソームを生成する。 (Production method) [0154] In another aspect, the present invention provides a method for producing a sugar chain-modified ribosome. provide. This method comprises the steps of: (a) providing a ribosome; (b) treating the ribosome with a hydrophilic treatment; (c) binding a linker to the hydrophilic ribosome, if necessary. A linker-linked ribosome; and (d) a step of binding a sugar chain to the ribosome to generate a sugar chain-modified ribosome. Preferably, in this method, the step of treating the ribosome in step (b) with a hydrophilic property is carried out directly or indirectly on the lipid membrane or linker of the ribosome. The linker used in step (c) is performed by binding a compound (for example, tris (hydroxyalkyl) aminoalkane) and the like, and a human-derived protein (for example, human serum albumin) is used. In step (d), a sugar chain is bound to the ribosome directly or indirectly under the condition for binding the sugar chain to produce a sugar chain-modified ribosome.

[0155] 別の局面において、本発明は、 目的の送達部位に薬物を送達するための糖鎖修飾 リボソームの製造方法を提供する。この方法は、（a)種々の糖鎖密度を有する、該目 的の送達部位への送達を達成する糖鎖修飾リボソームを提供する工程；（b)該糖鎖 修飾リボソーム上の糖鎖密度にっ ヽて、該送達部位への最適な送達を達成する密 度を決定する工程；および (c)該薬物を決定された最適な糖鎖修飾リボソームに組み 込んで薬物含有リボソームを生成する工程を包含する。 [0155] In another aspect, the present invention provides a method for producing a sugar chain-modified ribosome for delivering a drug to a target delivery site. This method comprises the steps of: (a) providing a sugar chain-modified ribosome having various sugar chain densities to achieve delivery to the intended delivery site; (b) adjusting the sugar chain density on the sugar chain-modified ribosome. Thus determining the density to achieve optimal delivery to the delivery site; and (c) incorporating the drug into the determined optimal glycosylated ribosome to produce a drug-containing ribosome. Include.

[0156] (リボソームの製造)リボソーム自体は、周知の方法に従い製造することができる力 こ れには、薄膜法、逆層蒸発法、エタノール注入法、脱水一再水和法等を挙げること ができる。  [0156] (Production of ribosome) The ribosome itself can be produced according to a well-known method. Examples thereof include a thin film method, a reverse layer evaporation method, an ethanol injection method, and a dehydration-one rehydration method. .

[0157] また、超音波照射法、エタストルージョン法、フレンチプレス法、ホモジナイゼーシヨン 法等を用いて、リボソームの粒子径を調節することも可能である。本発明のリボソーム 自体の製法について、具体的に述べると、例えば、まず、ホスファチジルコリン類、コ レステロール、ホスファチジルエタノールアミン類、ホスファチジン酸類、ガングリオシ ド類、糖脂質類もしくはホスファチジルグリセロール類を配合成分とする脂質と界面活 性剤コール酸ナトリウムとの混合ミセルを調製する。とりわけ、ホスファチジン酸類もし くはジセチルホスフェート等の長鎖アルキルリン酸塩類の配合は、リボソームを負に 荷電させるために必須であり、ホスファチジルエタノールァミン類の配合は親水性ィ匕 反応部位として、ガンダリオシド類または糖脂質類またはホスファチジルグリセロール 類の配合はリンカ一の結合部位として必須のものである。ガンダリオシド類、糖脂質 類、ホスファチジルグリセロール類、スフインゴミエリン類およびコレステロール類から なる群力 選択される少なくとも 1種の脂質はリボソーム中で集合し、リンカ一を結合 させる足場 (ラフト）として機能する。本発明のリボソームは、このような蛋白質を結合さ せうるラフトが形成されることによりさらに安定化される。すなわち、本発明のリポソ一 ムは、リンカ一を結合させるためのガンダリオシド、糖脂質、ホスファチジルグリセロー ル類、スフインゴミエリン類およびコレステロール類力 なる群力 選択される少なくと も、 1種の脂質のラフトが形成されたリボソームを含む。そして、これにより得られる混 合ミセルの限外濾過を行うことによりリボソームを作製する。本発明において使用する リボソームは、通常のものでも使用できる力 その表面は親水性ィ匕されていることが望 ま 、。上述のようにしてリボソームを作製した後にリボソーム表面を親水性ィ匕する。 [0157] In addition, the particle size of ribosome can be adjusted by using an ultrasonic irradiation method, an etrusion method, a French press method, a homogenization method, or the like. The production method of the ribosome itself of the present invention will be specifically described. For example, first, a lipid containing phosphatidylcholines, cholesterol, phosphatidylethanolamines, phosphatidic acids, gangliosides, glycolipids or phosphatidylglycerols as a component. Prepare mixed micelles with the surfactant sodium cholate. In particular, the combination of phosphatidic acids or long-chain alkyl phosphates such as dicetyl phosphate is essential to negatively charge the ribosome, and the combination of phosphatidylethanolamines is a hydrophilic reaction site. Gandariosides or glycolipids or phosphatidylglycerol The combination of the kinds is essential as a binding site of the linker. Group power consisting of gandiosides, glycolipids, phosphatidylglycerols, sphingomyelins, and cholesterols At least one selected lipid assembles in the ribosome and functions as a scaffold (raft) that binds the linker. The ribosome of the present invention is further stabilized by the formation of rafts that can bind such proteins. That is, the liposome of the present invention has at least one kind of lipid selected from the group forces of gandarioside, glycolipid, phosphatidylglycerol, sphingomyelins and cholesterol for binding the linker. It contains ribosomes with rafts. Then, ribosomes are produced by ultrafiltration of the mixed micelles obtained in this way. The ribosome used in the present invention is a force that can be used even if it is a normal one. The surface is desired to be hydrophilic. After preparing the ribosome as described above, the surface of the ribosome is made hydrophilic.

[0158] 本発明は、上記の親水性ィ匕化合物を用いて親水性ィ匕した糖鎖の結合していないリポ ソームそのものをも包含する。このような親水性化したリボソームは、リボソーム自体の 安定性が高まり、また糖鎖を結合したと [0158] The present invention also includes liposomes that are not bound to sugar chains that are hydrophilic using the above-mentioned hydrophilic compounds. Such hydrophilic ribosomes have increased stability of the ribosome itself, and are linked to sugar chains.

きに糖鎖の認識性が高まるという利点がある。本発明のリボソームは、例えば、リポソ ームの構成脂質が、ホスファチジルコリン類（モル比 0〜70%)、ホスファチジルェタノ ールァミン類（モル比 0〜30%)、ホスファチジン酸類、長鎖アルキルリン酸塩および ジセチルリン酸類力もなる群力も選択される 1種以上の脂質 (モル比 0〜30%)、ガン ダリオシド類、糖脂質類、ホスファチジルグリセロール類およびスフインゴミエリン類か らなる群力 選択される 1種以上の脂質 (モル比 0〜40%)、ならびにコレステロール 類（モル比 0〜70%)を含む、リボソームである。  There is an advantage that sugar chain recognition is enhanced. In the ribosome of the present invention, for example, liposomal lipids are phosphatidylcholines (molar ratio 0 to 70%), phosphatidylethanolamines (molar ratio 0 to 30%), phosphatidic acids, and long-chain alkyl phosphates. One or more lipids (molar ratio 0-30%), gandariosides, glycolipids, phosphatidylglycerols and sphingomyelins are selected. It is a ribosome containing the above lipids (molar ratio 0 to 40%) and cholesterols (molar ratio 0 to 70%).

[0159] 本発明は、さらにリボソームに上記に親水性ィ匕化合物を結合させて、リボソームを親 水性化する方法をも包含する。また、糖鎖の結合していない親水性ィ匕したリボソーム をも包含する。糖鎖の結合していないリボソームに糖鎖を結合することにより、本発明 の標的指向性リボソームまたは腸管吸収性リボソームを製造することができる。  [0159] The present invention further includes a method of hydrophilizing the ribosome by binding the above-described hydrophilic compound to the ribosome. It also includes hydrophilic ribosomes with no sugar chains attached. The target-directed ribosome or intestinal absorbable ribosome of the present invention can be produced by binding a sugar chain to a ribosome to which no sugar chain is bound.

[0160] (糖鎖の合成） 本発明の糖鎖修飾リボソームに使用され得る糖鎖は、一般的な糖鎖 合成方法によって合成され得る。これらの方法としては、（1)化学合成による方法、（ 2)遺伝子組換え細胞あるいは微生物による発酵法、 (3)糖加水分解酵素 (グリコシ ダーゼ)を用いて合成する方法、（4)糖転移酵素（グリコシルトランスフェラーゼ)を用 いて合成する方法が挙げられる。 (WO2002/081723,特開平 9 31095公報、 特開平 11—42096公報、特開 2004— 180676公報、畑中研一、西村紳一郎、大 内辰郎および小林一清（1997)糖質の科学と工業、講談社、東京などを参照のこと） (Synthesis of sugar chain) [0160] The sugar chain that can be used in the sugar chain-modified ribosome of the present invention can be synthesized by a general sugar chain synthesis method. These methods include (1) chemical synthesis, (2) fermentation using genetically modified cells or microorganisms, and (3) sugar hydrolase (glycosylation). (4) a synthesis method using a glycosyltransferase (glycosyltransferase). (WO2002 / 081723, JP-A-9 31095, JP-A-11-42096, JP-A-2004-180676, Kenichi Hatanaka, Shinichiro Nishimura, Goro Ouchi and Kazuyoshi Kobayashi (1997) Carbohydrate Science and Industry, Kodansha, (See Tokyo etc.)

[0161] 本発明の糖鎖修飾リボソームにおいて使用される糖鎖は、上記の方法により合成さ れた糖鎖であっても、市販の糖鎖であってもよい。 [0161] The sugar chain used in the sugar chain-modified ribosome of the present invention may be a sugar chain synthesized by the above method or a commercially available sugar chain.

[0162] (リボソームへの糖鎖の結合） 本発明においては、上記のようにして作製したリポソ ームに、上記の糖鎖のいずれかを直接結合させてもよいし、さら〖こ、リンカ一を介して 糖鎖を結合させてもよい。この際、リボソームに結合させる糖鎖の種類は 1種類に限ら ず、複数の糖鎖を結合させてもよい。この場合の複数の糖鎖は同じ組織または器官 の細胞表面に共通して存在する異なるレクチンに対して結合活性を有する複数の糖 鎖であってもよいし、異なる組織または器官の細胞表面に存在する異なるレクチンに 対して結合活性を有する糖鎖であってもよ ヽ。前者のような複数の糖鎖を選択するこ とにより、特定の標的組織または器官を確実に指向することができ、後者のような複 数の糖鎖を選択することにより、 1種類のリボソームに複数の標的を指向させることが でき、マルチパーパスな標的指向性リボソームを得ることができる。  (Coupling of sugar chain to ribosome) In the present invention, any of the above sugar chains may be directly bound to the liposome prepared as described above. A sugar chain may be bonded via one. At this time, the type of sugar chain to be bound to the ribosome is not limited to one, and a plurality of sugar chains may be bound. In this case, the plurality of sugar chains may be a plurality of sugar chains having binding activity to different lectins that are commonly present on the cell surface of the same tissue or organ, or may be present on the cell surface of different tissues or organs. It may be a sugar chain that has binding activity to different lectins. By selecting multiple sugar chains such as the former, it is possible to reliably target a specific target tissue or organ, and by selecting multiple sugar chains such as the latter, a single ribosome can be selected. Multiple targets can be directed, and multipurpose target-directed ribosomes can be obtained.

[0163] なお、糖鎖をリボソームに結合させるには、リボソームの製造時にリンカ一および/ま たは糖鎖を混合し、リボソームを製造させつつ糖鎖をその表面に結合させることも可 能である力 あら力じめリボソーム、リンカ一および糖鎖を別途準備し、製造が完了し たリボソームにリンカ一および Zまたは糖鎖を結合させたほうが望ましい。これは、リ ポソームにリンカ一および zまたは糖鎖を結合させることにより、結合させる糖鎖の密 度を制御できるからである。糖鎖のリボソームへの直接結合は、以下に述べるような 方法で行うことができる。  [0163] In order to bind sugar chains to ribosomes, it is also possible to mix the linkers and / or sugar chains during the production of ribosomes and to bind the sugar chains to the surface while producing ribosomes. It is desirable to prepare ribosomes, linkers, and sugar chains separately and add linkers and Z or sugar chains to the completed ribosomes. This is because the density of the sugar chain to be bound can be controlled by binding the linker and z or sugar chain to the liposome. Direct binding of sugar chains to ribosomes can be performed by the methods described below.

[0164] 糖鎖を糖脂質として混合してリボソームを製造するか、製造後のリボソームのリン脂質 に糖鎖を結合するとともに糖鎖密度を制御する。リンカ一を用いて糖鎖を結合させる 場合、リンカ一としては、生体由来の蛋白質、特にヒト由来蛋白質を用いるのが好まし い。生体由来の蛋白質は限定されないが、アルブミン等の血液中に存在する蛋白質 、その他生体に存在する生理活性物質等が挙げられる。例えば、ヒト血清アルブミン[0164] A ribosome is produced by mixing a sugar chain as a glycolipid, or a sugar chain is bound to a phospholipid of the ribosome after production and the sugar chain density is controlled. When linking sugar chains using a linker, it is preferable to use a biological protein, particularly a human-derived protein, as the linker. Proteins derived from living organisms are not limited, but proteins that exist in blood such as albumin And other physiologically active substances present in the living body. For example, human serum albumin

(HSA)、ゥシ血清アルブミン (BSA)等の動物の血清アルブミンが挙げられる力 特 にヒト血清アルブミンを使用する場合は、各組織に対する取り込みが多いことがマウ スについての実験により確かめられている。本発明のリボソームは、非常に安定であ り、リボソームを形成した後に蛋白質を結合させたり、リンカ一を結合させたり、糖鎖を 結合させるという後処理が可能である。従って、リボソームを大量に製造した後に、 目 的に応じてそれぞれ異なる蛋白質を結合させたり、リンカ一や糖鎖を結合させること により、 目的に応じた種々のリボソームを製造することが可能である。 (HSA), sushi serum albumin (BSA) and other animal serum albumin powers, especially when using human serum albumin, it has been confirmed by experiments on mice that the uptake into each tissue is high. . The ribosome of the present invention is very stable, and can be post-treated by binding a protein, binding a linker, or binding a sugar chain after the ribosome is formed. Therefore, after producing a large amount of ribosomes, it is possible to produce various ribosomes according to the purpose by binding different proteins or binding linkers or sugar chains depending on the purpose.

[0165] 本発明のリボソームには、糖鎖がリンカ一を介して、あるいはリボソームを構成する脂 質に直接結合している。本発明のリボソームは、糖脂質や糖蛋白質等の複合糖質型 リガンドを有し、低分子化合物で親水化処理されて 、るリボソームである。  [0165] In the ribosome of the present invention, a sugar chain is directly bonded to a lipid constituting the ribosome via a linker. The ribosome of the present invention is a ribosome having a complex carbohydrate type ligand such as glycolipid and glycoprotein and hydrophilized with a low molecular weight compound.

[0166] また、後述のように、本発明の標的指向性リボソームを医薬として用いる場合、該リポ ソームは医薬効果を有する化合物を含んでいる必要がある。該医薬効果を有する化 合物は、リボソーム中に封入させるか、あるいはリボソーム表面に結合させればよい 力 リンカ一として、医薬効果を有する蛋白質を用いてもよい。この場合、蛋白質がリ ポソ一ムと糖鎖を結合させるためのリンカ一および医薬効果を有する蛋白質を兼ねる こともある。薬効を有する蛋白質としては、生理活性蛋白質等が挙げられる。  [0166] Further, as described later, when the target-directed ribosome of the present invention is used as a medicine, the liposome needs to contain a compound having a pharmaceutical effect. The compound having a medicinal effect may be encapsulated in a ribosome, or may be bound to the ribosome surface. As a force linker, a protein having a medicinal effect may be used. In this case, the protein may also serve as a linker for binding the liposome and the sugar chain and a protein having a medicinal effect. Examples of proteins having medicinal effects include physiologically active proteins.

[0167] 本発明の糖鎖修飾リボソームの作製において、リボソームとリンカ一とを結合させる際 には、架橋剤が使用され得る。  [0167] In the production of the sugar chain-modified ribosome of the present invention, a cross-linking agent can be used when binding the ribosome and the linker.

[0168] リンカ一を介して糖鎖をリボソームへ結合させるには以下に述べる方法で行えばよい  [0168] The sugar chain can be bound to the ribosome via the linker by the method described below.

[0169] まずリボソーム表面に蛋白質を結合させる。リボソームを、 NalO [0169] First, a protein is bound to the ribosome surface. Ribosome, NalO

4、 Pb (0 CCH )  4, Pb (0 CCH)

2 3 4、 2 3 4,

NaBi03等の酸化剤で処理して、リボソーム膜面に存在するガンダリオシドを酸化し 、次いで、 NaBH CN、 NaBH等の試乗を用いて、リンカ一とリボソーム膜面上のガ Treatment with an oxidizing agent such as NaBi03 oxidizes the gandarioside present on the ribosome membrane surface, and then using a test drive such as NaBH CN, NaBH, etc.

3 4  3 4

ングリオシドを、還元的ァミノ化反応により結合させる。このリンカ一も、親水性化する のが好ましぐこれにはリンガー蛋白質にヒドロキシ基を有する化合物を結合させるが 、例えば、ビススルホスクシ-ミジルスべラート、ジスクシ-ミジルグルタレート、ジチォ ビススクシ-ミジノレプロピオネート、ジスクシ-ミジノレスべラート、 3, 3，一ジチオビス（ スノレホスクシ-ミジルプロピオネート）、エチレングリコールビススクシ-ミジノレスクシネ ート、エチレングリコールビススルホスクシ-ミジルスクシネート等の 2価試薬を用いて 、トリス (ヒドロキシメチル)ァミノメタン等の上述の親水性ィ匕に用いる化合物をリポソ一 ム上のリンカ一と結合させればよい。 Ngurioside is coupled by a reductive amination reaction. This linker is also preferably hydrophilized. For this purpose, a compound having a hydroxy group is bound to Ringer protein. Propionate, disuccimidinosberate, 3, 3, monodithiobis ( The above-mentioned hydrophilic properties such as tris (hydroxymethyl) aminomethane using a bivalent reagent such as ethylene glycol bissuccinimidolesuccinate and ethylene glycol bissulfosuccinimidyl succinate. The compound used for sex should be bound to the linker on the liposome.

[0170] これを具体的に述べると、まず、リンカ一のすべてのァミノ基に架橋用 2価試薬の一 端結合する。そして、各種糖鎖の還元末端をグリコシルァミノ化反応して得られる糖 鎖グリコシルァミンィ匕合物を調製し、この糖鎖のアミノ基とリボソーム上の上記で結合 された架橋 2価試薬の一部分の他の未反応末端とを結合する。糖鎖および Zまたは 親水性ィ匕合物とリボソームとの共有結合、または糖鎖および Zまたは親水性ィ匕合物 とリンカ一との共有結合は、リボソームが細胞内に取り込まれたときに切断することも 可能である。例えば、リンカ一と糖鎖がジスルフイド結合を介して共有結合されている 場合、細胞内で還元されて糖鎖が切断される。糖鎖が切断されることによりリボソーム 表面が疎水性になり、生体膜と結合し膜安定性が乱れリボソーム中に含まれる薬剤 が放出される。 [0170] Specifically, first, one end of a divalent reagent for crosslinking is bonded to all the amino groups of the linker. Then, a glycosylamine compound obtained by glycosylation of the reducing ends of various sugar chains is prepared, and the above-mentioned cross-linked divalent reagent on the ribosome and the amino group of this sugar chain is prepared. To other unreacted ends. The covalent bond between the sugar chain and Z or hydrophilic compound and the ribosome, or the covalent bond between the sugar chain and Z or hydrophilic compound and the linker is cleaved when the ribosome is taken into the cell. It is also possible to do this. For example, when a linker and a sugar chain are covalently bonded via a disulfide bond, the sugar chain is cleaved by reduction in the cell. When the sugar chain is cleaved, the ribosome surface becomes hydrophobic, binds to the biological membrane, disturbs the membrane stability, and releases the drug contained in the ribosome.

[0171] 次に、このようにして得られる糖鎖結合リボソーム膜面上蛋白質の表面に糖鎖が結合 して!/ヽな!ヽ未反応で残って!/ヽる大部分の 2価試薬未反応末端を用いて親水性化処 理を行う。つまり、このリボソーム上蛋白質に結合している 2価試薬の未反応末端とトリ ス (ヒドロキシメチル)ァミノメタン等の上述の親水性ィ匕に用いる化合物との結合反応 を行い、リボソーム表面全体を親水性化する。リボソーム表面およびリンカ一の親水 性ィ匕は、各種組織への移行性、および血中における滞留性および各種組織への移 行性を向上させる。これは、リボソーム表面およびリンカ一表面が親水性ィ匕されること によって、糖鎖以外の部分が、各組織等においてはあた力も生体内水分であるかの ようにみえ、これにより、標的以外の組織等に認識されず、糖鎖のみがその標的組織 のレクチン (糖鎖認識蛋白質）により認識されることに起因するものと思われる。  [0171] Next, most of the divalent reagents that bind to the surface of the protein on the sugar chain-bound ribosome membrane thus obtained! Perform hydrophilic treatment using the unreacted end. In other words, the unreacted end of the divalent reagent bound to the protein on the ribosome and the compound used for the above-mentioned hydrophilic property such as tris (hydroxymethyl) aminomethane are subjected to a binding reaction to make the entire ribosome surface hydrophilic. Turn into. The hydrophilicity of the ribosome surface and the linker improves migration to various tissues, retention in blood, and migration to various tissues. This is because the surface of the ribosome and the surface of the linker are made hydrophilic, so that the parts other than sugar chains appear to be water in the body in each tissue. This is probably due to the fact that only the sugar chain is recognized by the lectin (sugar chain recognition protein) of the target tissue.

[0172] 次いで、糖鎖をリボソーム上のリンカ一に結合させる。これには、糖鎖を構成する糖 類の還元末端を、 NH HCO 、 NH COONH等のアンモ-ゥム塩を用いてグリコシ  [0172] Next, the sugar chain is bound to a linker on the ribosome. For this purpose, the reducing end of the sugar constituting the sugar chain is glycosylated using ammonia salts such as NH HCO and NH COONH.

4 3 2 4  4 3 2 4

ルアミノィ匕し、次いで、ビススルホスクシ-ミジルスべラート、ジスクシ-ミジルグルタレ ート、ジチオビススクシ-ミジルプロピオネート、ジスクシ二ミジノレスべラート、 3, 3，一 ジチォビス（スノレホスクシ-ミジルプロピオネート）、エチレングリコールビススクシ-ミ ジルスクシネート、エチレングリコールビススルホスタシ-ミジルスクシネート等の 2価 試薬を用いて、リボソーム膜面上に結合したリンカ一と、上記グリコシルァミノ化された 糖類とを結合させてリボソームを得る。なお、これらの糖鎖は市販されている。 Then bissulfosucci-midyl suberate, disucci-midyl glutarate, dithiobis succi-midyl propionate, disuccinimidino resberate, 3, 3, 1 Using a divalent reagent such as dithiobis (sunolephosucci-midylpropionate), ethylene glycol bissuccinimidyl succinate, ethylene glycol bissulfostasis-midyl succinate, A ribosome is obtained by binding the glycosylated amino acid. These sugar chains are commercially available.

[0173] 本発明のリボソーム、糖鎖等結合リボソームの粒径は、 30〜500nm、好ましくは 50 〜350nmである。また、本発明のリボソームは、負に荷電していることが望ましい。負 に荷電していることにより、生体中の負に荷電している細胞との相互作用を防ぐことが できる。本発明のリボソーム表面のゼータ電位は、生理食塩水中において、 37°Cで、 50〜： LOmV、好ましくは一 40〜0mV、さらに好ましくは一 30〜一 10mVである。  [0173] The particle size of the ribosome or sugar chain-bound ribosome of the present invention is 30 to 500 nm, preferably 50 to 350 nm. Moreover, it is desirable that the ribosome of the present invention is negatively charged. By being negatively charged, interaction with negatively charged cells in the living body can be prevented. The zeta potential on the surface of the ribosome of the present invention is 50 to: LOmV, preferably 1 to 40 to 0 mV, more preferably 1 to 30 to 10 mV at 37 ° C. in physiological saline.

[0174] 本発明の糖鎖修飾リボソームに含ませる薬剤としては、バイオ医薬品またはバイオ 治療用物質（例えば、 siRNA、 shRNA、 siRNA誘導体、 shRNA誘導体、 RNA、 RNA誘 導体、 DNA、 DNA誘導体、モノクローナル抗体、ワクチン、インターフェロン、ホルモン 、プロスタグランジン、転写因子、組換えタンパク質、抗体医薬、核酸〉  [0174] The drug contained in the sugar chain-modified ribosome of the present invention includes biopharmaceuticals or biotherapeutic substances (eg, siRNA, shRNA, siRNA derivatives, shRNA derivatives, RNA, RNA derivatives, DNA, DNA derivatives, monoclonal antibodies) , Vaccine, interferon, hormone, prostaglandin, transcription factor, recombinant protein, antibody drug, nucleic acid>

医薬、遺伝子治療薬)、アルキル化系抗癌剤、代謝拮抗剤、植物由来抗癌剤、抗癌 性抗生物質、 BRM'サイト力イン類、白金錯体系抗癌剤、免疫療法剤、ホルモン系 抗癌剤、モノクローナル抗体等の腫瘍用薬剤、中枢神経用薬剤、末梢神経系'感覚 器官用薬剤、呼吸器疾患治療薬剤、循環器用薬剤、消化器官用薬剤、ホルモン系 用薬剤、泌尿器'生殖器用薬剤、ビタミン '滋養強壮剤、代謝性医薬品、抗生物質' 化学療法薬剤、検査用薬剤、抗炎症剤、眼疾患薬剤、中枢神経系薬剤、自己免疫 系薬剤、循環器系薬剤、糖尿病、高脂血症のような生活習慣病薬剤、副腎皮質ホル モン、免疫抑制剤、抗菌薬、抗ウィルス薬、血管新生抑制剤、サイト力イン、ケモカイ ン、抗サイト力イン抗体、抗ケモカイン抗体、抗サイト力イン'ケモカイン受容体抗体、 s iRNA、 shRNA、 miRNA、 smRNA、アンチセンス RNAまたは ODNまたは DNA のような遺伝子治療関連の核酸製剤、神経保護因子、抗体医薬、分子標的薬、骨粗 鬆症 ·骨代謝改善薬、神経ペプチド、生理活性ペプチド ·蛋白質等が挙げられる。例 えば、腫瘍用薬剤として、塩酸ナイトロジエンマスタードー N ォキシド、シクロホスフ アミド、ィホスフアミド、プルスファン、塩酸-ムスチン、ミトブロニートール、メルファラン 、ダカルバジン、ラ-ムスチン、リン酸エストラムスチンナトリウムなどのアルキル化剤、 メルカプトプリン、チォイノシン (メルカプトプリンリボシド）、メトトレキサート、エノシタビ ン、シタラビン、塩酸アンシタビン（塩酸サイクロシチジン）、フルォロウラシル、 5-FU 、テガフール、ドキシフルリジン、カルモフールなどの代謝拮抗剤、エトポシド、硫酸ビ ンプラスチン、硫酸ピンクリスチン、硫酸ビンデシン、パクリタキセル、タキノール、塩 酸イリノテカン、塩酸ノギテカンなどのアルカロイド等の植物由来抗癌剤、ァクチノマ イシン D、マイトマイシン C、クロモマイシン A3、塩酸ブレオマイシン、硫酸ブレオマイ シン、硫酸ぺプロマイシン、塩酸ダウノルビシン、塩酸ドキソルビシン、塩酸アクラルビ シン（アクラシノマイシン A)、塩酸ピラルビシン、塩酸ェピルビシン、ネオカルチノスタ チンなどの抗癌性抗生物質、その他、塩酸ミトキサントロン、カルボブラチン、シスブラ チン、 Lーァスパラギナーゼ、ァセグラトン、塩酸プロカルバジン、タエン酸タモキシフ ェン、ウベ二ヌクス、レンチナン、シゾフィラン、酢酸メドロキシプロゲステロン、ホスフエ ストロール、メピチォスタン、ェピチォスタノール等がある。本発明において、上述の 薬剤にはその誘導体も包含される。 Drugs, gene therapy drugs), alkylated anticancer agents, antimetabolites, plant-derived anticancer agents, anticancer antibiotics, BRM 'site force-ins, platinum complex anticancer agents, immunotherapeutic agents, hormonal anticancer agents, monoclonal antibodies, etc. Drugs for oncology, drugs for central nervous system, drugs for peripheral nervous system 'sensory organs, drugs for respiratory diseases, drugs for cardiovascular system, drugs for digestive organs, drugs for hormonal system, drugs for urinary organs, drugs for genital organs, vitamins' nutrient tonic, Metabolic drugs, antibiotics' chemotherapy drugs, test drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, autoimmune drugs, cardiovascular drugs, lifestyle diseases such as diabetes and hyperlipidemia Drug, Adrenocortical hormone, Immunosuppressant, Antibacterial agent, Antiviral agent, Anti-angiogenic agent, Cyto-force-in, Chemokine, Anti-site-force-in antibody, Anti-chemokine antibody, Anti-site force-in 'chemokine receptor anti , SiRNA, shRNA, miRNA, smRNA, antisense RNA or gene therapy-related nucleic acid products such as ODN or DNA, neuroprotective factor, antibody drug, molecular targeting drug, osteoporosis / bone metabolism improving drug, neuropeptide And bioactive peptides / proteins. For example, oncology drugs such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, prusphan, hydrochloric acid-mustine, mitoblonitol, melphalan, dacarbazine, ramustine, estramustine phosphate, etc. Agent, Antimetabolites such as mercaptopurine, thioinosine (mercaptopurine riboside), methotrexate, enocitabine, cytarabine, ancitabine hydrochloride (cyclocytidine hydrochloride), fluorouracil, 5-FU, tegafur, doxyfluridine, carmofur, etoposide, binplastin sulfate, sulfuric acid Plant-derived anticancer agents such as pinklistin, vindesine sulfate, paclitaxel, taquinol, alkaloids such as irinotecan hydrochloride and nogitecan hydrochloride, actinomycin D, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride , Doxorubicin hydrochloride, aclarubicin hydrochloride (aclacinomycin A), pirarubicin hydrochloride, epilubicin hydrochloride, neocarcinostatin Biomaterials, Others, Mitoxantrone hydrochloride, Carbobratin, Cisbratin, L-parasarginase, Acegraton, Procarbazine hydrochloride, Tamoxifen taenoate, Uveninux, Lentinan, Schizophyllan, Medroxyprogesterone acetate, Phosfestol, Mepitiostan And epiciostanol. In the present invention, the above-mentioned drugs include derivatives thereof.

[0175] 上述のような薬剤を含ませることにより、本発明のリボソームを、癌、炎症等の疾患の 治療に用いることができる。ここで、癌は、腫瘍や白血病等のあらゆる新生物による疾 患を含む。本発明の糖鎖修飾リボソームにこれらの薬剤を含ませて投与した場合、薬 剤を単独で投与した場合に比較し、薬剤が癌、炎症部位に集積する。単独投与の場 合に比べ、 2倍以上、好ましくは 5倍以上、さらに好ましくは 10倍以上、特に好ましく は 50倍以上集積し得る。トリス (ヒドロキシメチル)ァミノメタンを結合させたリボソーム（ 基準リボソーム)を経口投与した場合と比較すると、 3〜4倍、好ましくは 4〜6倍集積 し得る。 [0175] By including the drug as described above, the ribosome of the present invention can be used for the treatment of diseases such as cancer and inflammation. Here, cancer includes all neoplastic diseases such as tumors and leukemias. When these drugs are included in the sugar chain-modified ribosome of the present invention and administered, the drugs accumulate at sites of cancer and inflammation compared to when the drug is administered alone. Compared to the case of single administration, it can be accumulated 2 times or more, preferably 5 times or more, more preferably 10 times or more, particularly preferably 50 times or more. Compared with oral administration of a ribosome conjugated with tris (hydroxymethyl) aminomethane (reference ribosome), it can accumulate 3 to 4 times, preferably 4 to 6 times.

[0176] 本発明の糖鎖修飾リボソームは、上述のように薬剤を封入することにより様々な疾患 の治療に用いることができる。薬剤封入糖鎖修飾リボソームは、静脈注射によっても、 経口投与によっても投与することができる。本発明の糖鎖修飾リボソームは、経口投 与した場合の臓器への送達にっ 、ても、経口投与により血中に移行した媒体は静脈 注射と同様の傾向を示す なお、医薬効果を有する化合物は、リボソームの中に封 入させてもよいし、リボソーム表面に結合させてもよい。例えば、蛋白質は上記のリン カーの結合方法と同じ方法で表面に結合させることが可能であり、他の化合物もその 化合物が有する官能基を利用することにより、公知の方法で、結合させることができる 。また、リボソーム内部への封入は、以下の方法により行う。リボソームへ薬剤等を封 入するには、周知の方法を用いればよぐホスファチジルエタノールアミン類、ホスフ ァチジン酸類もしくは長鎖アルキルリン酸塩類、ガンダリオシド類、糖脂質類もしくは ホスファチジルグリセロール類およびコレステロール類を含む脂質を用いてリボソーム を形成することにより、薬剤等はリボソーム内に封入される。 [0176] The sugar chain-modified ribosome of the present invention can be used for treatment of various diseases by encapsulating a drug as described above. The drug-encapsulated sugar chain-modified ribosome can be administered by intravenous injection or oral administration. Even if the sugar chain-modified ribosome of the present invention is delivered to an organ when orally administered, the medium transferred into the blood by oral administration shows the same tendency as intravenous injection. May be encapsulated in the ribosome or bound to the ribosome surface. For example, a protein can be bound to the surface in the same manner as the above linker binding method, and other compounds can be bound to the surface. By using the functional group of the compound, it can be bonded by a known method. Encapsulation inside the ribosome is performed by the following method. In order to encapsulate drugs into ribosomes, phosphatidylethanolamines, phosphatidic acids or long-chain alkyl phosphates, gandiosides, glycolipids or phosphatidylglycerols and cholesterols can be used. By forming ribosomes using lipids, drugs and the like are enclosed in ribosomes.

[0177] したがって、本発明のリボソームに、治療あるいは診断に供しうる薬剤あるいは遺伝 子を封入することによって得られるリボソーム製剤は、ガン組織、炎症組織、各種組 織への移行性が選択的に制御されたものであり、治療薬剤あるいは診断剤の標的細 胞、組織への集中による効力の増強あるいは他の細胞、組織に対する薬剤の取り込 みの減少による副作用の軽減ィ匕等を図れるものである。  [0177] Therefore, the ribosome preparation obtained by encapsulating a drug or gene that can be used for treatment or diagnosis in the ribosome of the present invention selectively controls the migration to cancer tissue, inflammatory tissue, and various tissues. It is intended to increase the efficacy by concentrating therapeutic drugs or diagnostic agents on target cells and tissues, or to reduce side effects by reducing the uptake of drugs to other cells and tissues. .

[0178] また、本発明の静注投与用並びに経口投与用薬物送達媒体を診断用に用いる場合 は、リボソームに蛍光色素、放射性化合物等の標識化合物を封入又は結合させる。 該標識ィ匕合物結合リボソームが患部に結合し、標識ィ匕合物が患部細胞に取り込まれ 、該標識ィ匕合物の存在を指標に疾患を検出'診断することができる。  [0178] When the drug delivery vehicle for intravenous administration and oral administration of the present invention is used for diagnosis, a labeling compound such as a fluorescent dye or a radioactive compound is encapsulated or bound to the ribosome. The labeled compound binding ribosome binds to the affected area, the labeled compound is taken up by the affected cell, and a disease can be detected and diagnosed using the presence of the labeled compound as an index.

[0179] 本発明を診断として用いる場合は、例えば、 DNAプローブ診断薬、 X線造影剤、放 射性試薬、放射性造影剤、放射性診断薬、蛍光試薬、蛍光造影剤、蛍光診断薬、 C T用造影剤、 PET用造影剤、 SPECT用造影剤、 MRI用造影剤、エイズ診断薬、血 液学的検査用試薬、機能検査用試薬、微生物検査用試薬、分子イメージング、イン ビボイメージング、蛍光イメージング、発光イメージング、セルソーター、 PETおよび S PECT等に用いることができる。研究試薬としては、組換え DNA技術、ィムノアッセィ 、ノ、イブリダィゼーシヨン法、酵素アツセィにおいて使用される試薬などが挙げられる  [0179] When the present invention is used as a diagnosis, for example, a DNA probe diagnostic agent, an X-ray contrast agent, a radioactive reagent, a radioactive contrast agent, a radioactive diagnostic agent, a fluorescent reagent, a fluorescent contrast agent, a fluorescent diagnostic agent, for CT Contrast agent, PET contrast agent, SPECT contrast agent, MRI contrast agent, AIDS diagnostic agent, hematology test reagent, functional test reagent, microbial test reagent, molecular imaging, in vivo imaging, fluorescence imaging, It can be used for luminescence imaging, cell sorter, PET and S PECT. Research reagents include reagents used in recombinant DNA technology, immunoassay, immunology, hybridization methods, and enzyme assays.

[0180] 本発明の結果、例えば実施例 9と実施例 10と実施例 24と実施例 25、この糖鎖修飾リ ポソームがリガンドとしての糖鎖の機能を活用して、疾患患部や各種臓器へ薬物や 蛍光物質や放射標識物質などをアクティブターゲティングにより高効率に集積'送達 することを示すものである。従って、本発明の糖鎖修飾リボソームは、腫瘍などの標的 組織での集積を可視化できるので、治療用薬剤送達媒体としての利用とともに、研究 試薬や診断薬などとしての利用への送達媒体をも提供する。 [0180] As a result of the present invention, for example, Example 9, Example 10, Example 24, and Example 25, this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand, and can be used to treat diseased parts and various organs. It shows that drugs, fluorescent substances, radiolabeled substances, etc. are accumulated and delivered with high efficiency by active targeting. Therefore, the sugar chain-modified ribosome of the present invention can visualize the accumulation in a target tissue such as a tumor. It also provides a delivery vehicle for use as a reagent or diagnostic agent.

[0181] (保健'食品） 本発明はまた、保健'食品分野においても利用することができる。この ような場合、上述の経口医薬として用いられる場合の留意点を必要に応じて考慮す べきである。特に、特定保健食品のような機能性食品'健康食品などとして使用され る場合には、医薬に準じた扱いを行うことが好ましい。好ましくは、本発明の糖鎖修飾 リボソームに機能性食品、栄養補助食品または健康補助食品を封入または結合させ たものを食品組成物として用いることができる。本発明で用い得る機能性食品、栄養 補助食品または健康補助食品に限定はなぐ摂取されて食品機能を有効に発現す るように設計され、加工変換された食品ならば 、ずれのものも含まれる。  [0181] (Health 'food) The present invention can also be used in the field of health' food. In such a case, the points to be noted when using it as an oral medicine should be considered as necessary. In particular, when used as a functional food such as a specific health food, such as a “health food”, it is preferable to treat it in accordance with a medicine. Preferably, a food composition in which a functional food, nutritional supplement or health supplement is encapsulated or bound to the sugar chain-modified ribosome of the present invention can be used. Functional foods, nutritional supplements, or health supplements that can be used in the present invention are not limited to foods that are designed and processed and converted to effectively express food functions. .

[0182] 例えば、イチヨウ葉、ェキナシァ、ノコギリヤシ、セントジヨーンズワート、パレリアン、ブ ラックコホッシュ、ミルクシスル、月見草、ブドウ種子エキス、ビルペリー、ナツシロギク 、当帰、大豆、フランス海岸松、ガーリック、高麗ニンジン、茶、ショウガ、ァガリタス、メ シマコブ、紫ィぺ、 AHCC、酵母べ一タグルカン、マイタケ、プロポリス、ビール酵母、 穀類、梅、クロレラ、大麦若葉、青汁、ビタミン類、コラーゲン、ダルコサミン、桑葉、ル イボス茶、アミノ酸、ローヤルゼリー、シィタケ菌糸体エキス、スピルリナ、田七-ンジ ン、タレソン、植物発酵食品、 DHA、 EPA、 ARA、昆布、キャベツ、アロエ、メグスリノ 木、ホップ、カキ肉エキス、ピクジェノール、ゴマ等が本発明に用い得る機能性食品、 栄養補助食品または健康補助食品として例示できる。これらは、そのままリボソーム に含ませてもよいし、抽出物等の処理物を含ませてもよい。リボソームを含む食品組 成物は、経口摂取される。用いるリボソームは、糖鎖が結合していなくてもよぐまた腸 管吸収を高める糖鎖または特定の組織もしくは器官を標的とした糖鎖が結合してい てもよい。本発明のリボソームを食品組成物として投与する場合は、液体飲料、ゲル 状食品、固形食品等の食品に加工すればよい。また、錠剤、顆粒等に加工してもよ い。本発明の食品組成物は、リボソームが含む食品の種類に応じた機能性食品、栄 養補助食品または健康補助食品として用いることができる。  [0182] For example, yew, leaves, saw palmetto, St. John's wort, parelian, black cohosh, milk thistle, evening primrose, grape seed extract, bill perry, feverfew, toki, soybean, French coastal pine, garlic, ginseng, Tea, Ginger, Agaritas, Mashimakobu, Purple Ype, AHCC, Yeast Betaglecan, Maitake, Propolis, Beer Yeast, Cereals, Plum, Chlorella, Barley Young Leaves, Green Juice, Vitamins, Collagen, Darcosamine, Mulberry Leaves, Le Ivos tea, amino acid, royal jelly, shitake mushroom mycelium extract, spirulina, tachi-jinjin, taleson, plant fermented food, DHA, EPA, ARA, kelp, cabbage, aloe, megsurino tree, hop, oyster meat extract, picgenol, sesame Functional foods, dietary supplements, etc. It can be exemplified as a health supplement. These may be included in ribosomes as they are, or processed products such as extracts may be included. Food compositions containing ribosomes are taken orally. The ribosome to be used may not be bound to a sugar chain, or may be bound to a sugar chain that enhances intestinal absorption or a sugar chain that targets a specific tissue or organ. When the ribosome of the present invention is administered as a food composition, it may be processed into a food such as a liquid beverage, a gel food, or a solid food. It may also be processed into tablets, granules, etc. The food composition of the present invention can be used as a functional food, a nutritional supplement or a health supplement according to the type of food contained in the ribosome.

[0183] 例えば、 DHAを含むリボソームは、軽度老人性痴呆症や記憶改善に効果のある機 能性食品、栄養補助食品または健康補助食品として用いることができる。  [0183] For example, a ribosome containing DHA can be used as a functional food, nutritional supplement, or health supplement effective for mild senile dementia and memory improvement.

[0184] 本明細書において引用された、科学文献、特許、特許出願などの参考文献は、その 全体力 各々具体的に記載されたのと同じ程度に本明細書において参考として援用 される。 [0184] References such as scientific literature, patents, and patent applications cited in this specification are Overall power Each is incorporated herein by reference to the same extent as specifically described.

本発明の目的を達成するために好適な実施の形態としては、以下の項目が挙げられ る。（項目 1)ガラクトース（Gal)、 N ァセチルガラタトサミン（GalNAc)、マンノース（ Man)、グルコース（Glc)、 N ァセチルダルコサミン（GlcNAc)、フコース（Fuc)、 Nァセチルノイラミン酸（Neu5Ac)、ガラタトース 3—硫酸（3— (O— SO H)Gal)、セ Examples of preferred embodiments for achieving the object of the present invention include the following items. (Item 1) Galactose (Gal), N-acetyl galatatosamine (GalNAc), Mannose (Man), Glucose (Glc), N-acetyl dalcosamine (GlcNAc), Fucose (Fuc), N-acetyl neuraminic acid ( Neu5Ac), Galatatose 3-sulfuric acid (3- (O—SO H) Gal),

3  Three

ラミド (Cer)およびセリン (Ser)からなる群より選択される少なくとも 1つの糖を含む糖 鎖と、リボソームとを含む、糖鎖修飾リボソーム。（項目 2)前記糖鎖が、以下の構造: R ェ— X1— X2— R2を有し、ここで、該 R1および該 R2は、独立して、水素であるか、または 任意の糖鎖であり、該 X1は、 Fucゝ GalNAcゝ Gal, 3，一（O— SO H)Gal、 GlcNAc A sugar chain-modified ribosome comprising a sugar chain containing at least one sugar selected from the group consisting of ramid (Cer) and serine (Ser), and a ribosome. (Item 2) The sugar chain has the following structure: R 1 —X 1 —X 2 —R 2 , wherein R 1 and R 2 are independently hydrogen, or Any sugar chain, and X 1 is Fuc ゝ GalNAc ゝ Gal, 3, (O—SOH) Gal, GlcNAc

3  Three

、 Manおよび Neu5Acからなる群より選択され、そして該 X2は、 Gal、 Glc、 GlcNAc 、 Ser、 GalNAc, Cerおよび Man力もなる群より選択される、項目 1に記載の糖鎖修 飾リボソーム。（項目 3)前記糖鎖は、 R2側で直接的に力、または疎水性相互作用の ように間接的に前記リボソームに結合する、項目 2に記載の糖鎖修飾リボソーム。（項 目 4) X1と X2との間の結合が、 αΐ, 2結合、 αΐ, 3結合、 α 1, 4結合、 α 1, 6結合、 αΐ— Ο 結合、 «2, 3結合、 «2, 6結合、 β ΐ, 1結合、 β ΐ, 3結合、 β ΐ, 4結合 および j81, 6結合力 なる群より選択され、ここで、 a l—O 結合は X2が Serの場 合に存在する、項目 2に記載の糖鎖修飾リボソーム。（項目 5)前記 X1— X2力 3'-( O— SO H) Gal- GlcNAc, Fuc -Gal, Fuc -Glc, Fuc— GlcNAcゝ Gal- Gal, 2. The sugar chain-modified ribosome according to item 1, wherein the sugar chain-modified ribosome is selected from the group consisting of Man and Neu5Ac, and the X2 is selected from the group consisting of Gal, Glc, GlcNAc, Ser, GalNAc, Cer and Man force. (Item 3) The sugar chain-modified ribosome according to item 2, wherein the sugar chain directly binds to the ribosome like a force or hydrophobic interaction directly on the R 2 side. (Item 4) The bond between X 1 and X 2 is αΐ, 2 bond, αΐ, 3 bond, α 1, 4 bond, α 1, 6 bond, αΐ- 結合 bond, «2, 3 bond, «2, 6 bond, β ΐ, 1 bond, β ΐ, 3 bond, β ΐ, 4 bond and j81, 6 bond force, where al-O bond is when X 2 is Ser Item 3. The sugar chain-modified ribosome according to item 2, which is present in item 2. (Item 5) X 1 — X 2 force 3 ′-(O— SO H) Gal- GlcNAc, Fuc -Gal, Fuc -Glc, Fuc- GlcNAc ゝ Gal- Gal,

3 Three

Gal— GalNAcゝ Gal -Glc, Gal— GlcNAcゝ GalNAc -Gal, GalNAc— Serゝ Glc -Cer, GlcNAc— Gal、 GlcNAc— GlcNAcゝ Neu5Ac - GalNeu5Ac - GalNA cMan— Manおよび Man— GlcNAcからなる群より選択される構造を有する、項目 2 に記載の糖鎖修飾リボソーム。（項目 6)前記 X1— X2が、 Fuc α 1, 2Gal、 Fucal, 3 Glc、 Fucal, 3GlcNAc、 Fucal, 4GlcNAc、 3'— (O— SO H)Galj81, 3Glc Gal— GalNAc ゝ Gal -Glc, Gal— GlcNAc ゝ GalNAc -Gal, GalNAc— Ser ゝ Glc -Cer, GlcNAc— Gal, GlcNAc— GlcNAc ゝ Neu5Ac-GalNeu5Ac-GalNA cMan— Man and Man— GlcNAc Item 3. The sugar chain-modified ribosome according to Item 2, having a structure as described above. (Item 6) X 1 — X 2 is Fuc α 1, 2Gal, Fucal, 3 Glc, Fucal, 3GlcNAc, Fucal, 4GlcNAc, 3′— (O— SO H) Galj81, 3Glc

3  Three

NAc、 Gala 1, 3Gal、 GaljS 1, 3GalNAc、 GaljS 1, 3GlcNAc、 GaljS 1, 4Glc、 GaljS 1, 4GlcNAcゝ GaljS 1, 6GlcNAcゝ GalNAc a 1, 3Gal、 GalNAc a l-O : L Serゝ GalNAc β 1, 4Gal、 GlcNAc β 1, 3Gal、 GlcNAc β 1, 4GlcNAc、 G lcj81, !CerNeu5Ac 2, 3Gal、 Neu5Ac 2, 6GalNAcMan 1, 2ManMan 1, 3ManMana 1, 4ManMana 1, 6Manおよび ManjS 1, 4GlcNAcゝ力らな る群より選択される構造を有する、項目 5に記載の糖鎖修飾リボソーム。（項目 7)前 記糖鎖が、以下の構造: R1— X1— X2— X3— R2を有し、ここで、該 R1および該 R2は、 独立して、水素であるか、または任意の糖鎖であり、該 X1は、 Fuc、 Gal、 GalNAc, GlcNAc、 Manおよび Neu5Acからなる群より選択され、そして該 X2は、 Gal、 GlcN Ac、 GalNAcおよび Manからなる群より選択され、そして該 X3は、 Glc、 GlcN Ac, G al、 GalNAc, Ser、 Cerおよび Manからなる群より選択される、項目 1に記載の糖鎖 修飾リボソーム。（項目 8)前記糖鎖は、 R2側で直接的にか、または疎水性相互作用 のように間接的に前記リボソームに結合する、項目 7に記載の糖鎖修飾リボソーム。 ( 項目 9) X1と X2との間の結合および X2と X3との間の結合力 なる群より選択される少 なくとも 1つの糖鎖結合が規定されており、ここでここで該 X1と X2との間の結合が、 α 1, 2結合、 αΐ, 3結合、 αΐ, 4結合、 β 1, 3結合、 β 1, 4結合、 a 2, 3結合、 a 2, 6結合、 《1, 6結合および《1, 3結合力 なる群より選択され、該 X2と X3との間の結 合が、 β 1, 1結合、 β 1, 3結合、 β 1, 4結合、 a 1, 2結合、 ひ 1— O 結合、 αΐ, 6 結合、 a 1, 3結合および |81, 4結合力 なる群より選択され、ここで、 a l—O 結 合は X3が Serに存在する、項目 7に記載の糖鎖修飾リボソーム。（項目 10)X^X の間の結合および X2と X3との間の結合力 なる群より選択される糖鎖結合のすべて が規定されており、ここで該 X1と X2との間の結合が、 αΐ, 2結合、 《1, 3結合、 《1, 4結合、 β 1, 3結合、 β 1, 4結合、 a 2, 3結合、 a 2, 6結合、 αΐ, 6結合および αΐ , 3結合力 なる群より選択され、該 X2と X3との間の結合が、 β 1, 1結合、 β 1, 3結 合、 j81, 4結合、 αΐ, 2結合、 αΐ— Ο 結合、 αΐ, 6結合、 αΐ, 3結合および j81 , 4結合力 なる群より選択され、ここで、 oc NAc, Gala 1, 3Gal, GaljS 1, 3GalNAc, GaljS 1, 3GlcNAc, GaljS 1, 4Glc, GaljS 1, 4GlcNAc ゝ GaljS 1, 6GlcNAc ゝ GalNAc a 1, 3Gal, GalNAc a lO: L Ser ゝ GalNAc β 1, 4Gal , GlcNAc β 1, 3Gal, GlcNAc β 1, 4GlcNAc, G lcj81,! CerNeu5Ac 2, 3Gal, Neu5Ac 2, 6GalNAcMan 1, 2ManMan Item 6. The sugar chain-modified ribosome according to Item 5, having a structure selected from the group consisting of 1,3ManMana 1,4ManMana 1,6Man and ManjS 1,4GlcNAc. (Item 7) The aforementioned sugar chain has the following structure: R 1 — X 1 — X 2 — X 3 — R 2 , wherein R 1 and R 2 are independently hydrogen. Any or any sugar chain, X 1 is selected from the group consisting of Fuc, Gal, GalNAc, GlcNAc, Man and Neu5Ac, and the X 2 consists of Gal, GlcN Ac, GalNAc and Man The sugar chain-modified ribosome according to Item 1, wherein the sugar chain is selected from the group, and the X 3 is selected from the group consisting of Glc, GlcN Ac, Gal, GalNAc, Ser, Cer and Man. (Item 8) The sugar chain-modified ribosome according to item 7, wherein the sugar chain binds to the ribosome directly on the R 2 side or indirectly like a hydrophobic interaction. (Item 9) even without least selected from the avidity group consisting one glycosylation are defined between the coupling and X 2 and X 3 between X 1 and X 2, where here The bond between X 1 and X 2 is α 1, 2 bond, α ΐ, 3 bond, α 4, 4 bond, β 1, 3 bond, β 1, 4 bond, a 2, 3 bond, a 2, Selected from the group consisting of 6 bonds, << 1, 6 bonds and << 1, 3 bond strengths, and the bond between X 2 and X 3 is β 1, 1 bond, β 1, 3 bond, β 1, 4 bond, a 1, 2 bond, 1—O bond, αΐ, 6 bond, a 1, 3 bond and | 81, 4 bond force, where al—O bond is X 3 Item 9. The sugar chain-modified ribosome according to Item 7, present in Ser. (Item 10) X ^ all glycosylation selected from coupling force becomes the group are defined between X bond and X 2 and X 3 between, wherein the said X 1 and X 2 Bond between αΐ, 2 bond, << 1, 3 bond, << 1, 4 bond, β 1, 3 bond, β 1, 4 bond, a 2, 3 bond, a 2, 6 bond, αΐ, 6 bond And αΐ, 3 bond strength, and the bond between X 2 and X 3 is β 1,1 bond, β 1,3 bond, j81,4 bond, αΐ, 2 bond, αΐ— Oc bond, αΐ, 6 bond, αΐ, 3 bond and j81, 4 bond force, where oc

l— O 結合は X3が Serに存在する、項目 7に記載の糖鎖修飾リボソーム。 （項目 11 )前記 X1 - X2 - X3が、 Fuc - Gal - Glc、 Fuc - Gal - GlcN Acゝ Fuc - GlcNAc - Gal、 Gal -GalNAc -Gal, Gal -GlcNAc -Gal, Gal -GlcNAc -Gal, Gal— G lc Cer、 GlcNAc— Gal— Glc、 Neu5 Ac - Gal - GalNAc , Neu5Ac— Gal— Gl c、 Neu5 Ac― Gal― GlcNAc , Neu5Ac― GalNAc― Ser, Man— Man— Man, Man - Man - GlcNAc,および Man— GlcNAc - GlcNAcからなる群より選択され る構造を有する、項目 7に記載の糖鎖修飾リボソーム。（項目 12)前記 X1— X2— X3が , Fuca 1, 2Galj81, 3GlcNAc, Fuca 1, 2Galj81, 4Glc、 Fuc α 1, 2Galj81, 4GlcNAc、 Fuca 1, 4GlcNAC j81, 3Gal、 GaljS 1, 3GalNAC j81, 4Gal、 GaljS 1, 4GalNAC j81, ICerゝ GaljS 1, 3GlcNAC j81, 3Gal、 GalNAC j81, 4Gal β 1 , 4Glc、 GlcNAc β 1, 3Galj81, 4Glc、 Neu5Ac a 2, 3Galj81, 3GalNAc、 Neu 5Ac a 2, 3Gal β 1, 3GlcNAc、 Neu5Ac a 2, 3Gal β 1, 4Glc、 Neu5Ac «2, 3 GaljS 1, 4GlcNAc、 Neu5Ac a 2, 6GalNAc a l— 0— L— Ser、 Mana 1, 6Ma na 1, 6Man、 Man a 1, 2Man a 1, 2Man、 Man a 1, 2Man a 1, 3Man、 Man 1, 2Mana 1, 6Man、 Mana 1, 3Mana 1, 6Man、 Mana 1, 3Manj81, 4G1 cNAcゝ Mana 1, 6Manj81, 4GlcNAcゝおよび Man j81, 4GlcNAc β 1, 4GlcN Acからなる群より選択される構造を有する、項目 11に記載の糖鎖修飾リボソーム。 ( 項目 13)前記糖鎖が、以下の構造: R1— X1— X2— X3— X4— R2を有し、ここで、該 R1 および該 R2は、独立して、水素であるか、または任意の糖鎖であり、該 X1は、 Fuc、 G al、 Neu5Acおよび Manからなる群より選択され、そして該 X2は、 Gal、 GalNAc、 Gl cNAcおよび Manからなる群より選択され、該 X3は、 GlcNAc, GalNAc、 Galおよび Manからなる群より選択され、そして該 X4は、 Gal、 Glc、 Man, Cerおよび GlcNAc 力もなる群より選択される、項目 1に記載の糖鎖修飾リボソーム。（項目 14)前記糖鎖 は、 R2側で直接的に力、または疎水性相互作用のように間接的に前記リボソームに 結合する、項目 12に記載の糖鎖修飾リボソーム。（項目 15) X1と X2との間の結合、 X2 と X3との間の結合および X3と X4との間の結合力もなる群より選択される少なくとも 1つ の糖鎖結合が規定されており、ここで、該 X1と X2との間の結合が、 αΐ, 2結合、 《1, 3結合、 《2, 3結合、 131, 3結合および《1, 6結合力 なる群より選択され、該 X2と X3との間の結合が、 β 1, 3結合、 β 1, 4結合、 a 1, 2結合、 a 1, 3結合、および α 1, 6結合力 なる群より選択され、該 X3と X4との間の結合が、 β 1, 1結合、 β 1, 3結 合、 β 1, 4結合、 a 1, 3結合および a 1, 6結合力もなる群より選択される、項目 13 に記載の糖鎖修飾リボソーム。（項目 16) X1と X2との間の結合、 X2と X3との間の結合 および X3と X4との間の結合力 なる群より選択される少なくとも 2つの糖鎖結合が規 定されており、ここで、該 X1と X2との間の結合力 al, 2結合、 《1, 3結合、 《2, 3 結合、 β ΐ, 3結合および a 1, 6結合力 なる群より選択され、該 X2と X3との間の結 合が、 β 1, 3結合、 β 1, 4結合、 a 1, 2結合、 a 1, 3結合、および a 1, 6結合から なる群より選択され、該 X3と X4との間の結合が、 β 1, 1結合、 β 1, 3結合、 β 1, 4結 合、 ex 1, 3結合および a 1, 6結合力もなる群より選択される、項目 13に記載の糖鎖 修飾リボソーム。（項目 17) X1と X2との間の結合、 X2と X3との間の結合および X3と X4 との間の結合力 なる群より選択される糖鎖結合のすべてが規定されており、ここで、 該 X1と X2との間の結合が、 al, 2結合、 al, 3結合、 a 2, 3結合、 β 1, 3結合およ び《1, 6結合力 なる群より選択され、該 X2と X3との間の結合が、 β ΐ, 3結合、 /31 , 4結合、 a 1, 2結合、 a 1, 3結合、および a 1, 6結合力 なる群より選択され、該 X 3と X4との間の結合力 β 1, 1結合、 β 1, 3結合、 β 1, 4結合、 a 1, 3結合および a 1, 6結合力もなる群より選択される、項目 13に記載の糖鎖修飾リボソーム。（項目 18 )前記 X1— X2— X3— X4は、 Fuc— Gal— GlcNAc— Gal、 Fuc— GlcNAc— Gal— Glcゝ GalNAc— Gal— Glc— Cerゝ Gal— GalNAc— Gal— Glcゝ Gal -GlcNAc - Gal— Glc、 Neu5Ac— Gal— GalNAc— Gal、 Neu5Ac— Gal— Glc— Cer、 Man ― Man― Man― Man, Man— Man— Man— GlcNAc、および Man— Man— Glc NAc— GlcNAcカゝらなる群より選択される構造を有する、項目 13に記載の糖鎖修飾 リボソーム。（項目 19)前記 X1— X2— X3— X4は、 Fucal, 2Galj81, 3GlcNAc β 1 , 3Gal、 Fucal, 4GlcNAC j81, 3Galj81, 4Glc、 GalNAc j81, 4Galj81, 4Glc β 1, lCer、 GaljS 1, 3GalNAC j81, 4Galj81, 4Glc、 GaljS 1, 3GlcNAC j81, 3 GaljS 1, 4Glc、 Neu5Ac a 2, 3Galj81, 3GalNAc β 1, 4Gal、 Neu5Ac a 2, 3G alj81, 4Glcj81, 4Cer、 Man a 1, 2Mana 1, 2Mana 1, 3Man、 Man a 1, 2M ana 1, 3Mana 1, 6Man、 Mana 1, 2Mana 1, 3Manj81, 4GlcNAc、 Man a 1, 2Mana 1, 6Mana 1, 6Man、 Mana 1, 3Mana 1, 6Manj81, 4GlcNAc、 Mana 1, 3Manj81, 4GlcNAcj81, 4GlcNAc、 Man a 1, 6Mana 1, 6Manj8 1, 4GlcNAcぉょびManQ；l, 6Manj81, 4GlcNAcj81, 4GlcNAcからなる群より 選択される構造を有する、項目 18に記載の糖鎖修飾リボソーム。（項目 20)前記糖 鎖力 以下の構造: R1— X1— X2— X3— X4— X5— R2を有し、ここで、該 R1および該 R 2は、独立して、水素であるか、または任意の糖鎖であり、該 X1は、 Fuc、 Neu5Acお よび Manからなる群より選択され、該 X2は、 Gaほたは Manであり、該 X3は、 GlcNA c、 GalNAcおよび Manからなる群より選択され、該 X4は、 Gal, GlcNAcおよび Man からなる群より選択され、そして該 X5は、 Glc、 Cerおよび GlcNAcからなる群より選 択される、項目 1に記載の糖鎖修飾リボソーム。（項目 21)前記糖鎖は、 R2側で直接 的にか、または疎水性相互作用のように間接的に前記リボソームに結合する、項目 2 0に記載の糖鎖修飾リボソーム。（項目 22) X1と X2との間の結合、 X2と X3との間の結 合、 X3と X4との間の結合および X4と X5との間の結合力もなる群より選択される少なく とも 1つの糖鎖結合が規定されており、ここで、該 X1と X2との間の結合力 j81, 3結 合、 αΐ, 2結合、 《2, 3結合、 《1, 3結合および《1, 6結合力 なる群より選択さ れ、該 X2と X3との間の結合が、 β ΐ, 3結合、 αΐ, 2結合、 αΐ, 3結合および αΐ, 6 結合力 なる群より選択され、該 X3と X4との間の結合力 β 1, 3結合、 β 1, 4結合、 al, 3結合および a 1, 6結合力もなる群より選択され、該 X4と X5との間の結合力 β 1, 1結合または β 1, 4結合である、項目 20に記載の糖鎖修飾リボソーム。（項目 23 と X2との間の結合、 X2と X3との間の結合、 X3と X4との間の結合および X4と X5との 間の結合力 なる群より選択される少なくとも 2つの糖鎖結合が規定されており、ここ で、該 X1と X2との間の結合が、 β ΐ, 3結合、 al, 2結合、 a 2, 3結合、 al, 3結合 および al, 6結合力 なる群より選択され、該 X2と X3との間の結合力 β ΐ, 3結合、 al, 2結合、 《1, 3結合および a 1, 6結合力 なる群より選択され、該 X3と X4との間 の結合が、 β 1, 3結合、 β 1, 4結合、 a 1, 3結合および a 1, 6結合力 なる群より 選択され、該 X4と X5との間の結合力 β 1, 1結合または j81, 4結合である、項目 20 に記載の糖鎖修飾リボソーム。（項目 24) X1と X2との間の結合、 X2と X3との間の結合 、X3と X4との間の結合および X4と X5との間の結合力もなる群より選択される少なくとも 3つの糖鎖結合が規定されており、ここで、該 X1と X2との間の結合力 β 1, 3結合、 al, 2結合、 a 2, 3結合、 al, 3結合および a 1, 6結合からなる群より選択され、 該 X2と X3との間の結合が、 β ΐ, 3結合、 al, 2結合、 al, 3結合および a 1, 6結合 からなる群より選択され、該 X3と X4との間の結合力 j81, 3結合、 /31, 4結合、 al, 3結合および a 1, 6結合力 なる群より選択され、該 X4と X5との間の結合力 β ΐ, 1 結合または j81, 4結合である、項目 20に記載の糖鎖修飾リボソーム。（項目 25) と X2との間の結合、 X2と X3との間の結合、 X3と X4との間の結合および X4と X5との間の 結合力 なる群より選択される糖鎖結合のすべてが規定されており、ここで、該 X1と X 2との間の結合が、 β ΐ, 3結合、 αΐ, 2結合、 α2, 3結合、 αΐ, 3結合および αΐ, 6 結合力 なる群より選択され、該 X2と X3との間の結合力 β ΐ, 3結合、 αΐ, 2結合、 al, 3結合および a 1, 6結合力もなる群より選択され、該 X3と X4との間の結合力 β 1, 3結合、 131, 4結合、 《1, 3結合および a 1, 6結合からなる群より選択され、該 X 4と X5との間の結合力 ΐ, 1結合または |81, 4結合である、項目 20に記載の糖鎖 修飾リポ l-O bond X 3 is present in the Ser, glycosylation ribosome of claim 7. (Item 11) Said X 1 -X 2 -X 3 is Fuc-Gal-Glc, Fuc-Gal-GlcN Ac ゝ Fuc-GlcNAc-Gal, Gal -GalNAc -Gal, Gal -GlcNAc -Gal, Gal -GlcNAc- Gal, Gal— G lc Cer, GlcNAc— Gal— Glc, Neu5 Ac-Gal-GalNAc, Neu5Ac— Gal— Glc, Neu5 Ac— Gal— GlcNAc, Neu5Ac— GalNAc— Ser, Man— Man— Man, Man-Man -GlcNAc, and Man— GlcNAc-selected from the group consisting of GlcNAc Item 9. The sugar chain-modified ribosome according to Item 7, having a structure as described above. (Item 12) X 1 — X 2 — X 3 is Fuca 1, 2Galj81, 3GlcNAc, Fuca 1, 2Galj81, 4Glc, Fuc α 1, 2Galj81, 4GlcNAc, Fuca 1, 4GlcNA C j 81, 3Gal, GaljS 1, 3GalNA C j 81, 4Gal, GaljS 1, 4GalNA C j 81, ICer ゝ GaljS 1, 3GlcNA C j 81, 3Gal, GalNA C j 81, 4Gal β 1, 4Glc, GlcNAc β 1, 3Galj81, 4Glc, Neu5Ac a 2, 3Galj81, 3GalNAc, Neu 5Ac a 2, 3Gal β 1, 3GlcNAc, Neu5Ac a 2, 3Gal β 1, 4Glc, Neu5Ac «2, 3 GaljS 1, 4GlcNAc, Neu5Ac a 2, 6GalNAc al— 0— L— Ser, Mana 1 , 6Mana 1, 6Man, Man a 1, 2Man a 1, 2Man, Man a 1, 2Man a 1, 3Man, Man 1, 2Mana 1, 6Man, Mana 1, 3Mana 1, 6Man, Mana 1, 3Manj81, 4G1 cNAc Item 12. The sugar chain-modified ribosome according to Item 11, having a structure selected from the group consisting of Mana 1, 6Manj81, 4GlcNAc and Man j81, 4GlcNAc β1, 4GlcN Ac. (Item 13) The sugar chain has the following structure: R 1 — X 1 — X 2 — X 3 — X 4 — R 2 , wherein R 1 and R 2 are independently Is hydrogen or any sugar chain, the X 1 is selected from the group consisting of Fuc, Gal, Neu5Ac and Man, and the X 2 is a group consisting of Gal, GalNAc, GlcNAc and Man The X 3 is selected from the group consisting of GlcNAc, GalNAc, Gal and Man, and the X 4 is selected from the group also consisting of Gal, Glc, Man, Cer and GlcNAc force. Sugar chain-modified ribosome. (Item 14) The sugar chain-modified ribosome according to item 12, wherein the sugar chain binds to the ribosome directly by force on the R 2 side or indirectly like a hydrophobic interaction. (Item 15) At least one sugar chain bond selected from the group consisting of a bond between X 1 and X 2 , a bond between X 2 and X 3 and a binding force between X 3 and X 4 Where the bond between X 1 and X 2 is αΐ, 2 bond, << 1, 3 bond, << 2, 3 bond, 131, 3 bond and << 1, 6 bond force The bond between X 2 and X 3 is selected from the group consisting of β 1,3 bond, β 1,4 bond, a 1,2 bond, a 1,3 bond, and α 1,6 binding force. The bond between X 3 and X 4 is selected from the group consisting of β 1, 1 bond, β 1, 3 bond, β 1, 4 bond, a 1, 3 bond and a 1, 6 bond force. 14. The sugar chain-modified ribosome according to item 13, selected from the group consisting of: (Item 16) At least two sugar chain bonds selected from the group consisting of a bond between X 1 and X 2 , a bond between X 2 and X 3 and a bond force between X 3 and X 4 Where the binding force between X 1 and X 2 is al, 2 bonds, << 1, 3 bonds, << 2, 3 Bond, β ΐ, 3 bond and a 1, 6 bond strength, and the bond between X 2 and X 3 is β 1, 3 bond, β 1, 4 bond, a 1, 2 Selected from the group consisting of a bond, a 1, 3 bond, and a 1, 6 bond, and the bond between X 3 and X 4 is β 1, 1 bond, β 1, 3 bond, β 1, 4 14. The sugar chain-modified ribosome according to item 13, which is selected from the group consisting of a bond, ex 1,3 bond and a 1,6 bond. (Item 17) All of the sugar chain bonds selected from the group consisting of the bond between X 1 and X 2 , the bond between X 2 and X 3 and the bond strength between X 3 and X 4 are defined. Where the bond between X 1 and X 2 is al, 2 bond, al, 3 bond, a 2, 3 bond, β 1, 3 bond and << 1, 6 bond strength The bond between X 2 and X 3 is selected from the group consisting of β ΐ, 3 bond, / 31, 4 bond, a 1, 2 bond, a 1, 3 bond, and a 1, 6 bond force A group selected from the group consisting of: a bond strength between X 3 and X 4 β 1, 1 bond, β 1, 3 bond, β 1, 4 bond, a 1, 3 bond and a 1, 6 bond force 14. The sugar chain-modified ribosome according to item 13, which is selected from the above. (Item 18) X 1 — X 2 — X 3 — X 4 are Fuc—Gal—GlcNAc—Gal, Fuc—GlcNAc—Gal—Glc ゝ GalNAc—Gal—Glc—Cer ゝ Gal—GalNAc—Gal—Glc ゝGal -GlcNAc-Gal- Glc, Neu5Ac- Gal- GalNAc- Gal, Neu5Ac- Gal- Glc- Cer, Man- Man- Man- Man, Man- Man- Man- GlcNAc, and Man- Man- Glc NAc- GlcNAc 14. The sugar chain-modified ribosome according to item 13, having a structure selected from the group consisting of: (Item 19) X 1 — X 2 — X 3 — X 4 is Fucal, 2Galj81, 3GlcNAc β 1, 3Gal, Fucal, 4GlcNA C j 81, 3Galj81, 4Glc, GalNAc j81, 4Galj81, 4Glc β 1, lCer, GaljS 1, 3GalNA C j 81, 4Galj81, 4Glc, GaljS 1, 3GlcNA C j 81, 3 GaljS 1, 4Glc, Neu5Ac a 2, 3Galj81, 3GalNAc β 1, 4Gal, Neu5Ac a 2, 3G alj81, 4Glcj81, 4Cer, Man a 1, 2Mana 1, 2Mana 1, 3Man, Man a 1, 2M ana 1, 3Mana 1, 6Man, Mana 1, 2Mana 1, 3Manj81, 4GlcNAc, Man a 1, 2Mana 1, 6Mana 1, 6Man, Mana 1, 3Mana 1, 6Manj81, 4GlcNAc, Mana 1, 3Manj81, 4GlcNAcj81, 4GlcNAc, Man a 1, 6Mana 1, 6Manj8 1, 4GlcNAc and ManQ; items having a structure selected from the group consisting of 1, 6Manj81, 4GlcNAcj81, 4GlcNAc 18. The sugar chain-modified ribosome according to 18. (Item 20) The above-mentioned glycan force has the following structure: R 1 — X 1 — X 2 — X 3 — X 4 — X 5 — R 2 where R 1 and R 2 are independently Is hydrogen or any sugar chain, and the X 1 is Fuc, Neu5Ac or Is selected from the group consisting of and Man, the X 2 is, Ga Fireflys is Man, the X 3 is selected from the group consisting of GlcNAc c, GalNAc and Man, the X 4 is Gal, GlcNAc and Man The sugar chain-modified ribosome according to item 1, wherein the glycan is selected from the group consisting of: and X 5 is selected from the group consisting of Glc, Cer and GlcNAc. (Item 21) The sugar chain-modified ribosome according to item 20, wherein the sugar chain binds to the ribosome directly on the R 2 side or indirectly like a hydrophobic interaction. (Item 22) The bond between X 1 and X 2 , the bond between X 2 and X 3 , the bond between X 3 and X 4 and the bond force between X 4 and X 5 At least one sugar chain bond selected from the group is defined, where the bond strength between the X 1 and X 2 is j81, 3 bond, αΐ, 2 bond, << 2, 3 bond, Selected from the group of << 1, 3 bond and << 1, 6 bond force, and the bond between X 2 and X 3 is β ΐ, 3 bond, αΐ, 2 bond, αΐ, 3 bond and αΐ, Selected from the group consisting of 6 binding forces, and the binding force between X 3 and X 4 selected from the group also consisting of β 1,3 bond, β 1,4 bond, al, 3 bond and a 1, 6 bond force, Item 21. The sugar chain-modified ribosome according to Item 20, wherein the binding force is a β 1,1 bond or a β 1,4 bond between X 4 and X 5 . (Selected from the group consisting of the bond between items 23 and X 2 , the bond between X 2 and X 3 , the bond between X 3 and X 4 and the bond force between X 4 and X 5 And at least two sugar chain bonds are defined, wherein the bond between X 1 and X 2 is β ΐ, 3 bond, al, 2 bond, a 2, 3 bond, al, 3 bond And the binding force between X 2 and X 3 is selected from the group of β ΐ, 3 bond, al, 2 bond, << 1, 3 bond and a 1, 6 bond force is selected, the bond between the X 3 and X 4 are, beta 1, 3 bond, beta 1, 4 bonds, selected from a 1, 3 bond and a 1, 6 bond strength becomes the group, with the X 4 21. The sugar chain-modified ribosome according to item 20, which is a β 1,1 bond or a j81,4 bond between X 5 and 21. (Item 24) A bond between X 1 and X 2 , X 2 and X 3 bond between, is selected from the group becomes binding force between the coupling and X 4 and X 5 between X 3 and X 4 At least three glycosylation is defined, wherein the bonding force beta 1, 3 bond between the X 1 and X 2, al, 2 bond, a 2, 3 coupled, al, 3 bonds and a Selected from the group consisting of 1, 6 bonds, and the bond between X 2 and X 3 is selected from the group consisting of β ΐ, 3 bonds, al, 2 bonds, al, 3 bonds and a 1, 6 bonds The bond strength between X 3 and X 4 is selected from the group j81, 3 bond, / 31, 4 bond, al, 3 bond and a 1, 6 bond force, and the bond between X 4 and X 5 The sugar chain-modified ribosome according to Item 20, which has a binding force between β ΐ, 1 bond or j81, 4 bond (Item 25) and Bond between X 2, coupling between X 2 and X 3, glycosylation selected from coupling force group consisting of between the coupling and X 4 and X 5 between X 3 and X 4 Where the bond between X 1 and X 2 is β ΐ, 3 bond, αΐ, 2 bond, α2, 3 bond, αΐ, 3 bond and αΐ, 6 binding force. is selected from the group consisting, avidity beta I between the X 2 and X 3, 3 binding, Ai, 2 bond, is selected from al, 3 bond and a 1, 6 bond strength is also a group, with the X 3 Binding force between X 4 β 1, 3 bond, 131, 4 bond, << 1, 3 bond and a 1, 6 bond selected from the group consisting of a bond between X 4 and X 5 ΐ , 1 bond or | 81, 4 bond

ノーム。 （項目 26)前記 X1— X2— X3— X4— X5は、 Fuc— Gal— GlcNAc— Gal— G1 cゝ Gal— GalNAc— Gal— Glc— Cerゝ Neu5Ac— Gal— GalNAc— Gal— Glc、 M an― Man― Man― Man― GlcNAcおよび Man― Man― Man― GlcNAc― GlcN Acからなる群より選択される構造を有する、項目 20に記載の糖鎖修飾リボソーム。 ( 項目 27)前記 X1— X2— X3— X4— X5は、 Fuc a 1, 2Galj81, 3GlcNAc β 1, 3Gal β 1, 4Glc、 GaljS 1, 3GalNAc β 1, 4Galj81, 4Glc β 1, lCer、 Neu5Ac a 2, 3 GaljS 1, 3GalNAcj81, 4Galj81, 4Glc j8、 Man a 1, 2Mana 1, 2Mana 1, 3 ManjS 1, 4GlcNAc、 Man a 1, 2Mana 1, 3Mana 1, 6Manj81, 4GlcNAc、 Mana 1, 2Mana 1, 3Manj81, 4GlcNAc j81, 4GlcNAc, Mana 1, 2Mana 1, 6Mana 1, 6Manj81, 4GlcNAc、 Man a 1, 3Mana 1, 6Manj81, 4GlcNA c β 1, 4GlcNAc、 Man a 1, 6Man a 1, 6Man β 1, 4GlcNAc β 1, 4GlcNAc、 力もなる群より選択される構造を有する、項目 26に記載の糖鎖修飾リボソーム。（項 目 28)前記糖鎖が、以下の構造: R1— X1— X2— X3— X4— X5— X6— R2を有し、ここ で、該 R1および該 R2は、独立して、水素であるか、または任意の糖鎖であり、該 X1は 、 Manまたは Neu5Acであり、該 X2は、 Manまたは Galであり、該 X3は、 Manまたは GalNAcであり、該 X4は、 Manまたは Galあり、該 X5は、 GlcNAcまたは Glcあり、そ して該 X6は、 GlcNAcまたは Cerである、項目 1に記載の糖鎖修飾リボソーム。（項目 29)前記糖鎖は、 R2側で直接的に力、または疎水性相互作用のように間接的に前記 リボソームに結合する、項目 28に記載の糖鎖修飾リボソーム。（項目 3C X1と X2との 間の結合、 X2と X3との間の結合、 X3と X4との間の結合、 X4と X5との間の結合および X 5と X6との間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されて おり、ここで、該 X1と X2との間の結合が α 1, 2結合または α 2, 3結合であり、該 X2と X3との間の結合が α ΐ, 2結合、 α ΐ, 3結合、 α 1, 6結合または j8 1, 3結合であり、 該 X3と X4との間の結合が α 1, 3結合または α 1, 6結合であり、該 X4と X5との間の結 合が j8 1, 4結合であり、該 X5と X6との間の結合が、 β 1, 1結合または β 1, 4結合で ある、項目 28に記載の糖鎖修飾リボソーム。（項目 3D X1と X2との間の結合、 X2と X3 との間の結合、 X3と X4との間の結合、 X4と X5との間の結合および X5と X6との間の結 合力もなる群より選択される少なくとも 2つの糖鎖結合が規定されており、ここで、該 X 1と X2との間の結合が《1, 2結合または《2, 3結合であり、該 X2と X3との間の結合が a 1, 2結合、 α 1, 3結合、 α 1 , 6結合または β 1, 3結合であり、該 X3と X4との間の 結合が α 1, 3結合または α 1, 6結合であり、該 X4と X5との間の結合が β 1, 4結合で あり、該 X5と X6との間の結合が、 β 1, 1結合または j8 1, 4結合である、項目 28に記 載の糖鎖修飾リボソーム。 （項目 32) X1と X2との間の結合、 X2と X3との間の結合、 X3 と X4との間の結合、 X4と X5との間の結合および X5と X6との間の結合力もなる群より選 択される少なくとも 3つの糖鎖結合が規定されており、ここで、該 X1と X2との間の結合 が α ΐ, 2結合または a 2, 3結合であり、該 X2と X3との間の結合が a 1, 2結合、 《1, 3結合、 《1, 6結合または |8 1, 3結合であり、該 X3と X4との間の結合が a 1 , 3結合 または a 1, 6結合であり、該 X4と X5との間の結合が j8 1, 4結合であり、該 X5と X6との 間の結合が、 β 1, 1結合または j8 1, 4結合である、項目 28に記載の糖鎖修飾リポソ ーム。（項目 33) X1と X2との間の結合、 X2と X3との間の結合、 X3と X4との間の結合、 X 4と X5との間の結合および X5と X6との間の結合力 なる群より選択される少なくとも 4 つの糖鎖結合が規定されており、ここで、該 X1と X2との間の結合が a 1, 2結合また は ex 2, 3結合であり、該 X2と X3との間の結合が ex 1, 2結合、 ex 1, 3結合、 a 1, 6結 合または β 1, 3結合であり、該 X3と X4との間の結合が a 1, 3結合または a 1, 6結合 であり、該 X4と X5との間の結合が j8 1, 4結合であり、該 X5と X6との間の結合力 β 1 , 1結合または β 1, 4結合である、項目 28に記載の糖鎖修飾リボソーム。 （項目 34) X1と X2との間の結合、 X2と X3との間の結合、 X3と X4との間の結合、 X4と X5との間の結 合および X5と X6との間の結合力 なる群より選択される糖鎖結合のすべてが規定さ れており、ここで、該 X1と X2との間の結合が a 1, 2結合または a 2, 3結合であり、該 X2と X3との間の結合が αΐ, 2結合、 αΐ, 3結合、 α 1, 6結合または j81, 3結合であ り、該 X3と X4との間の結合が a 1, 3結合または a 1, 6結合であり、該 X4と X5との間の 結合が β 1, 4結合であり、該 X5と X6との間の結合が、 β 1, 1結合または β 1, 4結合 である、項目 28に記載の糖鎖修飾リボソーム。（項目 35)前記 X1— X2— X3— X4— X5 — X6は、 Man— Man— Man— Man— GlcNAc - GlcNAcまたは Neu5 Ac— Gal — GalNAc— Gal—Glc— Cerである、項目 28に記載の糖鎖修飾リボソーム。（項目 36)前記 X1— X2— X3— X4— X5— X6は、 Manal, 2Manal, 2Manal, 3Man β 1, 4GlcNAcj81, 4GlcNAc、 Man a 1, 2Mana 1, 3Mana 1, 6Manj81, 4 GlcNAc j81, 4GlcNAcゝ Man a 1, 2Mana 1, 6Mana 1, 6Manj81, 4GlcNA C j81, 4GlcNAcおよび Neu5Ac a 2, 3Galj81, 3GalNAc β 1, 4Galj81, 4Glc β 1, ICer力もなる群より選択される構造を有する、項目 35に記載の糖鎖修飾リポソ ーム。（項目 37)前記糖鎖のリボソーム最近位端の糖力 Gal、 GalNAc、 Man, Glc 、 GlcNAcおよび Serならびにそれらの組み合わせ力 なる群より選択される、項目 1 に記載の糖鎖修飾リボソーム。（項目 38)前記糖鎖のリボソーム最遠位端の糖が、 Ga 1、 3，一（O— SO H)Gal、 GalNAc、 Man, Fucおよび Neu5Acならびにそれらの Gnomes. (Item 26) X 1 — X 2 — X 3 — X 4 — X 5 is Fuc- Gal- GlcNAc- Gal- G1 c— Gal- GalNAc- Gal- Glc- Cer ゝ Neu5Ac- Gal- GalNAc- Gal- Item 21. The sugar chain-modified ribosome according to Item 20, which has a structure selected from the group consisting of Glc, Man-Man-Man-Man-GlcNAc, and Man-Man-Man-GlcNAc-GlcN Ac. (Item 27) X 1 -X 2 -X 3 -X 4 -X 5 is Fuc a 1, 2Galj81, 3GlcNAc β 1, 3Gal β 1, 4Glc, GaljS 1, 3GalNAc β 1, 4Galj81, 4Glc β 1, lCer, Neu5Ac a 2, 3 GaljS 1, 3GalNAcj81, 4Galj81, 4Glc j8, Man a 1, 2Mana 1, 2Mana 1, 3 ManjS 1, 4GlcNAc, Man a 1, 2Mana 1, 3Mana 1, 6Manj81, 4GlcNAc, Mana 1, 2Mana 1, 3Manj81, 4GlcNAc j81, 4GlcNAc, Mana 1, 2Mana 1, 6Mana 1, 6Manj81, 4GlcNAc, Man a 1, 3Mana 1, 6Manj81, 4GlcNA c β 1, 4GlcNAc, Man a 1, 6Man a 1, 6Man β 1 27. The sugar chain-modified ribosome according to Item 26, which has a structure selected from the group consisting of force, 4GlcNAc β1, 4GlcNAc and force. (Item 28) The sugar chain has the following structure: R 1 — X 1 — X 2 — X 3 — X 4 — X 5 — X 6 — R 2 , where R 1 and R 2 is independently hydrogen or any sugar chain, the X 1 is Man or Neu5Ac, the X 2 is Man or Gal, and the X 3 is Man or GalNAc The sugar chain-modified ribosome according to Item 1, wherein X 4 is Man or Gal, X 5 is GlcNAc or Glc, and X 6 is GlcNAc or Cer. (Item 29) The sugar chain-modified ribosome according to item 28, wherein the sugar chain directly binds to the ribosome like a force on the R 2 side or indirectly as a hydrophobic interaction. (Coupling between items 3C X 1 and X 2, coupling between X 2 and X 3, coupling between X 3 and X 4, binding and X between X 4 and X 5 At least one sugar chain bond selected from the group consisting of the binding forces between 5 and X 6 is defined, wherein the bond between X 1 and X 2 is an α 1, 2 bond or an α A bond between X 2 and X 3 is an α ΐ, 2 bond, an α ΐ, 3 bond, an α 1, 6 bond, or a j8 1, 3 bond, and the X 3 and X bond 4 is an α 1,3 bond or α 1,6 bond, and the bond between X 4 and X 5 is a j8 1,4 bond, and the bond between X 5 and X 6 Item 29. The sugar chain-modified ribosome according to Item 28, wherein the bond between them is a β1,1 bond or a β1,4 bond. (Item 3D Bond between X 1 and X 2 , Bond between X 2 and X 3 , Bond between X 3 and X 4 , Bond between X 4 and X 5 and X 5 and At least two sugar chain bonds selected from the group that also has a binding force between X 6 are defined, wherein the bond between X 1 and X 2 is << 1, 2 bond or << 2 , 3 bond, and the bond between X 2 and X 3 is a 1, 2 bond, α 1, 3 bond, α 1, 6 bond or β 1, 3 bond, and X 3 and X 4 Is a α 1,3 bond or α 1,6 bond, and the bond between X 4 and X 5 is a β 1,4 bond, and the bond between X 5 and X 6 is The sugar chain-modified ribosome according to Item 28, wherein the bond is a β 1,1 bond or a j8 1,4 bond (Item 32) A bond between X 1 and X 2 , a bond between X 2 and X 3 coupling between, the bond between X 3 and X 4, when less is selected from the group becomes binding force between the coupling and X 5 and X 6 between X 4 and X 5 Three glycosylation are defined, where binding alpha I between the X 1 and X 2, a 2 bond or a 2, 3 bond, between the X 2 and X 3 The bond is a 1, 2 bond, << 1, 3 bond, << 1, 6 bond or | 8 1,3 bond, and the bond between X 3 and X 4 is a 1, 3 bond or a 1, A bond between X 4 and X 5 is a j8 1,4 bond, and a bond between X 5 and X 6 is a β 1,1 bond or a j8 1,4 bond. The glycosylated liposome according to Item 28. (Item 33) A bond between X 1 and X 2 , a bond between X 2 and X 3 , a bond between X 3 and X 4 , At least four sugar chain bonds selected from the group consisting of a bond between X 4 and X 5 and a binding force between X 5 and X 6 , wherein X 1 and X 2 Is a 1, 2 bond or ex 2, 3 bond, and the bond between X 2 and X 3 is ex 1, 2 bond, ex 1, 3 bond, a 1, 6 bond Together Other are beta 1, 3 bond, the bond between the X 3 and X 4 is a 1, 3 bond or a 1, 6 bond, bond j8 1 between the X 4 and X 5 The sugar chain-modified ribosome according to Item 28, which is a 4-bond and a binding force between X 5 and X 6 β 1, 1 bond or β 1,4 bond. (Item 34) Bond between X 1 and X 2 , Bond between X 2 and X 3 , Bond between X 3 and X 4 , Bond between X 4 and X 5 and X All of the glycan bonds selected from the group of binding forces between 5 and X 6 are defined. Wherein the bond between X 1 and X 2 is an a 1, 2 bond or an a 2, 3 bond, and the bond between X 2 and X 3 is an αΐ, 2 bond, αΐ, 3 bond, α 1, 6 bond or j81, 3 bond, and the bond between X 3 and X 4 is a 1, 3 bond or a 1, 6 bond, and X 4 and X bond The sugar chain modification according to Item 28, wherein the bond between 5 is a β 1,4 bond, and the bond between X 5 and X 6 is a β 1,1 bond or a β 1,4 bond. Ribosome. (Item 35) X 1 — X 2 — X 3 — X 4 — X 5 — X 6 is Man- Man- Man- Man- GlcNAc-GlcNAc or Neu5 Ac- Gal-GalNAc- Gal-Glc- Cer The sugar chain-modified ribosome according to Item 28. (Item 36) X 1 — X 2 — X 3 — X 4 — X 5 — X 6 are Manal, 2Manal, 2Manal, 3Man β 1, 4GlcNAcj81, 4GlcNAc81, Mana 1, 2Mana 1, 3Mana 1, 6Manj81, 4 GlcNAc j81, 4GlcNAc ゝ Man a 1, 2Mana 1, 6Mana 1, 6Manj81, 4GlcNA C j 81, 4GlcNAc and Neu5Ac a 2, 3Galj81, 3GalNAc β1, 4Galj81, 4Glc β1, ICer 36. The sugar chain-modified liposome according to item 35, wherein (Item 37) The sugar chain-modified ribosome according to item 1, which is selected from the group consisting of the sugar powers Gal, GalNAc, Man, Glc, GlcNAc and Ser of the ribosome proximal end of the sugar chain and a combination force thereof. (Item 38) The sugar at the most distal end of the ribosome of the sugar chain is Ga 1, 3, 1 (O—SO 2 H) Gal, GalNAc, Man, Fuc and Neu5Ac and their

3  Three

組み合わせ力もなる群より選択される、項目 1に記載の糖鎖修飾リボソーム。（項目 3 9)前記糖鎖のリボソーム最近位端の糖力 Gal、 GalNAc、 Man, Glc、 GlcNAcお よび Serならびにそれらの組み合わせ力 なる群より選択され、かつ前記糖鎖のリポ ソーム最遠位端の糖力 Gal、 GalNAc、 3，一（O— SO H)Gal、 Man, Fucおよび 2. The sugar chain-modified ribosome according to item 1, wherein the sugar chain-modified ribosome is selected from the group consisting of a combination force. (Item 9) The sugar force at the proximal end of the ribosome of the sugar chain is selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc and Ser, and their combination power, and the most distal end of the liposome in the sugar chain Sugar powers Gal, GalNAc, 3, (O—SOH) Gal, Man, Fuc and

3  Three

Neu5Acならびにそれらの組み合わせ力もなる群より選択される、項目 1に記載の糖 鎖修飾リボソーム。（項目 40)前記糖鎖のリボソーム最近位端の糖力 Serまたは Cer である、項目 37に記載の糖鎖修飾リボソーム。（項目 41)前記糖鎖のリボソーム最遠 位端の糖が、 3，—（O— SO H) Galである、項目 38に記載の糖鎖修飾リボソーム。 (  Item 2. The sugar chain-modified ribosome according to Item 1, which is selected from the group consisting of Neu5Ac and a combination force thereof. (Item 40) The sugar chain-modified ribosome according to item 37, which is a sugar power Ser or Cer at the most proximal end of the ribosome of the sugar chain. (Item 41) The sugar chain-modified ribosome according to item 38, wherein the sugar at the most distal end of the ribosome of the sugar chain is 3, — (O—SO 2 H) Gal. (

3  Three

項目 42)前記糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造: Fuc1— A2 — RZを有し、ここで該 A2は、 Gal、 Glcおよび GlcNAcからなる群より選択され、そし て該 Rzは、水素であるか、または任意の糖である、項目 1に記載の糖鎖修飾リポソ一 ム。（項目 43) Fuc1と A2との間の結合が、 αΐ, 2結合、 αΐ, 3結合および αΐ, 4結 合力もなる群より選択される、項目 42に記載の糖鎖修飾リボソーム。（項目 44)前記 糖鎖のリボソーム遠位端力 該遠位端側より Fuc— Gal、 Fuc— Glcおよび Fuc— Glc NAc力もなる群より選択される構造を有する、項目 42に記載の糖鎖修飾リボソーム。 (項目 45)前記糖鎖のリボソーム遠位端力 該遠位端側より Fuc a 1, 2Gal、 Fuc a 1 , 3Glc、 Fuc a 1, 3GlcNAcおよび Fuc a 1, 4GlcNAcからなる群より選択される構 造を有する、項目 44に記載の糖鎖修飾リボソーム。（項目 46)前記糖鎖のリボソーム 遠位端が、該遠位端側より、以下の構造: Fuc1— A2— A3— Rzを有し、ここで該 A2は 、 Gaほたは GlcNAcであり、該 A3は、 Glc、 Galおよび GlcNAcからなる群より選択さ れ、そして該 Rzは、水素であるか、または任意の糖である、項目 1に記載の糖鎖修飾 リボソーム。（項目 47) Fuc1と A2との間の結合および A2と A3との間の結合力もなる群 より選択される少なくとも 1つの糖鎖結合が規定されており、ここで、該 Fuc1と A2との 間の結合が、 α 1, 2結合または a 1, 4結合であり、該 Α2と Α3との間の結合が、 β 1, 3結合または |8 1 , 4結合である、項目 46に記載の糖鎖修飾リボソーム。（項目 48) F uc1と A2との間の結合および A2と A3との間の結合力 なる群より選択される糖鎖結合 のすべてが規定されており、ここで、該 Fuc1と A2との間の結合が、 《1, 2結合または a 1, 4結合であり、該 A2と A3との間の結合が、 β 1, 3結合または |8 1, 4結合である 、項目 46に記載の糖鎖修飾リボソーム。（項目 49)前記糖鎖のリボソーム遠位端が、 該遠位端側より Fuc - Gal - Glc、 Fuc - Gal - GlcNAcおよび Fuc - GlcNAc - G alからなる群より選択される構造を有する、項目 46に記載の糖鎖修飾リボソーム。（項 目 50)前記糖鎖のリボソーム遠位端が、該遠位端側より F Item 42) The ribosome distal end of the sugar chain has the following structure from the distal end side: Fuc 1 — A 2 — R Z , where A 2 consists of Gal, Glc and GlcNAc Item 2. The sugar chain-modified liposome according to Item 1, wherein the liposome is selected from the group, and Rz is hydrogen or any sugar. (Item 43) The bond between Fuc 1 and A 2 is αΐ, 2 bond, αΐ, 3 bond and αΐ, 4 bond. 43. The sugar chain-modified ribosome according to item 42, which is selected from the group consisting of resultant forces. (Item 44) The sugar chain modification according to item 42, having a structure selected from the group consisting of Fuc-Gal, Fuc-Glc and Fuc-Glc NAc force from the distal end side of the ribosome distal end force of the sugar chain Ribosome. (Item 45) Ribosome distal end force of the sugar chain A structure selected from the group consisting of Fuc a 1, 2Gal, Fuc a 1, 3Glc, Fuc a 1, 3GlcNAc and Fuc a 1, 4GlcNAc from the distal end side 45. The sugar chain-modified ribosome according to item 44, having a structure. (Item 46) The ribosome distal end of the sugar chain has the following structure from the distal end side: Fuc 1 — A 2 — A 3 — R z , where A 2 is Ga is GlcNAc, the a 3 is Glc, is selected from the group consisting of Gal and GlcNAc, and the R z is hydrogen or is any sugar, sugar chain modification ribosome of claim 1 . (Item 47) At least one sugar chain bond selected from the group consisting of a bond between Fuc 1 and A 2 and a binding force between A 2 and A 3 is defined, where Fuc 1 And A 2 are α 1, 2 bonds or a 1, 4 bonds, and the bonds between Α 2 and 該3 are β 1, 3 bonds or | 8 1, 4 bonds. 47. The sugar chain-modified ribosome according to Item 46. 48. All glycosylation selected from coupling force becomes the group are defined between the coupling and A 2 and A 3 between the F uc 1 and A 2, wherein said Fuc 1 The bond between A 2 and A 2 is a << 1, 2 bond or a 1, 4 bond, and the bond between A 2 and A 3 is a β 1, 3 bond or | 8 1, 4 bond. 47. The sugar chain-modified ribosome according to item 46. (Item 49) The item wherein the ribosome distal end of the sugar chain has a structure selected from the group consisting of Fuc-Gal-Glc, Fuc-Gal-GlcNAc and Fuc-GlcNAc-Gal from the distal end side 46. The sugar chain-modified ribosome according to 46. (Item 50) The ribosome distal end of the sugar chain is F from the distal end side.

uc a 1, 2Gal j8 1, 4Glc、 Fuc a 1, 2Gal j8 1, 3GlcNAc、 Fuc a 1, 2Gal j8 1, 4G1 cNAcおよび Fuc a 1 , 4GlcNAC j8 1, 3Galからなる群より選択される構造を有する 、項目 49に記載の糖鎖修飾リボソーム。（項目 51)前記糖鎖のリボソーム遠位端が、 該遠位端側より、以下の構造: Fuc^ -A2— A3— A4— Rzを有し、ここで該 A2は、 Gal または GlcNAであり、該 A3は、 Gaほたは GlcNAであり、該 A4は、 Gaほたは Glcで あり、そして該 Rzは、水素であるか、または任意の糖である、項目 1に記載の糖鎖修 飾リボソーム。（項目 52) Fuc1と A2との間の結合、 A2と A3との間の結合および A3と A4 との間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており、 ここで、該 Fuc1と A2との間の結合が、 《1, 2結合または《1, 4結合であり、該 A2と A 3との間の結合が、 β 1, 3結合であり、該 Α3と Α4との間の結合力 β 1, 3結合または β ΐ, 4結合である、項目 51に記載の糖鎖修飾リボソーム。（項目 53) Fuc1と Α2との 間の結合、 A2と A3との間の結合および A3と A4との間の結合力もなる群より選択され る少なくとも 2つの糖鎖結合が規定されており、ここで、該 Fuc1と A2との間の結合が、 a 1, 2結合または α 1, 4結合であり、該 Α2と Α3との間の結合が、 β 1, 3結合であり、 該 Α3と Α4との間の結合が、 β 1, 3結合または |81, 4結合である、項目 51に記載の 糖鎖修飾リボソーム。（項目 54) Fuc1と Α2との間の結合、 A2と A3との間の結合および A3と A4との間の結合力もなる群より選択される糖鎖結合のすべてが規定されており、 ここで、該 Fuc1と A2との間の結合が、 《1, 2結合または《1, 4結合であり、該 A2と A 3との間の結合が、 β 1, 3結合であり、該 Α3と Α4との間の結合力 β 1, 3結合または j81, 4結合である、項目 51に記載の糖鎖修飾リボソーム。（項目 55)前記糖鎖のリポ ソーム遠位端が、該遠位端側より Fuc - Gal - GlcNAc - Galまたは Fuc - GlcNAc — Gal— Glcの構造を有する、項目 51に記載の糖鎖修飾リボソーム。 （項目 56)前記 糖鎖のリボソーム遠位端力 該遠位端側より Fuc a 1, 2Galj81, 3GlcNAc β 1, 3, Galまたは Fuc α 1, 4GlcNAC j81, 3Galj81, 4Glcの構造を有する、項目 55に記 載の糖鎖修飾リボソーム。 （項目 57)前記糖鎖のリボソーム遠位端が、該遠位端側よ り、以下の構造: Fuc1— A2— A3— A4— A5— Rzを有し、ここで該 A2は、 Galであり、 該 A3は、 GlcNAであり、該 A4は、 Galであり、該 A5は、 Glcであり、そして該 Rzは、水 素であるか、または任意の糖である、項目 1に記載の糖鎖修飾リボソーム。（項目 58) Fuc1と A2との間の結合、 A2と A3との間の結合、 A3と A4との間の結合および A4と A5と の間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており、こ こで、該 Fuc1と A2との間の結合力 αΐ, 2結合であり、該 Α2と Α3との間の結合力 β 1, 3結合であり、該 Α3と Α4との間の結合が、 β 1, 3結合であり、該 Α4と Α5との間の結 合力 j81, 4結合である、項目 57に記載の糖鎖修飾リボソーム。（項目 59) Fuc1と A 2との間の結合、 A2と A3との間の結合、 A3と A4との間の結合および A4と A5との間の 結合力 なる群より選択される少なくとも 2つの糖鎖結合が規定されており、ここで、該 Fuc1と A2との間の結合力 «1, 2結合であり、該 A2と A3との間の結合力 β ΐ, 3結 合であり、該 A3と A4との間の結合力 β 1, 3結合であり、該 Α4と Α5との間の結合が、 β ΐ, 4結合である、項目 57に記載の糖鎖修飾リボソーム。（項目 6C FUC1と Α2との 間の結合、 Α2と Α3との間の結合、 Α3と Α4との間の結合および Α4と Α5との間の結合か らなる群より選択される少なくとも 3つの糖鎖結合が規定されており、ここで、該 Fuc1と A2との間の結合が、 《1 , 2結合であり、該 A2と A3との間の結合が、 β ΐ, 3結合であ り、該 Α3と Α4との間の結合が、 β 1, 3結合であり、該 Α4と Α5との間の結合力 β 1, 4 結合である、項目 57に記載の糖鎖修飾リボソーム。（項目 61) Fuc1と Α2との間の結 合、 A2と A3との間の結合、 A3と A4との間の結合および A4と A5との間の結合カゝらなる 群より選択される少なくとも 4つの糖鎖結合が規定されており、ここで、該 Fuc1と A2と の間の結合が、 α ΐ, 2結合であり、該 Α2と Α3との間の結合が、 β ΐ, 3結合であり、該 Α3と Α4との間の結合が、 β ΐ, 3結合であり、該 Α4と Α5との間の結合が、 β ΐ, 4結合 である、項目 57に記載の糖鎖修飾リボソーム。（項目 62) Fuc1と Α2との間の結合、 A 2と A3との間の結合、 A3と A4との間の結合および A4と A5との間の結合力もなる群より 選択される糖鎖結合のすべてが規定されており、ここで、該 Fuc1と A2との間の結合 が、 α ΐ, 2結合であり、該 Α2と Α3との間の結合力 β ΐ, 3結合であり、該 Α3と Α4との 間の結合が、 β 1, 3結合であり、該 Α4と Α5との間の結合力 β 1, 4結合である、項 目 57に記載の糖鎖修飾リボソーム。（項目 63)前記糖鎖のリボソーム遠位端が、該遠 位端側より Fuc— Gal— GlcNAc— Gal— Glcの構造を有する、項目 57に記載の糖 鎖修飾リボソーム。（項目 64)前記糖鎖のリボソーム遠位端が、該遠位端側より Fuc a 1, 2Gal j8 1, 3GlcNAC j8 1, 3Gal j8 1, 4Glcの構造を有する、項目 63に記載の 糖鎖修飾リボソーム。（項目 65)前記糖鎖のリボソーム遠位端が、該遠位端側より、以 下の構造: Gal1— B2— Rzを有し、ここで該 Gal1は、硫酸化されていても硫酸化されて いなくてもよく、該 B2は、 Gal、 GalNAc、 GlcNAcおよび Glcからなる群より選択され 、そして該 RZは、水素であるか、または任意の糖である、項目 1に記載の糖鎖修飾リ ポソーム。 （項目 66) Gal1と B2との間の結合が、 《1, 3結合、 β 1, 3結合、 β 1, 4結 合および j8 1, 6結合力もなる群より選択される、項目 65に記載の糖鎖修飾リポソ一 ム。（項目 67)前記糖鎖のリボソーム遠位端力 該遠位端側より Gal— Gal、 Gal-Ga IN Ac, Gal— Glcおよび Gal— GlcNAcからなる群より選択される構造を有する、項 目 65に記載の糖鎖修飾リボソーム。（項目 68)前記糖鎖のリボソーム遠位端が、該遠 位端側より Gala 1, 3Gal、 GaljS 1, 3GalNAc、 GaljS 1, 3GlcNAc、 GaljS 1, 4G1 c、 GaljS 1, 4GlcNAcおよび GaljS 1, 6GlcNAcからなる群より選択される構造を有 する、項目 65に記載の糖鎖修飾リボソーム。（項目 69)前記糖鎖のリボソーム遠位端 が、該遠位端側より、以下の構造: Gal1— B2— B3— Rzを有し、ここで該 Gal1は、硫酸 化されていても硫酸化されていなくてもよぐ該 B2は、 GalNAcまたは GlcNAcであり 、該 B3は、 Galであり、そして該 RZは、水素であるか、または任意の糖である、項目 1 に記載の糖鎖修飾リボソーム。（項目 70) Gal1と B2との間の結合および B2と B3との間 の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており、ここで 該 Gal1と B2との間の結合が |81, 3結合であり、該 B2と B3との間の結合力 β 1, 4結 合または j81, 3結合である、項目 69に記載の糖鎖修飾リボソーム。（項目 71) Gal1と B2との間の結合および B2と B3との間の結合力 なる群より選択されるの糖鎖結合の すべてが規定されており、ここで該 Gal1と B2との間の結合が 1, 3結合であり、該 B2 と B3との間の結合力 β 1, 4結合または |81, 3結合である、項目 69に記載の糖鎖修 飾リボソーム。（項目 72)前記糖鎖のリボソーム遠位端が、該遠位端側より Gal— Gal N Ac— Gaほたは Gal— GlcNAc— Galの構造を有する、項目 69に記載の糖鎖修飾 リボソーム。（項目 73)前記糖鎖のリボソーム遠位端が、該遠位端側より Gal |81, 3G alNAcjS 1, 4Gal、 GaljS 1, 3GlcNAC j81, 3Galおよび GaljS 1, 3GlcNAC j81, 3Gal力もなる群より選択される構造を有する、項目 72に記載の糖鎖修飾リボソーム。 (項目 74)前記糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造: Gal1— B2 — B3— B4— Rzを有し、ここで該 Gal1は、硫酸ィ匕されていても硫酸ィ匕されていなくても よぐ該 B2は、 GalNAcまたは GlcNAcであり、該 B3は、 Galであり、該 B4は、 Glcであ り、そして該 Rzは、水素であるか、または任意の糖である、項目 1に記載の糖鎖修飾リ ポソーム。 （項目 75) Gal1と B2との間の結合、 B2と B3との間の結合および B3と との 間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており、ここ で該 Gal1と B2との間の結合が |81, 3結合であり、該 B2と B3との間の結合が 1, 4結 合または j81, 3結合であり、該 B3と B4との間の結合が /31, 4結合である、項目 74に 記載の糖鎖修飾リボソーム。 （項目 76) Gal1と B2との間の結合、 B2と B3との間の結合 および B3と B4との間の結合力 なる群より選択される少なくとも 2つの糖鎖結合が規 定されており、ここで該 Gal1と B2との間の結合が β A structure selected from the group consisting of uc a 1, 2Gal j8 1, 4Glc, Fuc a 1, 2Gal j8 1, 3GlcNAc, Fuc a 1, 2Gal j8 1, 4G1 cNAc and Fuc a 1, 4GlcNA C j 8 1, 3Gal The sugar chain-modified ribosome according to Item 49, wherein (Item 51) The ribosome distal end of the sugar chain has the following structure from the distal end side: Fuc ^ -A 2 — A 3 — A 4 — R z , where A 2 is Gal or GlcNA, the A 3 is Ga or GlcNA, the A 4 is Ga or Glc, and the R z is hydrogen or any sugar. The sugar chain-modified ribosome according to Item 1. (Item 52) At least one sugar chain bond selected from the group consisting of a bond between Fuc 1 and A 2 , a bond between A 2 and A 3, and a bond force between A 3 and A 4 Is defined, Here, the bond between the Fuc 1 and A 2 is a << 1 , 2 bond or << 1, 4 bond, and the bond between the A 2 and A 3 is a β 1,3 bond. , the Alpha 3 and the coupling force beta 1 between Alpha 4, 3 bond or beta I, a 4 binding, glycosylation ribosome of claim 51. (Item 53) There are at least two sugar chain bonds selected from the group consisting of the bond between Fuc 1 and Α 2 , the bond between A 2 and A 3, and the bond strength between A 3 and A 4. are defined, wherein, the bond between the Fuc 1 and a 2 is a a 1, 2 bond or alpha 1, 4 bond, the bond between the alpha 2 and alpha 3 is, beta 1 a 3 bond, the bond between the Alpha 3 and Alpha 4 is, beta 1, 3 bond or | 81, 4 is a bond, glycosylation ribosome of claim 51. (Item 54) All glycan bonds selected from the group consisting of the bond between Fuc 1 and Α 2 , the bond between A 2 and A 3 and the bond strength between A 3 and A 4 are specified. Here, the bond between the Fuc 1 and A 2 is a << 1 , 2 bond or << 1, 4 bond, and the bond between the A 2 and A 3 is β 1, 52. The sugar chain-modified ribosome according to Item 51, which is a 3-bond and has a binding force β 1,3 bond or j81,4-bond between Α 3 and Α 4 . (Item 55) The sugar chain-modified ribosome according to item 51, wherein the liposome distal end of the sugar chain has a structure of Fuc-Gal-GlcNAc-Gal or Fuc-GlcNAc-Gal-Glc from the distal end side. . (Item 56) Ribosome distal end force of the sugar chain Fuc a 1, 2Galj81, 3GlcNAc β 1, 3, Gal or Fuc α 1, 4GlcNA C j 81, 3Galj81, 4Glc from the distal end side, The sugar chain-modified ribosome according to Item 55. (Item 57) The ribosome distal end of the sugar chain has the following structure from the distal end side: Fuc 1 — A 2 — A 3 — A 4 — A 5 — R z , where A 2 is Gal, the A 3 is GlcNA, the A 4 is Gal, the A 5 is Glc, and the R z is hydrogen or any Item 2. The sugar chain-modified ribosome according to Item 1, which is a sugar. (Item 58) Bond between Fuc 1 and A 2 , bond between A 2 and A 3 , bond between A 3 and A 4 and bond between A 4 and A 5 And at least one sugar chain bond selected, wherein the binding force between Fuc 1 and A 2 is αΐ, 2 bond, and the bond between Α 2 and Α 3 a force beta 1, 3 bond, the bond between the Alpha 3 and Alpha 4 is a beta 1, 3 bond, a binding force J81, 4 bond between the Alpha 4 and Alpha 5, item 58. The sugar chain-modified ribosome according to 57. (Item 59) The bond between Fuc 1 and A 2 , the bond between A 2 and A 3 , the bond between A 3 and A 4 and the bond strength between A 4 and A 5 And at least two sugar chain bonds selected, wherein the binding force between Fuc 1 and A 2 is «1, 2 bond, and the bond between A 2 and A 3 Force β ΐ, 3 58. The binding force between A 3 and A 4 is a β 1,3 bond, and the bond between Α 4 and Α 5 is a β ΐ, 4 bond. Sugar chain-modified ribosome. (Group of items 6C FUC 1 and Α 2 bond, Α 2 and Α 3 bond, Α 3 and Α 4 bond and Α 4 and 結合5 bond And at least three sugar chain bonds selected from the above, wherein the bond between Fuc 1 and A 2 is << 1, 2 bond, and between A 2 and A 3 The bond is β ΐ, 3 bond, the bond between Α 3 and Α 4 is β 1, 3 bond, and the binding force between Α 4 and Α 5 β 1, 4 bond The sugar chain-modified ribosome according to Item 57. (Item 61) A bond between Fuc 1 and Α 2 , a bond between A 2 and A 3, and a bond between A 3 and A 4 And at least four sugar chain bonds selected from the group consisting of a bond between A 4 and A 5 , wherein the bond between Fuc 1 and A 2 is defined as α ΐ , 2 bond, and the bond between Α 2 and Α 3 is β ΐ, 3 bond, and between Α 3 and Α 4 Of binding, beta I, a 3 bond, the bond between the Alpha 4 and Alpha 5 is, beta I, a 4 binding, glycosylation ribosome of claim 57. (Item 62) Fuc 1 and coupling between the Alpha 2, glycosylation selected from also the group bonding force between the bond and a 4 and a 5 between binding and a 3 and a 4 between a 2 and a 3 In which the bond between Fuc 1 and A 2 is α ΐ, 2 bond, and the binding force β ΐ, 3 bond between Α 2 and Α 3 There, the bond between the Alpha 3 and Alpha 4 is a beta 1, 3 bond, a bond strength beta 1, 4 bond between the Alpha 4 and Alpha 5, sugars according to Item 57 (Item 63) The sugar chain-modified ribosome according to item 57, wherein the ribosome distal end of the sugar chain has a structure of Fuc-Gal-GlcNAc-Gal-Glc from the distal end side. 64) The ribosome distal end of the sugar chain is Fuc a 1 from the distal end side. , 2Gal j8 1, 3GlcNA C- linked ribosome according to item 63 having a structure of C j 8 1, 3Gal j8 1, 4Glc (Item 65) The ribosome distal end of the sugar chain is on the distal end side Thus, it has the following structure: Gal 1 —B 2 —R z , where Gal 1 may be sulfated or unsulfated, and B 2 may be Gal, GalNAc Item 2. The sugar chain-modified liposome according to Item 1, which is selected from the group consisting of GlcNAc and Glc, and wherein R Z is hydrogen or any sugar. (Item 66) The bond between Gal 1 and B 2 is selected from the group consisting of << 1,3 bond, β1,3 bond, β1,4 bond and j8 1,6 bond force. The sugar chain-modified liposome described in 1. (Item 67) Ribosome distal end force of the sugar chain having a structure selected from the group consisting of Gal-Gal, Gal-GaIN Ac, Gal-Glc and Gal-GlcNAc from the distal end side Item 66. A sugar chain-modified ribosome according to Item 65. (Item 68) The ribosome distal end of the sugar chain is Gala 1, 3Gal, GaljS 1, 3GalNAc, GaljS 1, 3GlcNAc, GaljS 1, 4G1 c, GaljS 1, 4GlcNAc and GaljS 1, 6GlcNAc from the distal end side. 66. The sugar chain-modified ribosome according to item 65, which has a structure selected from the group consisting of: (Item 69) The ribosome distal end of the sugar chain has the following structure from the distal end side: Gal 1 — B 2 — B 3 — R z , where Gal 1 is sulfated. The B 2, which may or may not be sulfated, is GalNAc or GlcNAc, the B 3 is Gal, and the R Z is hydrogen or any sugar. The sugar chain-modified ribosome according to Item 1. (Item 70) Gal 1 and has at least one glycosylation is defined is selected from the binding force becomes the group between the coupling and B 2 and B 3 between B 2, wherein the said Gal 1 70. The sugar chain modification according to Item 69, wherein the bond between B 2 is a | 81,3 bond, and the binding force between B 2 and B 3 is a β 1,4 bond or a j81,3 bond. Ribosome. 71. All of the sugar chain binding of selected from the binding force becomes a group are defined between the coupling and B 2 and B 3 between the Gal 1 and B 2, wherein the said Gal 1 a bond is 1, 3 bond between B 2, avidity beta 1, 4 bond or between the B 2 and B 3 | is 81, 3 binding, sugar qualified according to item 69 Ribosome. (Item 72) The sugar chain-modified ribosome according to item 69, wherein the ribosome distal end of the sugar chain has a structure of Gal-GalNAc-Ga or Gal-GlcNAc-Gal from the distal end side. (Item 73) The ribosome distal end of the sugar chain has a Gal | 81, 3G alNAcjS 1, 4Gal, GaljS 1, 3GlcNA C j 81, 3Gal and GaljS 1, 3GlcNA C j 81, 3Gal force from the distal end side. Item 73. The sugar chain-modified ribosome according to Item 72, which has a structure selected from the group consisting of: (Item 74) The ribosome distal end of the sugar chain has the following structure from the distal end side: Gal 1 — B 2 — B 3 — B 4 — R z , where Gal 1 is The B 2, which may or may not be sulfated, is GalNAc or GlcNAc, the B 3 is Gal, the B 4 is Glc, and the R 2. The sugar chain-modified liposome according to Item 1, wherein z is hydrogen or any sugar. (Item 75) At least one sugar chain bond selected from the group consisting of a bond between Gal 1 and B 2 , a bond between B 2 and B 3, and a bond between B 3 is defined. Where the bond between Gal 1 and B 2 is a | 81,3 bond, and the bond between B 2 and B 3 is a 1,4 bond or a j81,3 bond, bond between the B 3 and B 4 are / 31, 4 bonds, glycosylation ribosome of claim 74. (Item 76) Bond between Gal 1 and B 2 ; bond between B 2 and B 3 And at least two sugar chain bonds selected from the group consisting of binding forces between B 3 and B 4 are defined, wherein the bond between Gal 1 and B 2 is β

1, 3結合であり、該 Β2と Β3との間の結合が β 1, 4結合または β 1, 3結合であり、該 Β 3と Β4との間の結合が 1, 4結合である、項目 74に記載の糖鎖修飾リボソーム。（項 目 77) Gal1と Β2との間の結合、 B2と B3との間の結合および B3と B4との間の結合から なる群より選択される糖鎖結合のすべてが規定されており、ここで該 Gal1と B2との間 の結合が β 1, 3結合であり、該 Β2と Β3との間の結合が β 1, 4結合または β 1, 3結合 であり、該 Β3と Β4との間の結合が /3 1, 4結合である、項目 74に記載の糖鎖修飾リポ ノーム。 （項目 78)前記糖鎖のリボソーム遠位端力 該遠位端側より Gal— GalNAc Gal—GlcまたはGal—GlcNAc— Gal—Glcの構造を有する、項目 74に記載の 糖鎖修飾リボソーム。（項目 79)前記糖鎖のリボソーム遠位端が、該遠位端側より Gal β 1, 3GalNAC j8 1, 4Gal j8 1, 4Glcまたは Gal j8 1, 3GlcNAC j8 1, 3Gal j8 1, 4 Glcの構造を有する、項目 79に記載の糖鎖修飾リボソーム。（項目 80)前記糖鎖のリ ポソ一ム遠位端力 該遠位端側より、以下の構造: Gal1— B2— B3— B4— B5— RZを有 し、ここで該 Gal1は、硫酸ィ匕されていても硫酸ィ匕されていなくてもよぐ該 B2は、 GalN Acであり、該 B3は、 Galであり、該 B4は、 Glcであり、該 B5は、 Cerであり、そして該 RZ は、水素であるか、または任意の糖である、項目 1に記載の糖鎖修飾リボソーム。（項 目 81) Gal1と B2との間の結合、 B2と B3との間の結合、 B3と B4との間の結合および と B5との間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており 、ここで該 Gal1と B2との間の結合が β 1, 3結合であり、該 Β2と Β3との間の結合が β 1 , 4結合であり、該 Β3と Β4との間の結合が 1, 4結合であり、該 Β4と Β5との間の結合 が j8 1, 1結合である、項目 80に記載の糖鎖修飾リボソーム。（項目 82) Gal1と との 間の結合、 B2と B3との間の結合、 B3と B4との間の結合および B4と B5との間の結合か らなる群より選択される少なくとも 2つの糖鎖結合が規定されており、ここで該 Gal1と B 2との間の結合が β 1, 3結合であり、該 Β2と Β3との間の結合が β 1, 4結合であり、該 Β3と Β4との間の結合が β 1, 4結合であり、該 Β4と Β5との間の結合が β 1, 1結合であ る、項目 80に記載の糖鎖修飾リボソーム。（項目 83) Gal1と Β2との間の結合、 B2と B3 との間の結合、 B3と B4との間の結合および B4と B5との間の結合力 なる群より選択さ れる少なくとも 3つの糖鎖結合が規定されており、ここで該 Gal1と B2との間の結合が β 1, 3結合であり、該 Β2と Β3との間の結合が 1, 4結合であり、該 Β3と Β4との間の結 合が β 1, 4結合であり、該 Β4と Β5との間の結合が β 1, 1結合である、項目 80に記載 の糖鎖修飾リボソーム。 （項目 84) Gal1と Β2との間の結合、 B2と B3との間の結合、 B3と B4との間の結合および B4と B5との間の結合力 なる群より選択される糖鎖結合のす ベてが規定されており、ここで該 Gal1と B2との間の結合が 1, 3結合であり、該 と B3との間の結合が β 1, 4結合であり、該 Β3と Β4との間の結合が β 1, 4結合であり、 該 Β4と Β5との間の結合が /3 1, 1結合である、項目 80に記載の糖鎖修飾リボソーム。 (項目 85)前記糖鎖のリボソーム遠位端力 該遠位端側より Gal— GalNAc— Gal— Glc— Cerの構造を有する、項目 80に記載の糖鎖修飾リボソーム。（項目 86)前記糖 鎖のリボソーム遠位端力 該遠位端側より Gal j8 1, 3GalNAC j8 1, 4Gal j8 1, 4Glc j8 1, ICerの構造を有する、項目 85に記載の糖鎖修飾リボソーム。（項目 87)前記 糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造: GalNAc1— C2— RZを有 し、ここで該 C2は、 Gaほたは Serであり、そして該 RZは、水素であるか、または任意の 糖である、項目 1に記載の糖鎖修飾リボソーム。（項目 88) GalNAc1と C2との間の結 合が、 α ΐ, 3結合または l— O—結合であり、ここで、 α ΐ— Ο—結合は C2が Serの 場合に存在する、項目 80に記載の糖鎖修飾リボソーム。（項目 89)前記糖鎖のリポソ 一ム遠位端が、該遠位端側より GalNAc— Gaほたは GalNAc— Serの構造を有す る、項目 87に記載の糖鎖修飾リボソーム。（項目 90)前記糖鎖のリボソーム遠位端が 、該遠位端側より GalNAc a 1, 3Gaほたは GalNAc α 1— O— L— Serの構造を有 する、項目 89に記載の糖鎖修飾リボソーム。（項目 91)前記糖鎖のリボソーム遠位端 が、該遠位端側より、以下の構造: Man1— D2— Rzを有し、ここで該 D2は、 Manであ り、そして該 Rzは、水素であるか、または任意の糖である、項目 1に記載の糖鎖修飾リ ポソーム。 （項目 92) Man1と D2との間の結合が、 α ΐ, 2結合、 α ΐ, 3結合、 α ΐ, 4 結合および α 1, 6結合力もなる群より選択される、項目 91に記載の糖鎖修飾リポソ ーム。（項目 93)前記糖鎖のリボソーム遠位端が、該遠位端側より Man— Manの構 造を有する、項目 91に記載の糖鎖修飾リボソーム。（項目 94)前記糖鎖のリボソーム 遠位端が、該遠位端側より Man α 1, 2Man、 Man a l, 3Man、 Man a 1, 4Manお よび Man a 1, 6Manからなる群より選択される構造を有する、項目 93に記載の糖鎖 修飾リボソーム。（項目 95)前記糖鎖のリボソーム遠位端が、該遠位端側より、以下の 構造： Man1— D2— D3— Rzを有し、ここで該 D2は、 Manであり、該 D3は、 GlcNAcま たは Manであり、そして該 Rzは、水素であるか、または任意の糖である、項目 1に記 載の糖鎖修飾リボソーム。 （項目 96) Man1と D2との間の結合および D2と D3との間の 結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており、ここで該 Man1と D2との間の結合が、 α ΐ, 2結合、 α ΐ, 3結合および α ΐ, 6結合力 なる群よ り選択され、該 D2と D3との間の結合力 α ΐ, 2結合、 ひ 1, 3結合、 ひ 1, 6結合およ ぴ β ΐ, 4結合力もなる群より選択される、項目 95に記載の糖鎖修飾リボソーム。（項 目 97) Man1と D2との間の結合および D2と D3との間の結合力もなる群より選択される 糖鎖結合のすべてが規定されており、ここで該 Man1と D2との間の結合が、 ひ 1, 2結 合、 《1, 3結合および《1, 6結合力 なる群より選択され、該 D2と D3との間の結合 が、 α ΐ, 2結合、 《1, 3結合、 《1, 6結合および |8 1, 4結合力 なる群より選択され る、項目 95に記載の糖鎖修飾リボソーム。（項目 98)前記糖鎖のリボソーム遠位端が 、該遠位端側より Man -Man- Manまたは Man— Man— GlcNAcの構造を有する 、項目 95に記載の糖鎖修飾リボソーム。（項目 99)前記糖鎖のリボソーム遠位端が、 該遠位端側より Man a 1, 2Man a 1 , 2Man、 Man a 1 , 2Man a 1, 3Man、 Man 1, 2Man a 1, 6Man、 Man a 1, 3Man a 1 , 6Man、 Man a 1 , 3Man j8 1, 4G1 cNAc、 Man a 1, 6Man a 1, 6Manおよび Man a 1, 6Man j8 1, 4GlcNAc力らな る群より選択される構造を有する、項目 98に記載の糖鎖修飾リボソーム。（項目 100) 前記糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造: Mar^ -D2— D3— D 4— RZを有し、ここで該 D2は、 Manであり、該 D3は、 Manまたは GlcNAcであり、該 D 4は、 Manまたは GlcNAcであり、そして該 Rzは、水素であるか、または任意の糖であ る、項目 1に記載の糖鎖修飾リボソーム。（項目 101) Man1と D2との間の結合、 D2と D3との間の結合および D3と D4との間の結合力 なる群より選択される少なくとも 1つ の糖鎖結合が規定されており、ここで該 Man1と D2との間の結合が、 《1, 2結合、 α 1, 3結合および a 1, 6結合力もなる群より選択され、該 D2と D3との間の結合力 ひ 1 , 2結合、 《1, 3結合、 《1, 6結合および |8 1, 4結合力 なる群より選択され、該 D3 と D4との間の結合が、 《1, 3結合、 《1, 6結合および ΐ, 4結合力もなる群より選 択される、項目 100に記載の糖鎖修飾リボソーム。（項目 102) Man1と D2との間の結 合、 D2と D3との間の結合および D3と D4との間の結合力 なる群より選択される少なく とも 2つの糖鎖結合が規定されており、ここで該 Man1と D2との間の結合が、 《1, 2結 合、 《1, 3結合および《1, 6結合力 なる群より選択され、該 D2と D3との間の結合 が、 αΐ, 2結合、 《1, 3結合、 《1, 6結合および |81, 4結合力 なる群より選択され 、該 D3と D4との間の結合が、 α 1, 3結合、 α 1, 6結合および 1, 4結合力もなる群 より選択される、項目 100に記載の糖鎖修飾リボソーム。（項目 103) Man1と D2との 間の結合、 D2と D3との間の結合および D3と D4との間の結合力 なる群より選択され る糖鎖結合のすべてが規定されており、ここで該 Man1と D2との間の結合力 αΐ, 2 結合、 αΐ, 3結合および a 1, 6結合力 なる群より選択され、該 D2と D3との間の結 合力 al, 2結合、 《1, 3結合、 《1, 6結合および |81, 4結合力 なる群より選択さ れ、該 D3と D4との間の結合が、 al, 3結合、 al, 6結合および ΐ, 4結合からなる 群より選択される、項目 100に記載の糖鎖修飾リボソーム。（項目 104)前記糖鎖のリ ポソ一ム遠位端が、該遠位端側より Man— Man— Man— Man、 Man -Man -Ma n - GlcNAcおよび Man— Man - GlcNAc - GlcNAcからなる群より選択 される構造を有する、項目 100に記載の糖鎖修飾リボソーム。（項目 105)前記糖鎖 のリボソーム遠位端が、該遠位端側より Mana 1, 2Manal, 2Manal, 3Man、 Mana 1, 2Mana 1, 3Mana 1, 6Man、 Mana 1, 2Mana 1, 3Manj81, 4Glc NAc、 Mana 1, 2Mana 1, 6Mana 1, 6Man、 Mana 1, 3Mana 1, 6Manj81 , 4GlcNAc、 Mana 1, 3Manj81, 4GlcNAc β 1, 4GlcNAc、 Mana 1, 6Man a 1, 6Manj81, 4GlcNAcおよび Man a 1, 6Manj81, 4GlcNAcj81, 4GlcNA cからなる群より選択される構造を有する、項目 104に記載の糖鎖修飾リボソーム。 ( 項目 106)前記糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造: Man1— D 2— D3— D4— D5— Rzを有し、ここで該 D2は、 Manであり、該 D3は、 Manであり、該 D 4は、 Manまたは GlcNAcであり、該 D5は、 GlcNAcであり、そして該 Rzは、水素であ る力、または任意の糖である、項目 1に記載の糖鎖修飾リボソーム。 （項目 107) Man 1と D2との間の結合、 D2と D3との間の結合、 D3と D4との間の結合および D4と D5との 間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており、ここ で該 Man1と D2との間の結合が、 α ΐ, 2結合、 α ΐ, 3結合および α ΐ , 6結合からな る群より選択され、該 D2と D3との間の結合が、 《1, 2結合、 《1, 3結合および《1, 6結合力もなる群より選択され、該 D3と D4との間の結合が、 α ΐ, 3結合、 《1, 6結合 および ι8 1, 4結合力もなる群より選択され、該 D4と D5との間の結合が、 β 1, 4結合 である、項目 106に記載の糖鎖修飾リボソーム。（項目 108) Man1と D2との間の結合 、 D2と D3との間の結合、 D3と D4との間の結合および D4と D5との間の結合力 なる群 より選択される少なくとも 2つの糖鎖結合が規定されており、ここで該 Man1と D2との間 の結合が、 α ΐ, 2結合、 α ΐ, 3結合および α ΐ, 6結合からなる群より選択され、該 D 2と D3との間の結合が、 《1, 2結合、 《1, 3結合および《1, 6結合力 なる群より選 択され、該 D3と D4との間の結合力 a 1, 3結合、 a 1, 6結合および 1, 4結合から なる群より選択され、該 D4と D5との間の結合力 β 1, 4結合である、項目 106に記載 の糖鎖修飾リボソーム。 （項目 109) Man1と D2との間の結合、 D2と D3との間の結合、 D3と D4との間の結合および D4と D5との間の結合力 なる群より選択される少なくとも 3つの糖鎖結合が規定されており、ここで該 Man1と D2との間の結合が、 《1, 2結合 、 α ΐ, 3結合および a 1, 6結合力 なる群より選択され、該 D2と D3との間の結合が、 a l, 2結合、 《1, 3結合および a 1, 6結合力 なる群より選択され、該 D3と D4との 間の結合が、 a 1, 3結合、 a 1, 6結合および 1, 4結合力 なる群より選択され、該 D4と D5との間の結合力 β 1, 4結合である、項目 106に記載の糖鎖修飾リボソーム 。 （項目 110) Man1と D2との間の結合、 D2と D3との間の結合、 D3と D4との間の結合 および D4と D5との間の結合力もなる群より選択される糖鎖結合のすべてが規定され ており、ここで該 Man1と D2との間の結合が、 α ΐ, 2結合、 α ΐ, 3結合および α ΐ, 6 結合力もなる群より選択され、該 D2と D3との間の結合が、 α ΐ, 2結合、 《1, 3結合 および α ΐ, 6結合力 なる群より選択され、該 D3と D4との間の結合力 « 1, 3結合、 a 1, 6結合および |8 1, 4結合力 なる群より選択され、該 D4と D5との間の結合が、 β 1, 4結合である、項目 106に記載の糖鎖修飾リボソーム。 （項目 111)前記糖鎖の リボソーム遠位端力 該遠位端側より Man— Man— Man— Man— GlcNAcまたは Man—Man—Man—GlcNAc— GlcNAcの構造を有する、項目 106に記載の糖 鎖修飾リボソーム。（項目 112)前記糖鎖のリボソーム遠位端が、該遠位端側より Man 1, 2Mana 1, 2Mana 1, 3Man j81, 4GlcNAc、 Mana 1, 2Mana 1, 3Man a 1, 6Man β 1, 4GlcNAc、 Man a 1, 2Man a 1, 3Man β 1, 4GlcNAc β ΐ, 4 GlcNAc、 Mana 1, 2Mana 1, 6Mana 1, 6Manj81, 4GlcNAc、 Mana 1, 6 Mana 1, 6Manj81, 4GlcNAcj81, 4GlcNAcおよび Man a 1, 3Mana 1, 6M anjS 1, 4GlcNAc β 1, 4GlcNAcからなる群より選択される構造を有する、項目 11 1に記載の糖鎖修飾リボソーム。（項目 113)前記糖鎖のリボソーム遠位端が、該遠位 端側より、以下の構造: Man -D2— D3— D4— D5— D6— RZを有し、ここで該 D2は、 Manであり、該 D3は、 Manであり、該 D4は、 Manであり、該 D5は、 GlcNAcであり、 該 D6は、 GlcNAcであり、そして該 Rzは、水素であるか、または任意の糖である、項 目 1に記載の糖鎖修飾リボソーム。（項目 114) Man1と D2との間の結合、 D2と D3との 間の結合、 D3と D4との間の結合、 D4と D5との間の結合および D5と D6との間の結合 からなる群より選択される少なくとも 1つの糖鎖結合が規定されており、ここで該 Man1 と D2との間の結合が、 《1, 2結合であり、該 D2と D3との間の結合が、 《1, 2結合、 α 1, 3結合および a 1, 6結合力もなる群より選択され、該 D3と D4との間の結合力 ひ 1 , 3結合または a 1, 6結合であり、該 D4と D5との間の結合が β 1, 4結合であり、該 D5 と D6との間の結合が /31, 4結合である、項目 113に記載の糖鎖修飾リボソーム。（項 目 115) Man1と D2との間の結合、 D2と D3との間の結合、 D3と D4との間の結合、 D4と D5との間の結合および D5と D6との間の結合力 なる群より選択される少なくとも 2つ の糖鎖結合が規定されており、ここで該 Man1と D2との間の結合が、 《1, 2結合であ り、該 D2と D3との間の結合が、 《1, 2結合、 《1, 3結合および《1, 6結合からなる 群より選択され、該 D3と D4との間の結合力 αΐ, 3結合または a 1, 6結合であり、該 D4と D5との間の結合が β 1, 4結合であり、該 D5と D6との間の結合が β 1, 4結合で ある、項目 113に記載の糖鎖修飾リボソーム。（項目 116) Man1と D2との間の結合、 D2と D3との間の結合、 D3と D4との間の結合、 D4と D5との間の結合および D5と D6との 間の結合力 なる群より選択される少なくとも 3つの糖鎖結合が規定されており、ここ で該 Man1と D2との間の結合力 «1, 2結合であり、該 D2と D3との間の結合力 ひ 1 , 2結合、 《1, 3結合および《1, 6結合力 なる群より選択され、該 D3と D4との間の 結合が、 α ΐ, 3結合または a 1, 6結合であり、該 D4と D5との間の結合が 1, 4結合 であり、該 D5と D6との間の結合が β 1, 4結合である、項目 113に記載の糖鎖修飾リ ポソーム。 （項目 117) Man1と D2との間の結合、 D2と D3との間の結合、 D3と D4との間 の結合、 D4と D5との間の結合および D5と D6との間の結合力もなる群より選択される 少なくとも 4つの糖鎖結合が規定されており、ここで該 Man1と D2との間の結合が、 α 1, 2結合であり、該 D2と D3との間の結合力 α ΐ, 2結合、 《1, 3結合および《1 , 6 結合力もなる群より選択され、該 D3と D4との間の結合力 « 1, 3結合または《1, 6 結合であり、該 D4と D5との間の結合が /3 1, 4結合であり、該 D5と D6との間の結合が β 1, 4結合である、項目 113に記載の糖鎖修飾リボソーム。 （項目 118) Man1と D2と の間の結合、 D2と D3との間の結合、 D3と D4との間の結合、 D4と D5との間の結合およ び D5と D6との間の結合の糖鎖結合が規定されており、ここで該 Man1と D2との間の結 合が、 α ΐ, 2結合であり、該 D2と D3との間の結合が、 ひ 1, 2結合、 ひ 1, 3結合およ び α ΐ, 6結合力 なる群より選択され、該 D3と D4との間の結合力 « 1, 3結合また は a 1, 6結合であり、該 D4と D5との間の結合が /3 1, 4結合であり、該 D5と D6との間 の結合が β 1, 4結合である、項目 113に記載の糖鎖修飾リボソーム。（項目 119)前 記糖鎖のリボソーム遠位端が、該遠位端側より Man - Man - Man - Man - GlcN Ac— GlcNAcの構造を有する、項目 113に記載の糖鎖修飾リボソーム。（項目 120) 前記糖鎖のリボソーム遠位端力 該遠位端側より Man a l, 2Man a l, 2Man a l, 3Man j8 1, 4GlcNAc j8 1, 4GlcNAc、 Man a 1 , 2Man a 1, 3Man a 1, 6Man j8 1, 4GlcNAc j8 1, 401。 。ぉょび1^11 0；1, 2Man a 1, 6Man a 1, 6Man j8 1, 4GlcNAC j8 1, 4GlcNAc力もなる群より選択される構造を有する、項目 119に記 載の糖鎖修飾リボソーム。 （項目 121)前記糖鎖のリボソーム遠位端が、該遠位端側 より、以下の構造： NeuSAc1— E2— Rzを有し、ここで該 E2は、 Gaほたは GalNAcで あり、そして該 Rzは、水素であるか、または任意の糖である、項目 1に記載の糖鎖修 飾リボソーム。（項目 122) Neu5Ac1と E2との間の結合が、 α 2, 3結合または α 2, 6 結合である、項目 121に記載の糖鎖修飾リボソーム。（項目 123)前記糖鎖のリポソ一 ム遠位端が、該遠位端側よ 1, 3 bond, the bond between Β 2 and Β 3 is β 1, 4 bond or β 1, 3 bond, and the bond between Β 3 and Β 4 is 1, 4 bond 75. The sugar chain-modified ribosome according to Item 74. (Item 77) All of the sugar chain bonds selected from the group consisting of a bond between Gal 1 and Β 2 , a bond between B 2 and B 3 and a bond between B 3 and B 4 Where the bond between Gal 1 and B 2 is a β 1,3 bond, and the bond between Β 2 and Β 3 is a β 1,4 bond or a β 1,3 bond. , and the bond between the beta 3 and beta 4 are / 3 1, 4 bonds, glycosylation lipoic Nome of claim 74. (Item 78) The sugar chain-modified ribosome according to item 74, which has a structure of Gal-GalNAc Gal-Glc or Gal-GlcNAc-Gal-Glc from the distal end side of the ribosome distal end force of the sugar chain. (Item 79) The ribosome distal end of the sugar chain is Gal β 1, 3GalNA C j 8 1, 4Gal j8 1, 4Glc or Gal j8 1, 3GlcNA C j 8 1, 3Gal j8 1, from the distal end side. 80. The sugar chain-modified ribosome according to item 79, which has a structure of 4 Glc. (Item 80) Liposome distal end force of the sugar chain From the distal end side, it has the following structure: Gal 1 — B 2 — B 3 — B 4 — B 5 — R Z , where The Gal 1 may or may not be sulfated. The B 2 is GalN Ac, the B 3 is Gal, and the B 4 is Glc. The sugar chain-modified ribosome according to Item 1, wherein B 5 is Cer, and R Z is hydrogen or any sugar. (Item 81) The bond between Gal 1 and B 2 , the bond between B 2 and B 3 , the bond between B 3 and B 4 and the bond force between and B 5 At least one sugar chain bond selected is defined, wherein the bond between Gal 1 and B 2 is a β 1,3 bond, and the bond between Β 2 and Β 3 is β 1, 4 is a bond, a bond is 1, 4 bonds between the beta 3 and beta 4, coupling between the beta 4 and beta 5 is j8 1, 1 binding, claim 80 The sugar chain modified ribosome. (Item 82) From the group consisting of a bond between Gal 1 , a bond between B 2 and B 3 , a bond between B 3 and B 4 and a bond between B 4 and B 5 At least two selected sugar chain bonds are defined, wherein the bond between Gal 1 and B 2 is a β 1,3 bond, and the bond between Β 2 and Β 3 is β 1, 4 is a bond, a bond is beta 1, 4 bonds between the beta 3 and beta 4, Ru coupling beta 1, 1 binding der between the beta 4 and beta 5, item 80 The sugar chain-modified ribosome described in 1. (Item 83) Bond between Gal 1 and Β 2 , bond between B 2 and B 3 , bond between B 3 and B 4 and bond between B 4 and B 5 More selected At least three sugar chain bonds are defined, wherein the bond between Gal 1 and B 2 is a β 1,3 bond, and the bond between Β 2 and Β 3 is 1, 4 a bond, a binding is beta 1, 4 bonds between the beta 3 and beta 4, coupling between the beta 4 and beta 5 is beta 1, 1 binding, as described in item 80 Sugar chain-modified ribosome. (Item 84) Bond between Gal 1 and Β 2 , bond between B 2 and B 3 , bond between B 3 and B 4 and bond between B 4 and B 5 All of the selected sugar chain bonds are defined, wherein the bonds between Gal 1 and B 2 are 1, 3 bonds, and the bonds between B 1 and B 3 are β 1 , 4 bond, the bond between Β 3 and Β 4 is β 1, 4 bond, and the bond between Β 4 and Β 5 is / 3 1, 1 bond, item 80 The sugar chain-modified ribosome described. (Item 85) The sugar chain-modified ribosome according to item 80, which has a structure of Gal-GalNAc-Gal-Glc-Cer from the distal end side of the ribosome distal end force of the sugar chain. (Item 86) Ribosome distal end force of the sugar chain The sugar chain according to item 85 having a structure of Gal j8 1, 3GalNA C j 8 1, 4Gal j8 1, 4Glc j8 1, ICer from the distal end side Modified ribosome. (Item 87) The ribosome distal end of the sugar chain has the following structure from the distal end side: GalNAc 1 — C 2 — R Z , where C 2 is Ga or Ser. The sugar chain-modified ribosome according to Item 1, wherein R Z is hydrogen or any sugar. (Item 88) The bond between GalNAc 1 and C 2 is an α ΐ, 3 bond or l—O— bond, where α ΐ— Ο— bond is present when C 2 is Ser. 81. The sugar chain-modified ribosome according to Item 80. (Item 89) The sugar chain-modified ribosome according to item 87, wherein the liposome distal end of the sugar chain has a structure of GalNAc-Ga or GalNAc-Ser from the distal end side. (Item 90) The sugar chain according to item 89, wherein the ribosome distal end of the sugar chain has a structure of GalNAc a 1, 3Ga or GalNAc α1-O-L- Ser from the distal end side. Modified ribosome. (Item 91) The ribosome distal end of the sugar chain has the following structure from the distal end side: Man 1 — D 2 — R z , where D 2 is Man, and Item 2. The sugar chain-modified liposome according to Item 1, wherein Rz is hydrogen or any sugar. (Item 92) In item 91, the bond between Man 1 and D 2 is selected from the group consisting of α ΐ, 2 bond, α ΐ, 3 bond, α ΐ, 4 bond and α 1, 6 bond force. The described sugar chain-modified liposome. (Item 93) The sugar chain-modified ribosome according to item 91, wherein the ribosome distal end of the sugar chain has a Man-Man structure from the distal end side. (Item 94) The ribosome distal end of the sugar chain is located on the side of the distal end of Man α 1, 2Man, Man al, 3Man, Man a 1, 4Man. 94. The sugar chain-modified ribosome according to Item 93, which has a structure selected from the group consisting of Man a 1, 6Man. (Item 95) The ribosome distal end of the sugar chain has the following structure from the distal end side: Man 1 — D 2 — D 3 — R z , where D 2 is Man , wherein D 3 is GlcNAc or is Man, and said R z is hydrogen or is any sugar, sugar chain modification ribosomes placing serial to item 1. (Item 96) Man 1 and has at least one glycosylation is defined is selected from the binding force becomes the group between the bond and D 2 and D 3 between D 2, wherein the said Man 1 The bond between D 2 is selected from the group consisting of α ΐ, 2 bond, α ΐ, 3 bond and α ΐ, 6 bond force, and the bond force between D 2 and D 3 α ΐ, 2 96. A sugar chain-modified ribosome according to item 95, which is selected from the group consisting of a bond, a 1,3 bond, a 1,6 bond, and a βΐ, 4 binding force. (Item 97) Man 1 and all binding force glycosylation also be selected from the group consisting are defined between the coupling and the D 2 and D 3 between D 2, wherein the said Man 1 The bond between D 2 and the bond between D 2 and D 3 is selected from the group consisting of 1, 2 bond, << 1, 3 bond, and << 1, 6 bond force, α α, 96. The sugar chain-modified ribosome according to Item 95, which is selected from the group consisting of 2-bond, << 1,3 bond, << 1,6 bond and | 8 1,4 bond strength. (Item 98) The sugar chain-modified ribosome according to item 95, wherein the ribosome distal end of the sugar chain has a structure of Man-Man-Man or Man-Man-GlcNAc from the distal end side. (Item 99) The ribosome distal end of the sugar chain is connected to Man a 1, 2Man a 1, 2Man, Man a 1, 2Man a 1, 3Man, Man 1, 2Man a 1, 6Man, Man from the distal end side. a 1, 3Man a 1, 6Man, Man a 1, 3Man j8 1, 4G1 cNAc, Man a 1, 6Man a 1, 6Man and Man a 1, 6Man j8 1, 4GlcNAc 99. The sugar chain-modified ribosome according to Item 98. (Item 100) The ribosome distal end of the sugar chain has the following structure from the distal end side: Mar ^ -D 2 — D 3 — D 4 — R Z , where D 2 is a Man, the D 3 is a Man or GlcNAc, the D 4 is a Man or GlcNAc, and the R z is hydrogen or Ru any sugar der, of claim 1 Sugar chain-modified ribosome. (Item 101) At least one sugar chain bond selected from the group consisting of a bond between Man 1 and D 2 , a bond between D 2 and D 3, and a bond force between D 3 and D 4 Where the bond between Man 1 and D 2 is selected from the group of << 1, 2 bond, α 1, 3 bond and a 1, 6 bond force, and D 2 and D 2 The bond strength between 3 and 1 is selected from the group consisting of 1, 2 bond, << 1, 3 bond, << 1, 6 bond and | 8 1,4 bond force, and D 3 And the bond between D 4, "1, 3 bond," 1, 6 bond, and I, 4 bond strength is also selected from the group consisting, glycosylation ribosome of claim 100. (Item 102) At least two sugar chains selected from the group consisting of the bond between Man 1 and D 2 , the bond between D 2 and D 3, and the bond strength between D 3 and D 4 The bond between Man 1 and D 2 is selected from the group of << 1, 2 bond, << 1, 3 bond and << 1, 6 bond force, and D 2 bond between the 81, 4 is selected from the binding force becomes the group, the D 3 and D 4 | and the bond between D 3, αΐ, 2 bond, "1, 3 bond," 1, 6 bond and 101. The sugar chain-modified ribosome according to Item 100, wherein is selected from the group consisting of α 1,3 bond, α 1,6 bond and 1,4 bond. (Item 103) All of the sugar chain bonds selected from the group consisting of the bond between Man 1 and D 2 , the bond between D 2 and D 3, and the bond force between D 3 and D 4 are specified. Where the binding force between Man 1 and D 2 is selected from the group consisting of αΐ, 2 bond, αΐ, 3 bond and a 1, 6 bond force, and between D 2 and D 3 The binding force is selected from the group consisting of al, 2 bond, << 1, 3 bond, << 1, 6 bond and | 81, 4 bond force, and the bond between D 3 and D 4 is al, 3 bond, 101. The sugar chain-modified ribosome according to Item 100, which is selected from the group consisting of al, 6 bonds and ΐ, 4 bonds. (Item 104) The liposomal distal end of the sugar chain consists of Man-Man-Man-Man, Man-Man-Man-GlcNAc and Man-Man-GlcNAc-GlcNAc from the distal end side. 101. The sugar chain-modified ribosome according to Item 100, having a structure selected from the group. (Item 105) The ribosome distal end of the sugar chain is from the distal end side of Mana 1, 2Manal, 2Manal, 3Man, Mana 1, 2Mana 1, 3Mana 1, 6Man, Mana 1, 2Mana 1, 3Manj81, 4Glc NAc , Mana 1, 2Mana 1, 6Mana 1, 6Man, Mana 1, 3Mana 1, 6Manj81, 4GlcNAc, Mana 1, 3Manj81, 4GlcNAc β 1, 4GlcNAc, Mana 1, 6Man a 1, 6Manj81, 4GlcNAc and Man a 1, 6Manj81, 105. The sugar chain-modified ribosome according to Item 104, which has a structure selected from the group consisting of 4GlcNAcj81 and 4GlcNAc. (Item 106) The ribosome distal end of the sugar chain has the following structure from the distal end side: Man 1 — D 2 — D 3 — D 4 — D 5 — R z , where D 2 is Man, the D 3 is Man, the D 4 is Man or GlcNAc, the D 5 is GlcNAc, and the R z is a force that is hydrogen, or any Item 2. The sugar chain-modified ribosome according to Item 1, wherein (Item 107) The bond between Man 1 and D 2 , the bond between D 2 and D 3 , the bond between D 3 and D 4 and the connection between D 4 and D 5 At least one sugar chain bond selected from the group consisting of the binding forces between the Man 1 and D 2 is defined as α ΐ, 2 bond, α ΐ, 3 bond and α結合, selected from the group consisting of 6 bonds, and the bond between D 2 and D 3 is selected from the group of << 1, 2 bond, << 1, 3 bond and << 1, 6 bond force, The bond between D 3 and D 4 is selected from the group consisting of α ΐ, 3 bond, << 1, 6 bond and ι8 1, 4 bond force, and the bond between D 4 and D 5 is β 109. The sugar chain-modified ribosome according to Item 106, which is a 1,4 bond. (Item 108) Bonds between Man 1 and D 2 , bonds between D 2 and D 3 , bonds between D 3 and D 4 and bonds between D 4 and D 5 At least two sugar chain bonds selected from the above are defined, wherein the bond between Man 1 and D 2 consists of α ΐ, 2 bond, α ΐ, 3 bond and α ΐ, 6 bond Selected from the group, and the bond between D 2 and D 3 is selected from the group of << 1, 2 bond, << 1, 3 bond and << 1, 6 bond force, and D 3 and D 4 coupling force a 1, 3 bond between, it is selected from the group consisting of a 1, 6 bond and 1, 4 bond, a bond strength beta 1, 4 bond between the D 4 and D 5, item 106 The sugar chain-modified ribosome according to 1. (Item 109) Man 1 and D 2 bond, D 2 and D 3 bond, D 3 and D 4 bond, and D 4 and D 5 bond force At least three sugar chain bonds selected from the above are defined, and the bond between Man 1 and D 2 is << 1, 2 bond, α ΐ, 3 bond and a 1, 6 bond force Selected from the group, and the bond between D 2 and D 3 is selected from the group consisting of al, 2 bond, << 1, 3 bond and a 1, 6 bond force, and between D 3 and D 4 In item 106, the bond of is selected from the group consisting of a 1, 3 bond, a 1, 6 bond and 1, 4 bond force, and is a bond force β 1, 4 bond between D 4 and D 5 The sugar chain-modified ribosome described. (Item 110) The bond between Man 1 and D 2 , the bond between D 2 and D 3 , the bond between D 3 and D 4, and the bond between D 4 and D 5 All of the selected sugar chain bonds are defined, wherein the bonds between Man 1 and D 2 are also α α, 2 bonds, α ΐ, 3 bonds, and α ΐ, 6 bonds. The bond between D 2 and D 3 is selected from the group consisting of α ΐ, 2 bond, << 1, 3 bond and α ΐ, 6 bond force, and between D 3 and D 4 The binding force of «1, 3 bond, a 1, 6 bond and | 8 1, 4 bond force, and the bond between D 4 and D 5 is β 1, 4 bond 109. The sugar chain-modified ribosome according to 106. (Item 111) Ribosome distal end force of the sugar chain The sugar according to item 106, which has a structure of Man-Man-Man-Man-GlcNAc or Man-Man-Man-GlcNAc-GlcNAc from the distal end side. Strand-modified ribosome. (Item 112) The ribosome distal end of the sugar chain, from the distal end side, Man 1, 2Mana 1, 2Mana 1, 3Man j81, 4GlcNAc, Mana 1, 2Mana 1, 3Man a 1, 6Man β 1, 4GlcNAc, Man a 1, 2Man a 1, 3Man β 1, 4GlcNAc β ΐ, 4 GlcNAc, Mana 1, 2Mana 1, 6Mana 1, 6Manj81, 4GlcNAc, Mana 1, 6 Mana 1, 6Manj81, 4GlcNAcj81, 4GlcNAc and Man a 1, 3Mana Item 1. The sugar chain-modified ribosome according to Item 111, having a structure selected from the group consisting of 1,6M anjS 1,4GlcNAc β 1,4GlcNAc. (Item 113) The ribosome distal end of the sugar chain has the following structure from the distal end side: Man -D 2 — D 3 — D 4 — D 5 — D 6 — R Z , where The D 2 is Man, the D 3 is Man, the D 4 is Man, the D 5 is GlcNAc, the D 6 is GlcNAc, and the R z is The sugar chain-modified ribosome according to Item 1, which is hydrogen or any sugar. (Item 114) Bond between Man 1 and D 2 , Bond between D 2 and D 3 , Bond between D 3 and D 4 , Bond between D 4 and D 5 and D 5 And at least one sugar chain bond selected from the group consisting of the bond between D 6 and D 6 , wherein the bond between Man 1 and D 2 is << 1, 2 bond, The bond between D 2 and D 3 is selected from the group consisting of << 1, 2 bond, α 1, 3 bond and a 1, 6 bond force, and the bond force between D 3 and D 4 is 1, 3 bond or a 1, 6 bond, bond between D 4 and D 5 is β 1, 4 bond, bond between D 5 and D 6 is / 31, 4 bond 114. The sugar chain-modified ribosome according to Item 113, wherein (Item 115) Bond between Man 1 and D 2 , Bond between D 2 and D 3 , Bond between D 3 and D 4 , Bond between D 4 and D 5 and D At least two sugar chain bonds selected from the group consisting of binding forces between 5 and D 6 are defined, where the bonds between Man 1 and D 2 are << 1, 2 bonds. And the bond between D 2 and D 3 is selected from the group consisting of << 1, 2 bond, << 1, 3 bond and << 1, 6 bond, and the bond between D 3 and D 4 Binding force αΐ, 3 bond or a 1, 6 bond, bond between D 4 and D 5 is β 1, 4 bond, bond between D 5 and D 6 is β 1, 114. The sugar chain-modified ribosome according to Item 113, which is a 4-bond. (Item 116) Bond between Man 1 and D 2 , Bond between D 2 and D 3 , Bond between D 3 and D 4 , Bond between D 4 and D 5 and D 5 And at least three sugar chain bonds selected from the group consisting of the binding forces between D 6 and D 6 , where the binding forces between Man 1 and D 2 are «1, 2 bonds, The binding force between D 2 and D 3 is selected from the group consisting of 1, 2 bond, << 1, 3 bond and << 1, 6 bond force, and between D 3 and D 4 The bond is α ΐ, 3 bond or a 1, 6 bond, the bond between D 4 and D 5 is 1, 4 bond, and the bond between D 5 and D 6 is β 1 114. A sugar chain-modified liposome according to Item 113, which is a 4-bond. (Item 117) Bond between Man 1 and D 2 , Bond between D 2 and D 3 , Bond between D 3 and D 4 , Bond between D 4 and D 5 and D 5 And at least four sugar chain bonds selected from the group consisting of the binding forces between D 6 and D 6 , wherein the bond between Man 1 and D 2 is an α 1,2 bond, The binding force between D 2 and D 3 is selected from the group consisting of α 結合, 2 bond, << 1, 3 bond and << 1, 6 bond force, and the bond force between D 3 and D 4 «1 , 3 bond or << 1, 6 bond, bond between D 4 and D 5 is / 3 1, 4 bond, bond between D 5 and D 6 is β 1, 4 bond 114. The sugar chain-modified ribosome according to Item 113, wherein (Item 118) The bond between Man 1 and D 2 , the bond between D 2 and D 3 , the bond between D 3 and D 4 , the bond between D 4 and D 5 and The sugar chain bond of the bond between D 5 and D 6 is defined, where the bond between Man 1 and D 2 is α ΐ, 2 bond, and D 2 and D 3 Is selected from the group consisting of a 1, 2, 1 bond, a 1, 3 bond, and an α ΐ, 6 bond force, and the bond force between D 3 and D 4 «1, 3 bond Or a 1, 6 bond, bond between D 4 and D 5 is / 3 1, 4 bond, bond between D 5 and D 6 is β 1, 4 bond 114. The sugar chain-modified ribosome according to item 113. (Item 119) The sugar chain-modified ribosome according to Item 113, wherein the ribosome distal end of the sugar chain has a structure of Man-Man-Man-Man-GlcN Ac-GlcNAc from the distal end side. (Item 120) Ribosome distal end force of the sugar chain From the distal end side Man al, 2Man al, 2Man al, 3Man j8 1, 4GlcNAc j8 1, 4GlcNAc, Man a 1, 2Man a 1, 3Man a 1, 6Man j8 1, 4GlcNAc j8 1, 401. . 1 ^ 11 0 ； 1, 2Man a 1, 6Man a 1, 6Man j8 1, 4GlcNA C j 8 1, 4 GlcNAc The structure of the sugar chain-modified ribosome according to item 119, having a structure selected from the group consisting of forces . (Item 121) The ribosome distal end of the sugar chain has the following structure from the distal end side: NeuSAc 1 — E 2 — R z , where E 2 is Ga or GalNAc. The sugar chain-modified ribosome according to Item 1, wherein Rz is hydrogen or any sugar. (Item 122) is coupled between Neu5Ac 1 and E 2, alpha 2, 3 is a bond or alpha 2, 6 bond, glycosylation ribosome of claim 121. (Item 123) The liposome distal end of the sugar chain is the distal end side.

り Neu5Ac— Galまたは Neu5Ac— GalNAcの構造を有する、項目 121に記載の糖 鎖修飾リボソーム。（項目 124)前記糖鎖のリボソーム遠位端が、該遠位端側より Neu 5Ac a 2, 3Galまたは Neu5Ac a 2, 6GalNAcの構造を有する、項目 123に記載の 糖鎖修飾リボソーム。（項目 125)前記糖鎖のリボソーム遠位端が、該遠位端側より、 以下の構造： NeuSAc1— E2— E3— Rzを有し、ここで該 E2は、 Galまたは GalNAcで あり、該 E3は、 GlcNAc、 Glc、 GalNAcおよび Serからなる群より選択され、そして該 RZは、水素であるか、または任意の糖である、項目 1に記載の糖鎖修飾リボソーム。 ( 項目 126) NeuSAc1と E2との間の結合および E2と E3との間の結合力もなる群より選 択される少なくとも 1つの糖鎖結合が規定されており、ここで該 NeuSAc1と E2との間 の結合が、 α 2, 3結合または a 2, 6結合であり、該 E2と E3との間の結合力 β 1, 3 結合、 β 1, 4結合および a l—O—結合力 なる群より選択され、ここで、 a l—O— 結合は E3が Serの場合に存在する、求項 125に記載の糖鎖修飾リボソーム。（項目 1 27) NeuSAc1と E2との間の結合および E2と E3との間の結合力 なる群より選択され る糖鎖結合のすべてが規定されており、ここで該 NeuSAc1と E2との間の結合が、 a 2 , 3結合または a 2, 6結合であり、該 E2と E3との間の結合が、 β 1, 3結合、 β 1, 4結 合および a l—O—結合力 なる群より選択され、ここで、 a l—O—結合は E3が Ser の場合に存在する、項目 125に記載の糖鎖修飾リボソーム。（項目 128)前記糖鎖の リボソーム遠位端力 該遠位端側ょりNeu5Ac— Gal— GalNAc、 Neu5Ac— Gal— GlcNAcゝ Neu5Ac - Gal— Glcおよび Neu5Ac - GalNAc - Serからなる群より選 択される構造を有する、項目 125に記載の糖鎖修飾リボソーム。（項目 129)前記糖 鎖のリボソーム遠位端力 該遠位端側より Neu5Ac o; 2, 3Gal j8 1, 3GalNAc、 Ne u5Ac a 2, 3Gal 1, 3GlcNAc、 Neu5Ac a 2, 3Gal 1, 4Glc、 Neu5Ac a 2, 3Gal j8 1, 4GlcNAcおよび Neu5Ac a 2, 6GalNAc a 1— O— L— Serからなる群 より選択される構造を有する、項目 128に記載の糖鎖修飾リボソーム。 （項目 130)前 記糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造: NeuSAc1— E2— E3— E4— Rzを有し、ここで該 E2は、 Galであり、該 E3は、 Glcおよび GalNAcからなる群よ り選択され、該 E4は、 Galおよび Cer力 なる群より選択され、そして該 Rzは、水素で あるか、または任意の糖である、項目 1に記載の糖鎖修飾リボソーム。（項目 131) Ne U5AC1と E2との間の結合、 E2と E3との間の結合および E3と E4との間の結合力 なる 群より選択される少なくとも 1つの糖鎖結合が規定されており、ここで該 NeuSAc1と E2 との間の結合が、 α2, 3結合であり、該 Ε2と Ε3との間の結合が、 β ΐ, 3結合または 1, 4結合であり、該 Ε3と Ε4との間の結合力 β 1, 4結合または 1, 1結合からなる 群より選択される、項目 130に記載の糖鎖修飾リボソーム。（項目 132)Neu5Ac1と Ε 2との間の結合、 E2と E3との間の結合および E3と E4との間の結合力 なる群より選択さ れる少なくとも 2つの糖鎖結合が規定されており、ここで該 NeuSAc1と E2との間の結 合が、 α2, 3結合であり、該 Ε2と Ε3との間の結合が、 β ΐ, 3結合または ΐ, 4結合 であり、該 Ε3と Ε4との間の結合力 1, 4結合または |81, 1結合力 なる群より選択 される、項目 130に記載の糖鎖修飾リボソーム。（項目 133)Neu5Ac1と E2との間の 結合、 E2と E3との間の結合および E3と E4との間の結合力 なる群より選択されるすべ ての糖鎖結合が規定されており、ここで該 NeuSAc1と E2との間の結合力 a 2, 3結 合であり、該 E2と E3との間の結合力 β 1, 3結合または 1, 4結合であり、該 Ε3と Ε4 との間の結合が、 β 1, 4結合または |81, 1結合力もなる群より選択される、項目 130 に記載の糖鎖修飾リボソーム。（項目 134)前記糖鎖のリボソーム遠位端が、該遠位 端側より Neu5 Ac - Gal - GalNAc - Galおよび Neu5 Ac - Gal - Glu - Cerからな る群より選択される構造を有する、項目 130に記載の糖鎖修飾リボソーム。（項目 13 5)前記糖鎖のリボソーム遠位端力 該遠位端側より Neu5Aco; 2, 3Galj81, 3Gal NAcjS 1, 4Galおよび Neu5Ac α 2, 3Galj81, 4Gluj81, ICerからなる群より選 択される構造を有する、項目 134に記載の糖鎖修飾リボソーム。（項目 136)前記糖 鎖のリボソーム遠位端力 該遠位端側より、以下の構造: NeuSAc1— E2— E3— E4— E5— Rzを有し、ここで該 E2は、 Galであり、該 E3は、 GalNAcであり、該 E4は、 Galで あり、該 E5は、 Glcであり、そして該 Rzは、水素であるか、または任意の糖である、項 目 1に記載の糖鎖修飾リボソーム。（項目 137)Neu5Ac1と E2との間の結合、 E2と E3 との間の結合、 E3と E4との間の結合および E4と E5との間の結合力 なる群より選択さ れる少なくとも 1つの糖鎖結合が規定されており、ここで該 NeuSAc1と E2との間の結 合力 a 2, 3結合であり、該 E2と E3との間の結合力 β ΐ, 3結合であり、該 Ε3と Ε4と の間の結合が、 β 1, 4結合であり、該 Ε4と Ε5との間の結合が β 1, 4である、項目 13 6に記載の糖鎖修飾リボソーム。（項目 138)Neu5Ac1と Ε2との間の結合、 E2と E3と の間の結合、 E3と E4との間の結合および E4と E5との間の結合力 なる群より選択され る少なくとも 2つの糖鎖結合が規定されており、ここで該 NeuSAc1と E2との間の結合 が、 α 2, 3結合であり、該 Ε2と Ε3との間の結合が、 β ΐ , 3結合であり、該 Ε3と Ε4との 間の結合が、 β 1 , 4結合であり、該 Ε4と Ε5との間の結合が β 1 , 4である、項目 136 に記載の糖鎖修飾リボソーム。（項目 l SW NeuSAc1と Ε2との間の結合、 E2と E3との 間の結合、 E3と E4との間の結合および E4と E5との間の結合力 なる群より選択される 少なくとも 3つの糖鎖結合が規定されており、ここで該 NeuSAc1と E2との間の結合が 、 a 2, 3結合であり、該 E2と E3との間の結合力 β ΐ , 3結合であり、該 Ε3と Ε4との間 の結合が、 β 1 , 4結合であり、該 Ε4と Ε5との間の結合が β 1 , 4である、項目 136に 記載の糖鎖修飾リボソーム。 （項目 MC^ NeuSAc1と Ε2との間の結合、 E2と E3との間 の結合、 E3と E4との間の結合および E4と E5との間の結合のすべてのの糖鎖結合が 規定されており、ここで該 NeuSAc1と E2との間の結合力 a 2, 3結合であり、該 E2と E3との間の結合が、 β 1 , 3結合であり、該 Ε3と Ε4との間の結合が、 β 1 , 4結合であり 、該 Ε4と Ε5との間の結合が /3 1 , 4である、項目 136に記載の糖鎖修飾リボソーム。 ( 項目 141)前記糖鎖のリボソーム遠位端力 該遠位端側より Neu5Ac— Gal— GalN Ac— Gal— Clcである構造を有する、項目 136に記載の糖鎖修飾リボソーム。（項目 142)前記糖鎖のリボソーム遠位端力 該遠位端側より Neu5Ac o; 2, 3Gal j8 1 , 3G alNAC j8 1 , 4Gal |8 1 , 4Clcである構造を有する、項目 141に記載の糖鎖修飾リポ ノーム。 （項目 143)前記糖鎖のリボソーム遠位端が、該遠位端側より、以下の構造： NeuSAc1— E2— E3— E4— E5— E6— Rzを有し、ここで該 E2は、 Galであり、該 E3は、 GalNAcであり、該 E4は、 Galであり、該 E5は、 Glcであり、該 E6は、 Cerであり、そし て該 RZは、水素であるか、または任意の糖である、項目 1に記載の糖鎖修飾リポソ一 ム。（項目 M^ NeuSAc1と E2との間の結合、 E2と E3との間の結合、 E3と E4との間の 結合、 E4と E5との間の結合および E5と E6との間の結合力 なる群より選択される少な くとも 1つの糖鎖結合が規定されており、ここで該 NeuSAc1と E2との間の結合力 « 2 , 3結合であり、該 E2と E3との間の結合が、 β ΐ , 3結合であり、該 Ε3と Ε4との間の結 合が、 β 1 , 4結合であり、該 Ε4と Ε5との間の結合が 1 , 4であり、該 Ε5と Ε6との間の 結合が j8 1 , 1である項目 143に記載の糖鎖修飾リボソーム。（項目 145) Neu5Ac1と E2との間の結合、 E2と E3との間の結合、 E3と E4との間の結合、 E4と E5との間の結合 および E5と E6との間の結合力 なる群より選択される少なくとも 2つの糖鎖結合が規 定されており、ここで該 NeuSAc1と E2との間の結合が、 α 2, 3結合であり、該 Ε2と Ε3 との間の結合が、 β 1, 3結合であり、該 Ε3と Ε4との間の結合が、 β 1, 4結合であり、 該 Ε4と Ε5との間の結合が 1, 4であり、該 Ε5と Ε6との間の結合が 1, 1である項目 143に記載の糖鎖修飾リボソーム。（項目 146) Neu5Ac1と Ε2との間の結合、 E2と E3 との間の結合、 E3と E4との間の結合、 E4と E5との間の結合および E5と E6 122. The sugar according to item 121, having a structure of Neu5Ac-Gal or Neu5Ac-GalNAc Strand-modified ribosome. (Item 124) The sugar chain-modified ribosome according to item 123, wherein the ribosome distal end of the sugar chain has a structure of Neu5Aca2,3Gal or Neu5Aca2,6GalNAc from the distal end side. (Item 125) The ribosome distal end of the sugar chain has the following structure from the distal end side: NeuSAc 1 — E 2 — E 3 — R z , where E 2 is Gal or GalNAc The sugar chain-modified ribosome according to Item 1, wherein E 3 is selected from the group consisting of GlcNAc, Glc, GalNAc and Ser, and R Z is hydrogen or an arbitrary sugar. (Item 126) NeuSAc 1 and at least one carbohydrate binding avidity is also selected from the group consisting are defined between the coupling and E 2 and E 3 between E 2, wherein said NeuSAc 1 Bond between E 2 and E 2 is α 2,3 bond or a 2,6 bond, and the binding force between E 2 and E 3 is β 1,3 bond, β 1,4 bond and al— 126. A sugar chain-modified ribosome according to claim 125, wherein the al—O— bond is present when E 3 is Ser. (Item 1 27) all carbohydrate binding that will be selected from the binding force becomes a group are defined between the coupling and E 2 and E 3 between NeuSAc 1 and E 2, wherein the said NeuSAc 1 The bond between E 2 is a 2, 3 bond or a 2, 6 bond, and the bond between E 2 and E 3 is β 1, 3 bond, β 1, 4 bond and al 126. A sugar chain-modified ribosome according to Item 125, wherein the —O— bond is selected from the group consisting of: al—O— bond present when E 3 is Ser (Item 128) Ribosome distal end force of the sugar chain The distal end side is selected from the group consisting of Neu5Ac-Gal-GalNAc, Neu5Ac-Gal-GlcNAc ゝ Neu5Ac-Gal-Glc and Neu5Ac-GalNAc-Ser 126. A sugar chain-modified ribosome according to Item 125, which has a structure as described above. (Item 129) Ribosome distal end force of the sugar chain From the distal end side Neu5Ac; 2, 3Gal j8 1, 3GalNAc, Neu5Ac a 2, 3Gal 1, 3GlcNAc, Neu5Ac a 2, 3Gal 1, 4Glc, Neu5Ac 129. The sugar chain-modified ribosome according to item 128, which has a structure selected from the group consisting of a 2, 3Gal j8 1, 4GlcNAc and Neu5Ac a 2, 6GalNAc a 1—O—L—Ser. (Item 130) The ribosome distal end of the sugar chain has the following structure from the distal end side: NeuSAc 1 — E 2 — E 3 — E 4 — R z , where E 2 is , Gal, E 3 is selected from the group consisting of Glc and GalNAc, E 4 is selected from the group consisting of Gal and Cer forces, and R z is hydrogen or any Item 2. The sugar chain-modified ribosome according to Item 1, which is a sugar. (Item 131) Ne U5AC Bond between 1 and E 2 , bond between E 2 and E 3, and bond between E 3 and E 4 At least one sugar chain bond selected from the group is defined, wherein the bond between NeuSAc 1 and E 2 is an α2,3 bond, and the bond between Ε 2 and Ε 3 131, wherein β is a β ΐ, 3 bond or 1, 4 bond, and the binding force between 該3 and Ε 4 is selected from the group consisting of β 1, 4 bond or 1, 1 bond. Sugar chain-modified ribosome. (Item 132) At least two sugar chain bonds selected from the group consisting of a bond between Neu5Ac 1 and Ε 2 , a bond between E 2 and E 3 and a bond force between E 3 and E 4 are defined, wherein the binding between the NeuSAc 1 and E 2, [alpha] 2, a 3 bond, the bond between the E 2 and E 3 are, beta I, 3 bond or I, 4 a bond, bonding force 1 between the E 3 and E 4, 4 bond or | 81, 1 is selected from the binding force becomes group, glycosylation ribosome of claim 130. (Item 133) All glycan bonds selected from the group consisting of the bond between Neu5Ac 1 and E 2 , the bond between E 2 and E 3 and the bond strength between E 3 and E 4 Where the binding force between the NeuSAc 1 and E 2 is a 2, 3 bond, and the binding force between the E 2 and E 3 is β 1, 3 bond or 1, 4 bond. , and the bond between the E 3 and E 4 is, beta 1, 4 bond or | 81, 1 binding force is also selected from the group consisting, glycosylation ribosome of claim 130. (Item 134) The item wherein the ribosome distal end of the sugar chain has a structure selected from the group consisting of Neu5 Ac-Gal-GalNAc-Gal and Neu5 Ac-Gal-Glu-Cer from the distal end side 130. The sugar chain-modified ribosome according to 130. (Item 135) Ribosome distal end force of the sugar chain Structure selected from the group consisting of Neu5Aco; 2, 3Galj81, 3Gal NAcjS 1, 4Gal and Neu5Ac α2, 3Galj81, 4Gluj81, ICer from the distal end side 135. The sugar chain-modified ribosome according to item 134, wherein (Item 136) Ribosome distal end force of the sugar chain From the distal end side, it has the following structure: NeuSAc 1 — E 2 — E 3 — E 4 — E 5 — R z , where E 2 Is Gal, the E 3 is GalNAc, the E 4 is Gal, the E 5 is Glc, and the R z is hydrogen or any sugar The sugar chain-modified ribosome according to item 1. (Item 137) The bond between Neu5Ac 1 and E 2 , the bond between E 2 and E 3 , the bond between E 3 and E 4, and the bond force between E 4 and E 5 And at least one sugar chain bond selected from the above, wherein the binding force between the NeuSAc 1 and E 2 is a 2, 3 bond, and the binding force between the E 2 and E 3 Item 13 wherein β ΐ, 3 bond, the bond between Ε 3 and Ε 4 is β 1, 4 bond, and the bond between Ε 4 and Ε 5 is β 1, 4 6. The sugar chain-modified ribosome according to 6. (Item 138) Binding between Neu5Ac 1 and Ε 2 , E 2 and E 3 And at least two sugar chain bonds selected from the group consisting of the bond between E 3 and E 4 and the bond strength between E 4 and E 5 , wherein the NeuSAc 1 And E 2 is an α 2,3 bond, and the bond between Ε 2 and Ε 3 is a β,, 3 bond, and the bond between Ε 3 and Ε 4 The sugar chain-modified ribosome according to Item 136, wherein is a β 1, 4 bond and the bond between 結合4 and Ε 5 is β 1, 4. (Group l SW NeuSAc 1 and Ε 2 bond, E 2 and E 3 bond, E 3 and E 4 bond and E 4 and E 5 bond force And at least three sugar chain bonds selected from the above, wherein the bond between NeuSAc 1 and E 2 is a 2, 3 bond, and the bond between E 2 and E 3 A force β,, 3 bond, a bond between Ε 3 and Ε 4 is β 1, 4 bond, and a bond between Ε 4 and Ε 5 is β 1, 4 The glycosylated ribosome according to 136. (Items MC ^ NeuSAc 1 and Ε 2 binding, E 2 and E 3 binding, E 3 and E 4 binding, and E 4 and E 4 All glycan bonds of the bond between 5 and 5 are defined, where the binding force between the NeuSAc 1 and E 2 is a 2, 3 bond, and between the E 2 and E 3 Is a β 1, 3 bond, and a bond between Ε 3 and Ε 4 is a β 1, 4 bond, and Ε 4 and Ε 141. The sugar chain-modified ribosome according to item 136, wherein the bond between 5 and / 3 1, 4 is (item 141) the ribosome distal end force of the sugar chain from the distal end side to Neu5Ac—Gal—GalN Ac — The sugar chain-modified ribosome according to item 136, having a structure of Gal—Clc (Item 142) The ribosome distal end force of the sugar chain from the distal end side Neu5Ac; 2, 3Gal j8 1, 3G alNA 142. The sugar chain-modified liposome according to item 141, which has a structure of C j 8 1, 4Gal | 8 1, 4Clc. (Item 143) A ribosome distal end of the sugar chain is Structure: NeuSAc 1 — E 2 — E 3 — E 4 — E 5 — E 6 — R z , where E 2 is Gal, E 3 is GalNAc, and E 4 The sugar chain according to Item 1, wherein Gal is Gal, E 5 is Glc, E 6 is Cer, and R Z is hydrogen or any sugar. Modified liposomes (items M ^ NeuSAc 1 and E 2 , E 2 and E 3 , E 3 and E 4 , E 4 and E 5 , and E 5 and E 6 At least one sugar chain bond selected from the group is defined, where the binding force between the NeuSAc 1 and E 2 is «2, 3 bond, and the E 2 and E 3 bond The bond between Ε 3 and Ε 4 is a β 1, 4 bond, and the bond between Ε 4 and Ε 5 is 1, 4 , and the glycosylation ribosome of claim 143 bond is j8 1, 1 between E 6 and the E 5. (Item 145) Neu5Ac 1 and Bond between E 2 , bond between E 2 and E 3 , bond between E 3 and E 4 , bond between E 4 and E 5 and between E 5 and E 6 At least two sugar chain bonds selected from the group of binding force are defined, wherein the bond between NeuSAc 1 and E 2 is an α 2,3 bond, and Ε 2 and Ε 3 Is a β 1,3 bond, a bond between β 3 and Ε 4 is a β 1,4 bond, and a bond between Ε 4 and Ε 5 is 1, 4 a and, glycosylation ribosome of claim 143 bonds are 1, 1 between E 6 and the E 5. (Item 146) The bond between Neu5Ac 1 and Ε 2 , the bond between E 2 and E 3 , the bond between E 3 and E 4 , the bond between E 4 and E 5 and E 5 And E 6

との間の結合力 なる群より選択される少なくとも 3つの糖鎖結合が規定されており、 ここで該 NeuSAc1と E2との間の結合が、 《2, 3結合であり、該 E2と E3との間の結合 力 β 1, 3結合であり、該 Ε3と Ε4との間の結合が、 /3 1, 4結合であり、該 Ε4と Ε5との 間の結合が β 1, 4であり、該 Ε5と Ε6との間の結合が β 1, 1である項目 143に記載の 糖鎖修飾リボソーム。（項目 147) Neu5Ac1と Ε2との間の結合、 E2と E3との間の結合 、 E3と E4との間の結合、 E4と E5との間の結合および E5と E6との間の結合力 なる群よ り選択される少なくとも 4つの糖鎖結合が規定されており、ここで該 NeuSAc1と E2との 間の結合が、 α 2, 3結合であり、該 Ε2と Ε3との間の結合が、 β ΐ, 3結合であり、該 Ε3 と Ε4との間の結合が、 β 1, 4結合であり、該 Ε4と Ε5との間の結合が β 1, 4であり、該 Ε5と Ε6との間の結合が /3 1, 1である項目 143に記載の糖鎖修飾リボソーム。（項目 1 48) Neu5Ac1と Ε2との間の結合、 E2と E3との間の結合、 E3と E4との間の結合、 E4と E 5との間の結合および E5と E6との間の結合力 なる群より選択される糖鎖結合のすべ てが規定されており、ここで該 NeuSAc1と E2との間の結合が、 α 2, 3結合であり、該 Ε2と Ε3との間の結合力 β 1, 3結合であり、該 Ε3と Ε4との間の結合が、 β 1, 4結合 であり、該 Ε4と Ε5との間の結合が β 1, 4であり、該 Ε5と Ε6との間の結合が β 1, 1であ る項目 143に記載の糖鎖修飾リボソーム。（項目 149)前記糖鎖のリボソーム遠位端 が、該遠位端側より Neu5Ac— Gal GalNAc Gal-Clc Cerである構造を有す る、項目 143に記載の糖鎖修飾リボソーム。（項目 150)前記糖鎖のリボソーム遠位 端が、該遠位端側より Neu5Ac a 2, 3Gal j8 1, 3GalNAc β 1, 4Gal j8 1, 4Clc β 1 , ICerである構造を有する、項目 149に記載の糖鎖修飾リボソーム。（項目 151)前 記糖鎖のリボソーム近位端力 以下の構造: R1— F2— GlcNAc3を有し、ここで該 R1 は、独立して、水素であるか、または任意の糖鎖であり、該 F2は、 Gal、 Fuc、 GlcNA cおよび 3，一（O— SO H) Galからなる群より選択され、ここで該 GlcNAc3はリポソ一 At least three glycosylation is defined is selected from the binding force becomes the group between, wherein coupling between said NeuSAc 1 and E 2 is the "2, 3 bond, the E 2 Is the bond between β and E 3 , the bond between Ε 3 and Ε 4 is the / 3 1, 4 bond, and the bond between Ε 4 and Ε 5 There beta 1, 4, and glycosylation ribosome of claim 143 bonds are beta 1, 1 between E 6 and the E 5. (Item 147) The bond between Neu5Ac 1 and Ε 2 , the bond between E 2 and E 3 , the bond between E 3 and E 4 , the bond between E 4 and E 5 and E 5 and has at least four glycosylation is defined is selected Ri by the group consisting of binding force between the E 6, wherein coupling between said NeuSAc 1 and E 2 are, be alpha 2, 3 bond The bond between Ε 2 and Ε 3 is a β ΐ, 3 bond, the bond between Ε 3 and Ε 4 is a β 1, 4 bond, and Ε 4 and Ε 5 144. The sugar chain-modified ribosome according to Item 143, wherein the bond between is β 1, 4 and the bond between Ε 5 and Ε 6 is / 3 1, 1. (Item 1 48) The bond between Neu5Ac 1 and Ε 2 , the bond between E 2 and E 3 , the bond between E 3 and E 4 , the bond between E 4 and E 5 and E All of the sugar chain bonds selected from the group consisting of the binding forces between 5 and E 6 are defined, where the bonds between NeuSAc 1 and E 2 are α 2, 3 bonds. , The binding force between 3 2 and Ε 3 is a β 1,3 bond, and the bond between Ε 3 and Ε 4 is a β 1,4 bond, and 結合4 and Ε 5 1 binding beta between a 4, glycosylation ribosomes according to binding beta 1, 1 der Ru item 143 between the E 6 and the E 5. (Item 149) The sugar chain-modified ribosome according to item 143, wherein the ribosome distal end of the sugar chain has a structure of Neu5Ac-Gal GalNAc Gal-Clc Cer from the distal end side. (Item 150) In item 149, the ribosome distal end of the sugar chain has a structure of Neu5Ac a 2, 3Gal j8 1, 3GalNAc β1, 4Gal j8 1, 4Clc β1, ICer from the distal end side. The sugar chain-modified ribosome described. (Item 151) Ribosome proximal end force of the aforementioned sugar chain It has the following structure: R 1 — F 2 — GlcNAc 3 , where R 1 Is independently hydrogen or any sugar chain, and the F 2 is selected from the group consisting of Gal, Fuc, GlcNA c and 3, one (O—SO 2 H) Gal, The GlcNAc 3 is liposomal

3  Three

ムの最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム。（項目 152)F2と Glc NAc3との間の結合が、 a 1, 3結合、 a 1, 4結合、 β 1, 3結合、 β 1, 4結合および β 1, 6結合力もなる群より選択される、項目 151に記載の糖鎖修飾リボソーム。（項 目 153)前記糖鎖のリボソーム近位端が、 3， - (O-SO H)Gal— GlcNAc、 Fuc— 2. The sugar chain-modified ribosome according to item 1, present at the most proximal end of the mouse. (Item 152) From the group in which the bond between F 2 and Glc NAc 3 is also composed of a 1, 3 bond, a 1, 4 bond, β 1, 3 bond, β 1, 4 bond and β 1, 6 bond 152. The sugar chain-modified ribosome according to Item 151, which is selected. (Item 153) The ribosome proximal end of the sugar chain is 3,-(O-SO H) Gal— GlcNAc, Fuc—

3  Three

GlcNAc、 Gal—GlcNAcぉょびGlcNAc— GlcNAcからなる群ょり選択される構造 を有する、項目 151に記載の糖鎖修飾リボソーム。（項目 154)前記糖鎖のリボソーム 近位端が、 3，一（O— SO H)Galj81, 3GlcNAcゝ Fuc a 1, 3GlcNAcゝ Fuc a 1,  150. The sugar chain-modified ribosome according to Item 151, which has a structure selected from the group consisting of GlcNAc, Gal—GlcNAc and GlcNAc—GlcNAc. (Item 154) The proximal end of the ribosome of the sugar chain is 3, 1 (O—SO 2 H) Galj81, 3GlcNAc ゝ Fuc a 1, 3GlcNAc ゝ Fuc a 1,

3  Three

4GlcNAc、 GaljS 1, 3GlcNAc、 GaljS 1, 4GlcNAc、 GaljS 1, 6GlcNAcおよび G lcNAciS 1, 4GlcNAc力もなる群より選択される構造を有する、項目 153に記載の 糖鎖修飾リボソーム。（項目 155)前記糖鎖のリボソーム近位端が、以下の構造: R1— F2— F3— GlcNAc4を有し、ここで該 R1は、独立して、水素であるか、または任意の糖 鎖であり、該 F2は、 Man、 Fucおよび Neu5Acからなる群より選択され、該 F3は、 Gal または GlcNAcであり、ここで該 GlcNAc4はリボソームの最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム。（項目 156) F3と F2との間の結合および F3と GlcNAc 4との間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており、 ここで該 F3と F2との間の結合が、 ひ1, 2結合、 β ΐ, 4結合およびひ 2, 3結合からな る群より選択され、該 F3と GlcNAc4との間の結合力 β 1, 3結合または |81, 4結合 である、項目 155に記載の糖鎖修飾リボソーム。（項目 157) F3と F2との間の結合およ び F3と GlcNAc4との間の結合力 なる群より選択されるの糖鎖結合のすべてが規定 されており、ここで該 F3と F2との間の結合が、 ひ1, 2結合、 β ΐ, 4結合およびひ 2, 3 結合力 なる群より選択され、該 F3と GlcNAc4との間の結合力 β ΐ, 3結合または 1, 4結合である、項目 155に記載の糖鎖修飾リボソーム。 （項目 158)前記糖鎖のリ ポソ一ム近位端が、 Fuc— Gal— GlcNAc、 Man— GlcNAc— GlcNAcおよび Neu 5Ac— Gal— GlcNAc力もなる群より選択される構造を有する、項目 155に記載の糖 鎖修飾リボソーム。（項目 159)前記糖鎖のリボソーム近位端力 Fucひ 1, 2ΩαΙβ 1 , 4GlcNAc、 ManjS 1, 4GlcNAc β 1, 4GlcNAc、 Neu5Ac a 2, 3Galj81, 3Glc NAcおよび Neu5Ac α 2, 3Gal j8 1, 4GlcNAcからなる群より選択される構造を有 する、項目 158に記載の糖鎖修飾リボソーム。（項目 160)前記糖鎖のリボソーム近 位端が、以下の構造: R1— F2— F3— F4— GlcNAc5を有し、ここで該 F1は、独立して 、水素であるか、または任意の糖鎖であり、該 F2は、 Manであり、該 F3は、 Manであり 、該 F4は、 GlcNAcであり、ここで該 GlcNAc5はリボソームの最近位端に存在する、 項目 1に記載の糖鎖修飾リボソーム。（項目 161) F2と F3との間の結合、 F3と F4との間 の結合および F4と GlcNAc5との間の結合力 なる群より選択される少なくとも 1つの 糖鎖結合が規定されており、ここで該 F2と F3との間の結合力 α ΐ, 3結合またはひ 1 , 6結合であり、該 F3と F4との間の結合が β 1, 4結合であり、該 F4と GlcNAc5との間 の結合が β 1, 4結合である、項目 160に記載の糖鎖修飾リボソーム。（項目 162) F2 と F3との間の結合、 F3と F4との間の結合および F4と GlcNAc5との間の結合力 なる 群より選択される少なくとも 2つの糖鎖結合が規定されており、ここで該 F2と F3との間 の結合が、 α 1, 3結合または α 1, 6結合であり、該 F3と F4との間の結合が β 1, 4結 合であり、該 F4と GlcNAc5との間の結合が β 1, 4結合である、項目 160に記載の糖 鎖修飾リボソーム。（項目 163) F2と F3との間の結合、 F3と F4との間の結合および F4と GlcNAc5との間の結合力 なる群より選択される糖鎖結合のすべてが規定されてお り、ここで該 F2と F3との間の結合力 α ΐ, 3結合または a 1, 6結合であり、該 F3と F4と の間の結合が β 1, 4結合であり、該 F4と GlcNAc5との間の結合が β 1, 4結合である 、項目 160に記載の糖鎖修飾リボソーム。（項目 164)前記糖鎖のリボソーム近位端 力 Man— Man— GlcNAc— GlcNAcの構造を有する、項目 160に記載の糖鎖修 飾リボソーム。（項目 165)前記糖鎖のリボソーム近位端力 Man a l, 3Man j8 1, 4 GlcNAc j8 1, 4GlcNAcまたは Man a 1, 6Man j8 1, 4GlcNAc j8 1, 4GlcNAcの 構造を有する、項目 164に記載の糖鎖修飾リボソーム。（項目 166)前記糖鎖のリポ ソーム近位端力 以下の構造: R1— F2— F3— F4— F5— GlcNAc6を有し、ここで該 R1 は、独立して、水素であるか、または任意の糖鎖であり、該 F2は、 Manであり、該 F3は 、 Manであり、該 F4は、 Manであり、該 F5は、 GlcNAcであり、ここで該 GlcNAc6はリ ポソームの最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム。（項目 167) F 2と F3との間の結合、 F3と F4との間の結合、 F4と F5との間の結合および F5と GlcNAc6 との間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており、 ここで該 F2と F3との間の結合が、 《1, 2結合、 《1, 3結合および《1, 6結合からな る群より選択され、該 F3と F4との間の結合力 αΐ, 3結合または a 1, 6結合であり、 該 F4と F5との間の結合が β 1, 4結合であり、該 F5と GlcNAc6との間の結合が β 1, 4 結合である、項目 166に記載の糖鎖修飾リボソーム。（項目 168) F2と F3との間の結 合、 F3と F4との間の結合、 F4と F5との間の結合および F5と GlcNAc6との間の結合か らなる群より選択される少なくとも 2つの糖鎖結合が規定されており、ここで該 F2と F3と の間の結合が、 al, 2結合、 《1, 3結合および a 1, 6結合力 なる群より選択され、 該 F3と F4との間の結合力 al, 3結合または a 1, 6結合であり、該 F4と F5との間の 結合が β 1, 4結合であり、該 F5と GlcNAc6との間の結合が β 1, 4結合である、項目 166に記載の糖鎖修飾リボソーム。（項目 169) F2と F3との間の結合、 F3と F4との間の 結合、 F4と F5との間の結合および F5と GlcNAc6との間の結合力 なる群より選択され る少なくとも 3つの糖鎖結合が規定されており、ここで該 F2と F3との間の結合が、 a 1 , 2結合、 《1, 3結合および a 1, 6結合力 なる群より選択され、該 F3と F4との間の 結合が、 al, 3結合または a 1, 6結合であり、該 F4と F5との間の結合が 1, 4結合 であり、該 F5と GlcNAc6との間の結合が β 1, 4結合である、項目 166に記載の糖鎖 修飾リボソーム。（項目 170) F2と F3との間 154. The sugar chain-modified ribosome of Item 153, having a structure selected from the group consisting of 4GlcNAc, GaljS1,3GlcNAc, GaljS1,4GlcNAc, GaljS1,6GlcNAc and GlcNAciS1,4GlcNAc. (Item 155) The ribosome proximal end of the sugar chain has the following structure: R 1 — F 2 — F 3 — GlcNAc 4 , wherein R 1 is independently hydrogen, or Any sugar chain, wherein F 2 is selected from the group consisting of Man, Fuc and Neu5Ac, and F 3 is Gal or GlcNAc, wherein GlcNAc 4 is present at the proximal end of the ribosome, Item 2. The sugar chain-modified ribosome according to item 1. (Item 156) and at least one carbohydrate binding is defined is selected from the binding force becomes the group between the coupling and F 3 and GlcNAc 4 between F 3 and F 2, wherein the said F 3 The bond between F 2 is selected from the group consisting of a 1, 2 bond, a β ΐ, 4 bond and a 2, 3 bond, and the binding force β 1, 3 between the F 3 and GlcNAc 4 156. Sugar chain-modified ribosome according to item 155, which is a bond or | 81, 4 bond. (Item 157) All of the glycan bonds selected from the group consisting of the bond between F 3 and F 2 and the bond strength between F 3 and GlcNAc 4 are defined. The bond between 3 and F 2 is selected from the group consisting of: 1, 2 bond, β ΐ, 4 bond and ひ 2, 3 bond force, and the bond force between F 3 and GlcNAc 4 β ΐ, 156. The sugar chain-modified ribosome according to Item 155, which is a 3-bond or a 1,4-bond. (Item 158) In item 155, the liposomal proximal end of the sugar chain has a structure selected from the group consisting of Fuc-Gal-GlcNAc, Man-GlcNAc-GlcNAc and Neu5Ac-Gal-GlcNAc force. The sugar chain-modified ribosome described. (Item 159) Ribosome proximal end force of the sugar chain Fuc 1, 2ΩαΙβ 1, 4GlcNAc, ManjS 1, 4GlcNAc β 1, 4GlcNAc, Neu5Ac a 2, 3Galj81, 3Glc 164. The sugar chain-modified ribosome according to Item 158, having a structure selected from the group consisting of NAc and Neu5Ac α2,3Gal j81,4GlcNAc. (Item 160) The ribosome proximal end of the sugar chain has the following structure: R 1 — F 2 — F 3 — F 4 — GlcNAc 5 , where F 1 is independently hydrogen Or any sugar chain, the F 2 is Man, the F 3 is Man, and the F 4 is GlcNAc, where the GlcNAc 5 is present at the proximal end of the ribosome The sugar chain-modified ribosome according to Item 1. (Item 161) At least one sugar chain bond selected from the group consisting of a bond between F 2 and F 3 , a bond between F 3 and F 4 and a bond force between F 4 and GlcNAc 5 Where the binding force between the F 2 and F 3 is α ΐ, 3 bond or 1, 6 bond, and the bond between the F 3 and F 4 is β 1, 4 bond , and the bond between the F 4 and GlcNAc 5 is beta 1, 4 bonds, glycosylation ribosome of claim 160. (Item 162) At least two sugar chain bonds selected from the group consisting of the bond between F 2 and F 3 , the bond between F 3 and F 4 and the bond force between F 4 and GlcNAc 5 Wherein the bond between the F 2 and F 3 is an α 1,3 bond or an α 1,6 bond, and the bond between the F 3 and F 4 is β 1,4 binding a case, the bond between the F 4 and GlcNAc 5 is beta 1, 4 bonds, glycosylation ribosome of claim 160. (Item 163) All the sugar chain bonds selected from the group consisting of the bond between F 2 and F 3 , the bond between F 3 and F 4 and the bond force between F 4 and GlcNAc 5 are specified. Where the binding force between F 2 and F 3 is α ΐ, 3 bond or a 1, 6 bond, and the bond between F 3 and F 4 is β 1, 4 bond. The sugar chain-modified ribosome according to Item 160, wherein the bond between F 4 and GlcNAc 5 is a β1,4 bond. (Item 164) The sugar chain-modified ribosome according to Item 160, wherein the sugar chain has a ribosome proximal end force Man-Man-GlcNAc-GlcNAc structure. (Item 165) The ribosome proximal end force Man al, 3Man j8 1, 4 GlcNAc j8 1, 4GlcNAc or Man a 1, 6Man j8 1, 4GlcNAc j8 1, 4GlcNAc of the sugar chain has a structure of Item 164 Sugar chain-modified ribosome. (Item 166) Liposome proximal end force of the sugar chain The structure has the following structure: R 1 — F 2 — F 3 — F 4 — F 5 — GlcNAc 6 , wherein R 1 is independently Hydrogen or any sugar chain, the F 2 is Man, the F 3 is Man, the F 4 is Man, and the F 5 is GlcNAc, where 2. The sugar chain-modified ribosome according to Item 1, wherein the GlcNAc 6 is present at the most proximal end of the liposome. (Item 167) Bond between F 2 and F 3 , Bond between F 3 and F 4 , Bond between F 4 and F 5 and F 5 and GlcNAc 6 At least one sugar chain bond selected from the group consisting of the binding forces between and F 2 and F 3 is defined as << 1, 2 bond, << 1, 3 bond Selected from the group consisting of 1, 6 bonds, and the binding force between F 3 and F 4 is αΐ, 3 bond or a 1, 6 bond, and the bond between F 4 and F 5 166. The sugar chain-modified ribosome according to Item 166, wherein is a β 1,4 bond, and the bond between F 5 and GlcNAc 6 is a β 1,4 bond. (Item 168) From the bond between F 2 and F 3 , the bond between F 3 and F 4 , the bond between F 4 and F 5 and the bond between F 5 and GlcNAc 6 Wherein at least two sugar chain bonds selected from the group are defined, wherein the bond between F 2 and F 3 is defined as al, 2 bond, << 1, 3 bond and a 1, 6 bond strength The bond between F 3 and F 4 is selected from the group consisting of al, 3 bonds or a 1, 6 bond, and the bond between F 4 and F 5 is β 1, 4 bond , the bond between the F 5 and GlcNAc 6 is beta 1, 4 bonds, glycosylation ribosome of claim 166. (Item 169) The bond between F 2 and F 3 , the bond between F 3 and F 4 , the bond between F 4 and F 5 and the bond force between F 5 and GlcNAc 6 At least three sugar chain bonds selected from the above are defined, where the bond between F 2 and F 3 is a 1, 2 bond, << 1, 3 bond and a 1, 6 bond strength Selected from the group, wherein the bond between F 3 and F 4 is an al, 3 bond or a 1, 6 bond, and the bond between F 4 and F 5 is a 1, 4 bond; coupling between the F 5 and GlcNAc 6 is beta 1, 4 bonds, glycosylation ribosome of claim 166. (Item 170) Between F 2 and F 3

の結合、 F3と F4との間の結合、 F4と F5との間の結合および F5と GlcNAc6との間の結 合力 なる群より選択されるの糖鎖結合のすべてが規定されており、ここで該 F2と F3 との間の結合が、 al, 2結合、 《1, 3結合および a 1, 6結合力 なる群より選択され 、該 F3と F4との間の結合力 a 1, 3結合または a 1, 6結合であり、該 F4と F5との間の 結合が β 1, 4結合であり、該 F5と GlcNAc6との間の結合が β 1, 4結合である、項目 166に記載の糖鎖修飾リボソーム。（項目 171)前記糖鎖のリボソーム近位端力 Ma n— Man— Man— GlcNAc— GlcNAcの構造を有する、項目 166に記載の糖鎖修 飾リボソーム。（項目 172)前記糖鎖のリボソーム近位端力 Man al, 3Manal, 6 ManjS 1, 4GlcNAcj81, 4GlcNAc Man a 1, 2Mana 1, 3Manj81, 4GlcNA c β 1, 40 八。ぉょび1^&110；1, 6Mana 1, 6Manj81, 4GlcNAc β 1, 4GlcN Acからなる群より選択される構造を有する、項目 171に記載の糖鎖修飾リボソーム。 (項目 173)前記糖鎖のリボソーム近位端が、以下の構造: R1— F2— F3— F4— F5— F6— GlcNAc7を有し、ここで該 R1は、独立して、水素であるか、または任意の糖鎖で あり、該 F2は、 Manであり、該 F3は、 Manであり、該 F4は、 Manであり、該 F5は、 Man であり、該 F6は、 GlcNAcであり、ここで該 GlcNAc7はリボソームの最近位端に存在 する、項目 1に記載の糖鎖修飾リボソーム。（項目 174) F2と F3との間の結合、 F3と F4 との間の結合、 F4と F5との間の結合、 F5と F6との間の結合および F6と GlcNAc7との 間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規定されており、ここ で該 F2と F3との間の結合が《1, 2結合であり、該 F3と F4との間の結合が、 《1, 2結 合、 αΐ, 3結合および a 1, 6結合力 なる群より選択され、該 F4と F5との間の結合が 、 a 1, 3結合または a 1, 6結合であり、該 F5と F6との間の結合が β 1, 4結合であり、 該 F6と GlcNAc7との間の結合が /31, 4結合である、項目 173に記載の糖鎖修飾リポ ノーム。 （項目 175) F2と F3との間の結合、 F3と F4との間の結合、 F4と F5との間の結合 、F5と F6との間の結合および F6と GlcNAc7との間の結合力 なる群より選択される少 なくとも 2つの糖鎖結合が規定されており、ここで該 F2と F3との間の結合が a 1, 2結 合であり、該 F3と F4との間の結合が、 《1, 2結合、 《1, 3結合および a 1, 6結合か らなる群より選択され、該 F4と F5との間の結合力 al, 3結合または a 1, 6結合であ り、該 F5と F6との間の結合が β 1, 4結合であり、該 F6と GlcNAc7との間の結合が β 1 , 4結合である、項目 173に記載の糖鎖修飾リボソーム。（項目 176) F2と F3との間の 結合、 F3と F4との間の結合、 F4と F5との間の結合、 F5と F6との間の結合および F6と G1 cNAc7との間の結合力 なる群より選択される少なくとも 3つの糖鎖結合が規定され ており、ここで該 F2と F3との間の結合が a 1, 2結合であり、該 F3と F4との間の結合が 、 al, 2結合、 《1, 3結合および a 1, 6結合力 なる群より選択され、該 F4と F5との 間の結合が、 a 1, 3結合または a 1, 6結合であり、該 F5と F6との間の結合が β 1, 4 結合であり、該 F6と GlcNAc7との間の結合が β 1, 4結合である、項目 173に記載の 糖鎖修飾リボソーム。（項目 177) F2と F3との間の結合、 F3と F4との間の結合、 F4と F5 との間の結合、 F5と F6との間の結合および F6と GlcNAc7との間の結合力 なる群より 選択される少なくとも 4つの糖鎖結合が規定されており、ここで該 F2と F3との間の結合 が al, 2結合であり、該 F3と F4との間の結合力 al, 2結合、 a 1, 3結合および a 1 , 6結合力 なる群より選択され、該 F4と F5との間の結合力 «1, 3結合または《1, 6結合であり、該 F5と F6との間の結合が |81, 4結合であり、該 F6と GlcNAc7との間の 結合が β 1, 4結合である、項目 173に記載の糖鎖修飾リボソーム。（項目 178) F2と F3との間の結合、 F3と F4との間の結合、 F4と F5との間の結合、 F5と F6との間の結合お よび F6と GlcNAc7との間の結合力 なる群より選択される糖鎖結合のすべてが規定 されており、ここで該 F2と F3との間の結合が α 1, 2結合であり、該 F3と F4との間の結 合力 αΐ, 2結合、 《1, 3結合および《1, 6結合力 なる群より選択され、該 F4と F5 との間の結合が、 αΐ, 3結合または a 1, 6結合であり、該 F5と F6との間の結合が 1 , 4結合であり、該 F6と GlcNAc7との間の結合が β 1, 4結合である、項目 173に記載 の糖鎖修飾リボソーム。 （項目 179)前記糖鎖のリボソーム近位端力 Man— Man— Man— Man— GlcNAc— GlcNAcの構造を有する、項目 173に記載の糖鎖修飾リ ポソーム。 （項目 180)前記糖鎖のリボソーム近位端力 Man al, 2Manal, 2Ma ηα 1, 3Manj81, 4GlcNAcj81, 4GlcNAc、 Man a 1, 2Mana 1, 3Mana 1, 6 ManjS 1, 4GlcNAcj81, 401。 。ぉょび1^110；1, 2Mana 1, 6Mana 1, 6M anjS 1, 4GlcNAc β 1, 4GlcNAcからなる群より選択される構造を有する、項目 17 8に記載の糖鎖修飾リボソーム。（項目 181)前記糖鎖のリボソーム近位端力 以下の 構造: R1— G2— Gal3を有し、ここで該 R1は、独立して、水素であるか、または任意の 糖鎖であり、該 G2は、 Fuc、 Galおよび GalNacからなる群より選択され、ここで Gal3 はリボソームの最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム。 （項目 18 2) G2と Gal3との間の結合が、 《1, 2結合または《1, 3結合である、項目 181に記載 の糖鎖修飾リボソーム。 （項目 183)前記糖鎖のリボソーム近位端力 Fuc-Gal, Ga 1— Galおよび GalNAc— Galからなる群より選択される構造を有する、項目 181に記 載の糖鎖修飾リボソーム。 （項目 184)前記糖鎖のリボソーム近位端が、 Fuc a 1, 2G al、 Gala 1, 3Galおよび GalNAc a 1, 3Galからなる群より選択される構造を有する 、項目 183に記載の糖鎖修飾リボソーム。（項目 185)前記糖鎖のリボソーム近位端 が、以下の構造: I^— H2— GalNAc3を有し、ここで該 R1は、独立して、水素であるか 、または任意の糖鎖であり、そして該 H2は、 Galであり、ここで GalNAc3はリボソーム の最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム。（項目 186)H2と GalN Ac3との間の結合力 β ΐ, 3結合である、項目 184に記載の糖鎖修飾リボソーム。 ( 項目 187)前記糖鎖のリボソーム近位端力 Gal— GalNAcの構造を有する、項目 1 84に記載の糖鎖修飾リボソーム。（項目 188)前記糖鎖のリボソーム近位端力 Gal β 1, 3GalNAcの構造を有する、項目 187に記載の糖鎖修飾リボソーム。（項目 189 )前記糖鎖のリボソーム近位端力 以下の構造: R1— I2— Ser3を有し、ここで該 R1は、 独立して、水素であるか、または任意の糖鎖であり、そして該 I2は、 GalNAcであり、 ここで Ser3はリボソームの最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム 。 （項目 190) I2と Ser3との間の結合が、 a l— O—結合である、項目 189に記載の糖 鎖修飾リボソーム。（項目 191)前記糖鎖のリボソーム近位端力 GalNAc— Serの構 造を有する、項目 189に記載の糖鎖修飾リボソーム。（項目 192)前記糖鎖のリポソ 一ム近位端力 GalNAc a l— O— L— Serの構造を有する、項目 191に記載の糖 鎖修飾リボソーム。（項目 193)前記糖鎖のリボソーム近位端が、以下の構造: R1— I2 — I3— Ser4を有し、ここで該 R1は、独立して、水素であるか、または任意の糖鎖であり 、そして該 I2は、 Neu5Acであり、該 fは、 GalNAcであり、ここで Ser4はリボソームの 最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム。（項目 194) I2と I3との間 の結合および I3と Ser4との間の結合力 なる群より選択される少なくとも 1つの糖鎖結 合が規定されており、ここで該 I2と I3との間の結合が a 2, 6結合であり、該 I3と Ser4と の間の結合が α 1— O—結合である、項目 193に記載の糖鎖修飾リボソーム。（項目 195) I2と I3との間の結合および I3と Ser4との間の結合力もなる群より選択される糖鎖 結合のすべてが規定されており、ここで該 I2と I3との間の結合が α 2, 6結合であり、該 I3と Ser4との間の結合がひ 1— O—結合である、項目 193に記載の糖鎖修飾リポソ一 ム。（項目 196)前記糖鎖のリボソーム近位端力 Neu5Ac— GalNAc— Serの構造 を有する、項目 193に記載の糖鎖修飾リボソーム。（項目 197)前記糖鎖のリボソーム 近位端が、 Neu5Ac a 2, 6GalNAc α 1— O— L— Serの構造を有する、項目 196 に記載の糖鎖修飾リボソーム。（項目 198)前記糖鎖のリボソーム近位端が、以下の 構造: R1— J2—Glc3を有し、ここで該 R1は、独立して、水素であるか、または任意の 糖鎖であり、そして謝2は、 Galまたは Fucであり、ここで Glc3はリボソームの最近位端 に存在する、項目 1に記載の糖鎖修飾リボソーム。（項目 199) と Glc3との間の結合 が、 αΐ, 3結合または |81, 4 All of the glycan bonds selected from the group consisting of: the bond between F 3 and F 4 , the bond between F 4 and F 5 and the bond force between F 5 and GlcNAc 6 Wherein the bond between F 2 and F 3 is selected from the group consisting of al, 2 bond, << 1, 3 bond and a 1, 6 bond force, and F 3 and F 4 A bond between the F 4 and F 5 is a β 1,4 bond, and a bond between the F 5 and GlcNAc 6 is 166. The sugar chain-modified ribosome according to Item 166, which is a β1,4 bond. (Item 171) The sugar chain-modified ribosome according to item 166, which has a structure of ribosome proximal end force Man-Man-Man-GlcNAc-GlcNAc of the sugar chain. (Item 172) Ribosome proximal end force of the sugar chain Man al, 3Manal, 6 ManjS 1, 4GlcNAcj81, 4GlcNAc Man a 1, 2 Mana 1, 3Manj81, 4GlcNA c β 1, 40 172. Sugar chain-modified ribosome according to item 171 having a structure selected from the group consisting of 1 ^ &110; 1, 6Mana 1, 6Manj81, 4GlcNAc β1, 4GlcN Ac. (Item 173) The ribosome proximal end of the sugar chain has the following structure: R 1 — F 2 — F 3 — F 4 — F 5 — F 6 — GlcNAc 7 , where R 1 is independent And F 2 is Man, F 3 is Man, F 4 is Man, and F 5 is Man. There, the F 6 is GlcNAc, wherein said GlcNAc 7 is present in the proximal-most end of the ribosome, glycosylation ribosome of claim 1. (Item 174) Bond between F 2 and F 3 , Bond between F 3 and F 4 , Bond between F 4 and F 5 , Bond between F 5 and F 6 and F 6 And at least one sugar chain bond selected from the group consisting of the binding force between GlcNAc 7 and the bond between F 2 and F 3 is << 1, 2 bond, The bond between F 3 and F 4 is selected from the group of << 1, 2 bond, αΐ, 3 bond and a 1, 6 bond force, and the bond between F 4 and F 5 is a 1, 3 bond or a 1, 6 bond, bond between F 5 and F 6 is β 1, 4 bond, bond between F 6 and GlcNAc 7 is / 31, 4 bond The sugar chain-modified liposome according to Item 173, wherein (Item 175) Bond between F 2 and F 3 , Bond between F 3 and F 4 , Bond between F 4 and F 5 , Bond between F 5 and F 6 and F 6 And at least two sugar chain bonds selected from the group consisting of the binding strengths between GlcNAc 7 and GlcNAc 7 are defined, wherein the bonds between F 2 and F 3 are a 1, 2 bonds. And the bond between F 3 and F 4 is selected from the group consisting of << 1, 2 bond, << 1, 3 bond and a 1, 6 bond, and the bond between F 4 and F 5 Binding force al, 3 bond or a 1, 6 bond, bond between F 5 and F 6 is β 1, 4 bond, bond between F 6 and GlcNAc 7 is β 1 , The sugar chain-modified ribosome according to Item 173, which is a 4-bond. (Item 176) Bond between F 2 and F 3 , Bond between F 3 and F 4 , Bond between F 4 and F 5 , Bond between F 5 and F 6 and F 6 If at least three glycosylation is defined is selected from the binding force becomes the group between the G1 CNAC 7, wherein a bond is a 1, 2 coupled between said F 2 and F 3, The bond between F 3 and F 4 is selected from the group consisting of al, 2 bond, << 1, 3 bond and a 1, 6 bond force, and the bond between F 4 and F 5 is a 1, 3 bond or a 1, 6 bond, the bond between F 5 and F 6 is β 1, 4 bond, and the bond between F 6 and GlcNAc 7 is β 1, 4 bond The sugar chain-modified ribosome according to Item 173, wherein (Item 177) Bond between F 2 and F 3 , Bond between F 3 and F 4 , Bond between F 4 and F 5 , Bond between F 5 and F 6 and F 6 And at least four sugar chain bonds selected from the group consisting of the binding forces between GlcNAc 7 and Al, 2 bonds are defined as the bonds between F 2 and F 3. Binding force between 3 and F 4 al, 2 bond, a 1, 3 bond and a 1 , 6 bond force, and the bond force between F 4 and F 5 is «1, 3 bond or << 1, 6 bond, and the bond between F 5 and F 6 is | 81 , 4 is a bond, the bond between the F 6 and GlcNAc 7 is beta 1, 4 bonds, glycosylation ribosome of claim 173. (Item 178) Bond between F 2 and F 3 , Bond between F 3 and F 4 , Bond between F 4 and F 5 , Bond between F 5 and F 6 and F All of the sugar chain bonds selected from the group consisting of the binding force between 6 and GlcNAc 7 are defined, wherein the bonds between F 2 and F 3 are α 1,2 bonds, and binding force Ai between F 3 and F 4, 2 bond, "1, 3 bond and" is selected from 1, 6 bond strength becomes the group, the bond between the F 4 and F 5, αΐ, 3 Or a 1, 6 bond, the bond between F 5 and F 6 is a 1, 4 bond, and the bond between F 6 and GlcNAc 7 is a β 1, 4 bond, 173. The sugar chain-modified ribosome according to 173. (Item 179) The sugar chain-modified liposome according to Item 173, which has a structure of ribosome proximal end force Man-Man-Man-Man-GlcNAc-GlcNAc of the sugar chain. (Item 180) Ribosome proximal end force of the sugar chain Man al, 2Manal, 2Ma ηα 1, 3Manj81, 4GlcNAcj81, 4GlcNAc, Man a 1, 2Mana 1, 3Mana 1, 6 ManjS 1, 4GlcNAcj81, 401 . Item 1. The sugar chain-modified ribosome according to Item 178, which has a structure selected from the group consisting of 1 ^ 110; 1,2Mana 1,6Mana 1,6M anjS 1,4GlcNAc β 1,4GlcNAc. (Item 181) Ribosome proximal end force of the sugar chain The following structure: R 1 —G 2 —Gal 3 wherein R 1 is independently hydrogen or any sugar chain The sugar chain-modified ribosome according to item 1, wherein the G 2 is selected from the group consisting of Fuc, Gal and GalNac, wherein Gal 3 is present at the most proximal end of the ribosome. (Item 18 2) The sugar chain-modified ribosome according to Item 181, wherein the bond between G 2 and Gal 3 is << 1, 2 bond or << 1, 3 bond. (Item 183) The sugar chain-modified ribosome according to item 181, wherein the sugar chain has a structure selected from the group consisting of Fuc-Gal, Ga 1-Gal and GalNAc-Gal. (Item 184) The sugar chain modification according to item 183, wherein the ribosome proximal end of the sugar chain has a structure selected from the group consisting of Fuc a 1, 2Gal, Gala 1, 3Gal and GalNAc a 1, 3Gal Ribosome. (Item 185) The ribosome proximal end of the sugar chain has the following structure: I ^ —H 2 —GalNAc 3 , wherein R 1 is independently hydrogen or any sugar 2. The sugar chain-modified ribosome of item 1, wherein the H 2 is Gal and GalNAc 3 is present at the most proximal end of the ribosome. (Item 186) H 2 and GalN 184. The sugar chain-modified ribosome according to Item 184, which is a binding force between Ac 3 and β 3. (Item 187) The sugar chain-modified ribosome according to Item 184, which has a structure of a ribosome proximal end force Gal—GalNAc of the sugar chain. (Item 188) The sugar chain-modified ribosome according to item 187, which has a structure of ribosome proximal end force Gal β1,3GalNAc of the sugar chain. (Item 189) Ribosome proximal end force of the sugar chain having the following structure: R 1 —I 2 — Ser 3 , wherein the R 1 is independently hydrogen or any sugar chain , and the and said I 2 is GalNAc, where Ser 3 is present in the proximal-most end of the ribosome, glycosylation ribosome of claim 1. (Item 190) The sugar chain-modified ribosome according to Item 189, wherein the bond between I 2 and Ser 3 is an al—O— bond. (Item 191) The sugar chain-modified ribosome according to Item 189, which has a structure of a ribosome proximal end force GalNAc-Ser of the sugar chain. (Item 192) The sugar chain-modified ribosome according to Item 191, having a structure of a liposomal proximal end force GalNAcal-OL-L-Ser of the sugar chain. (Item 193) The ribosome proximal end of the sugar chain has the following structure: R 1 —I 2 —I 3 — Ser 4 , wherein R 1 is independently hydrogen, or The sugar chain-modified ribosome according to item 1, wherein the sugar chain is an arbitrary sugar chain, and the I 2 is Neu5Ac and the f is GalNAc, wherein Ser 4 is present at the most proximal end of the ribosome. 194. at least one Tokusariyui case selected from the binding force becomes a group are defined between the coupling and I 3 and Ser 4 between I 2 and I 3, wherein said I 2 and a bond is a 2, 6 bond between I 3, coupling between the I 3 and Ser 4 are alpha 1-O-bonds, glycosylation ribosome of claim 193. (Item 195) I 2 and all binding force of glycosylation also be selected from the group consisting are defined between the coupling and I 3 and Ser 4 between I 3, wherein said I 2 and I 194. The sugar chain-modified liposome according to Item 193, wherein the bond between 3 is an α 2,6 bond, and the bond between I 3 and Ser 4 is a 1—O— bond. (Item 196) The sugar chain-modified ribosome according to item 193, which has the structure of ribosome proximal end force Neu5Ac-GalNAc-Ser of the sugar chain. (Item 197) The sugar chain-modified ribosome according to item 196, wherein the ribosome proximal end of the sugar chain has a structure of Neu5Ac a 2,6GalNAc α 1-O-L-Ser. (Item 198) The ribosome proximal end of the sugar chain has the following structure: R 1 —J 2 —Glc 3 , wherein R 1 is independently hydrogen or any sugar a chain and Xie 2 is Gal or Fuc, wherein Glc 3 is present in the proximal-most end of the ribosome, glycosylation ribosome of claim 1. Coupling between (item 199) and Glc 3 Is αΐ, 3 bonds or | 81, 4

結合である、項目 198に記載の糖鎖修飾リボソーム。（項目 200)前記糖鎖のリポソ一 ム近位端力 Fuc— Glcまたは Gal— Glcの構造を有する、項目 199に記載の糖鎖修 飾リボソーム。（項目 201)前記糖鎖のリボソーム近位端力 Fuc al, 3Glcまたは Ga Ιβ ΐ, 4Glcの構造を有する、項目 200に記載の糖鎖修飾リボソーム。（項目 202)前 記糖鎖のリボソーム近位端力 以下の構造:

Figure imgf000088_0001
ここで該 R1は 、独立して、水素であるか、または任意の糖鎖であり、そして謝2は、 Fuc、 GlcNAc および Neu5Acからなる群より選択され、ここで謝3は、 Galであり、ここで Glc4はリポ ノームの最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム。 （項目 203)J2^J 3との間の結合および J3と Glc4との間の結合力 なる群より選択される少なくとも 1つの 糖鎖結合が規定されており、ここで、言 ¾J3との間の結合力 αΐ, 2結合、 《2, 3結 合および j81, 3結合力 なる群より選択され、謝3と Glc4との間の結合が β 1, 4結合 である、項目 202に記載の糖鎖修飾リボソーム。（項目 204)J2^J3との間の結合およ び J3と Glc4との間の結合力 なる群より選択される糖鎖結合のすべてが規定されてお り、ここで、言 ¾J3との間の結合力 αΐ, 2結合、 《2, 3結合および |81, 3結合から なる群より選択され、謝3と Glc4との間の結合が |81, 4結合である、項目 202に記載 の糖鎖修飾リボソーム。 （項目 205)前記糖鎖のリボソーム近位端力 Fuc— Gal— G1 c、 GlcNAc Gal— Glcおよび Neu5Ac— Gal Glcからなる群より選択される構造 を有する、項目 202に記載の糖鎖修飾リボソーム。（項目 206)前記糖鎖のリボソーム 近位端力 Fuc a 1, 2Galj81, 4Glc、 GlcNAc β 1, 3Galj81, 4Glcおよび Neu5 Ac a 2, 3Gal|81, 4Glcからなる群より選択される構造を有する、項目 203に記載の 糖鎖修飾リボソーム。（項目 207)前記糖鎖のリボソーム近位端が、以下の構造: R1— J2— J3— J4— Glc5を有し、ここで該 R1は、独立して、水素であるか、または任意の糖鎖 であり、そして謝2は、 Fucまたは Galであり、謝3は、 GlcNAcであり、謝4は、 Galで あり、ここで Glc5はリボソームの最近位端に存在する、項目 1に記載の糖鎖修飾リポソ ーム。（項目 208)J2^J3との間の結合、 J3iJ4との間の結合および J4と Glc5との間の結 合力もなる群より選択される少なくとも 1つの糖鎖結合が規定されており、ここで、 m2 ij3との間の結合が、 ひ1, 4結合または |81, 3結合であり、謝3 ^J4との間の結合が β 1, 3結合または 13 1, 4結合であり、謝4と Glc5との間の結合が 13 1, 4結合である、 項目 207に記載の糖鎖修飾リボソーム。（項目 209)J2^J3との間の結合、 J3iJ4との間 の結合および J4と Glc5との間の結合力 なる群より選択される少なくとも 2つの糖鎖結 合が規定されており、ここで、謝2 ^J3との間の結合力 a 1, 4結合または β 1, 3結合 であり、謝3 ^J4との間の結合が β 1, 3結合または β 1, 4結合であり、謝4と Glc5との 間の結合が β 1, 4結合である、項目 207に記載の糖鎖修飾リボソーム。（項目 210)J 2^J3との間の結合、 J3^J4との間の結合および J4と Glc5との間の結合力 なる群より選 択される糖鎖結合のすべてが規定されており、ここで、謝2^ [3との間の結合が、 a 1 , 4結合または |8 1, 3結合であり、謝3 ^J4との間の結合が j8 1, 3結合または |8 1, 4 結合であり、謝4と Glc5との間の結合が β 1, 4結合である、項目 207に記載の糖鎖 修飾リボソーム。（項目 211)前記糖鎖のリボソーム近位端力 Fuc-GlcNAc-Gal GlcまたはGal—GlcNAc— Gal—Glcの構造を有する、項目 207に記載の糖鎖 修飾リボソーム。（項目 212)前記糖鎖のリボソーム近位端力 Fuc a l, 4GlcNAc β 1, 3Gal j8 1, 4Glcまたは Gal j8 1, 3GlcNAC j8 1, 3Gal j8 1 , 4Glcの構造を有する 、項目 211に記載の糖鎖修飾リボソーム。（項目 213)前記糖鎖のリボソーム近位端 が、以下の構造: ^ - - - -f -Glc6を有し、ここで該 R1は、独立して、水素で あるか、または任意の糖鎖であり、言 2は、 Fucであり、言 3は、 Galであり、言 4は、 G1 cNAcまたは GalNAcであり、謝5は、 Galであり、ここで Glc6はリボソームの最近位端 に存在する、項目 1に記載の糖鎖修飾リボソーム。（項目 214)J2iJ3との間の結合、 J3 ij4との間の結合、 J4^J5との間の結合および J5と Glc6との間の結合力 なる群より選 択される少なくとも 1つの糖鎖結合が規定されており、ここで、謝2 ^J3との間の結合が a 1, 2結合であり、謝3 ^J4との間の結合が β 1, 3結合であり、謝4 ^J5との間の結合 が β 1, 3結合であり、謝5と Glc6との間の結合とが β 1, 4結合である、項目 213に記 載の糖鎖修飾リボソーム。 （項目 215)J2^J3との間の結合、 J3^J4との間の結合、 J4tJ5 との間の結合および J5と Glc6との間の結合力 なる群より選択される少なくとも 2つの 糖鎖結合が規定されており、ここで、謝2 3との間の結合が ex 1, 2結合であり、 m3 ij4との間の結合が β 1, 3結合であり、謝4 ^J5との間の結合が β 1, 3結合であり、該 J5と Glc6との間の結合とが 13 1, 4結合である、項目 213に記載の糖鎖修飾リボソーム 。 （項目 216)J¾J3との間の結合、 J3iJ4との間の結合、 J4iJ5との間の結合および J5と Glc6との間の結合力 なる群より選択される少なくとも 3つの糖鎖結合が規定されて おり、ここで、謝2 ^J3との間の結合が ex 1 , 2結合であり、謝3 ^J4との間の結合が β 1 , 3結合であり、謝4 ^J5との間の結合が β 1 , 3結合であり、謝5と Glc6との間の結合と が j8 1 , 4結合である、項目 213に記載の糖鎖修飾リボソーム。（項目 217)J2^J3との 間の結合、 J3^J4との間の結合、 J4iJ5との間の結合および J5と Glc6との間の結合から なる群より選択される糖鎖結合のすべてが規定されており、ここで、謝2 ^J3との間の 結合が ex 1 , 2結合であり、謝3 ^J4との間の結合が β 1 , 3結合であり、謝4 ^J5との間 の結合が β 1 , 3結合であり、謝5と Glc6との間の結合とが β 1 , 4結合である、項目 2 13に記載の糖鎖修飾リボソーム。（項目 218)前記糖鎖のリボソーム近位端力 Fuc — Gal— GlcNAc— Gal— Glcの構造を有する、項目 213に記載の糖鎖修飾リポソ ーム。（項目 219)前記糖鎖のリボソーム近位端力 Fuc a l , 2Gal j8 1 , 3GlcNAc β 1 , 3Gal |8 1 , 4Glcの構造を有する、項目 218に記載の糖鎖修飾リボソーム。（項 目 220)前記糖鎖のリボソーム近位端力 以下の構造: R1— K2— Man3を有し、ここ で該 R1は、独立して、水素であるか、または任意の糖鎖であり、そして該 K2は、 Man であり、ここで Man3はリボソームの最近位端に存在する、項目 1に記載の糖鎖修飾リ ポソーム。 （項目 221) K2と Man3との間の結合が、 α ΐ , 2結合、 α ΐ , 3結合および α 1 , 4結合力もなる群より選択される、項目 220に記載の糖鎖修飾リボソーム。（項目 2 22)前記糖鎖のリボソーム近位端力 Man— Manの構造を有する、項目 220に記載 の糖鎖修飾リボソーム。 （項目 223)前記糖鎖のリボソーム近位端力 Man « 1 , 2Ma n、 Man a l , 3Manおよび Man α 1 , 4Manからなる群より選択される構造を有する 、項目 222に記載の糖鎖修飾リボソーム。（項目 224)前記糖鎖のリボソーム近位端 が、以下の構造: R1— L2— Cer3を有し、ここで該 R1は、独立して、水素であるか、ま たは任意の糖鎖であり、そして該 L2は、 Glcであり、ここで Cer3はリボソームの最近位 端に存在する、項目 1に記載の糖鎖修飾リボソーム。（項目 225) L2と Cer3との間の 結合が、 j8 1 , 1結合である、項目 224に記載の糖鎖修飾リボソーム。（項目 226)前 記糖鎖のリボソーム近位端力 Glc— Cerの構造を有する、項目 224に記載の糖鎖 修飾リボソーム。（項目 227)前記糖鎖のリボソーム近位端力 Glc |8 1 , ICerの構造 を有する、項目 226に記載の糖鎖修飾リボソーム。（項目 228)前記糖鎖のリボソーム 近位端が、以下の構造: R1— L2— L3— Cer4を有し、ここで該 R1は、独立して、水素 であるか、または任意の糖鎖であり、そして該 L2は、 Galであり、該 L3は、 Glcであり、 ここで Cer4はリボソームの最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム 。 （項目 229) L2と L3との間の結合および L3と Cer4との間の結合力もなる群より選択さ れる少なくとも 1つの糖鎖結合が規定されており、ここで、該 L2と L3との間の結合が、 β 1, 4結合であり、該 L3と Cer4との間の結合が β 1, 1結合である、項目 228に記載 の糖鎖修飾リボソーム。 （項目 230) L2と L3との間の結合および L3と Cer4との間の結 合からなる群より選択される糖鎖結合のすべてが規定されており、ここで、該 L2と L3と の間の結合が、 j8 1, 4結合であり、該 L3と Cer4との間の結合が |8 1, 1結合である、 項目 228に記載の糖鎖修飾リボソーム。（項目 231)前記糖鎖のリボソーム近位端が 、 Gal— Glc— Cerの構造を有する、 199. Sugar chain-modified ribosome according to item 198, which is a bond. (Item 200) The sugar chain-modified ribosome according to Item 199, which has a structure of the liposomal proximal end force Fuc-Glc or Gal-Glc of the sugar chain. (Item 201) The sugar chain-modified ribosome according to item 200, which has a structure of a ribosome proximal end force Fucal, 3Glc or Ga Ιβ ΐ, 4Glc of the sugar chain. (Item 202) The ribosome proximal end force of the aforementioned sugar chain The following structure:
Figure imgf000088_0001
Wherein R 1 is independently hydrogen or any sugar chain, and Xie 2 is selected from the group consisting of Fuc, GlcNAc and Neu5Ac, where Xie 3 is Gal Wherein Glc 4 is present at the most proximal end of the liposome, The sugar chain-modified ribosome according to item 1. (Item 203) At least one sugar chain bond selected from the group consisting of the bond between J 2 ^ J 3 and the bond strength between J 3 and Glc 4 is defined, where ¾J 3 The bond between α と, 2 bond, << 2, 3 bond and j81, 3 bond force, and the bond between Xie 3 and Glc 4 is β 1, 4 bond, item 202 The sugar chain-modified ribosome described in 1. (Item 204) All of the glycan bonds selected from the group consisting of the bond between J 2 ^ J 3 and the bond strength between J 3 and Glc 4 are defined. ¾ J 3 binding force αΐ, 2 bond, << 2, 3 bond and | 81, 3 bond selected from the group consisting of, and the bond between Xie 3 and Glc 4 is | 81, 4 bond, Item 202. A sugar chain-modified ribosome according to Item 202. (Item 205) The sugar chain-modified ribosome according to item 202, wherein the sugar chain has a structure selected from the group consisting of Fuc-Gal-G1c, GlcNAc Gal-Glc and Neu5Ac-Gal Glc. (Item 206) Ribosome proximal end force of the sugar chain Fuc a 1, 2Galj81, 4Glc, GlcNAc β 1, 3Galj81, 4Glc and Neu5 Ac a 2, 3Gal | 81, 4Glc Item 202. A sugar chain-modified ribosome according to Item 203. (Item 207) The ribosome proximal end of the sugar chain has the following structure: R 1 — J 2 — J 3 — J 4 — Glc 5 where R 1 is independently hydrogen. Or any sugar chain, and Xie 2 is Fuc or Gal, Xie 3 is GlcNAc, Xie 4 is Gal, where Glc 5 is at the proximal end of the ribosome 2. The sugar chain-modified liposome according to item 1. (Item 208) At least one sugar chain bond selected from the group consisting of a bond between J 2 ^ J 3 , a bond between J 3 iJ 4 and a bond force between J 4 and Glc 5 Where the bond between m 2 ij 3 is a 3,4 bond or | 81, 3 bond, and the bond between Xie 3 ^ J 4 is 209. The sugar chain-modified ribosome according to Item 207, which is a β 1,3 bond or a 13 1,4 bond, and the bond between Xie 4 and Glc 5 is a 13 1,4 bond. (Item 209) At least two sugar chain bonds selected from the group consisting of a bond between J 2 ^ J 3 , a bond between J 3 iJ 4 and a bond force between J 4 and Glc 5 Where the binding force between Xie 2 ^ J 3 is a 1,4 bond or β 1,3 bond and the bond between Xie 3 ^ J 4 is β 1,3 bond or 209. The sugar chain-modified ribosome according to Item 207, which is a β 1,4 bond, and the bond between Xie 4 and Glc 5 is a β 1,4 bond. (Item 210) All of the glycan bonds selected from the group consisting of the bond between J 2 ^ J 3 , the bond between J 3 ^ J 4 and the bond strength between J 4 and Glc 5 Where the bond between Xie 2 ^ [ 3 is an a 1, 4 bond or | 8 1, 3 bond and the bond between Xie 3 ^ J 4 is j8 1, 3 209. The sugar chain-modified ribosome according to Item 207, which is a bond or | 8 1,4 bond, and the bond between Xie 4 and Glc 5 is a β 1,4 bond. (Item 211) The sugar chain-modified ribosome according to item 207, which has a structure of ribosome proximal end force Fuc-GlcNAc-Gal Glc or Gal-GlcNAc-Gal-Glc of the sugar chain. (Item 212) ribosomal proximal end force Fuc al of the sugar chain, having 4GlcNAc β 1, 3Gal j8 1, 4Glc or Gal j8 1, 3GlcNA C j 8 1, 3Gal j8 1, the structure of 4Glc, claim 211 The sugar chain modified ribosome. (Item 213) The ribosome proximal end of the sugar chain has the following structure: ^----f -Glc 6 where R 1 is independently hydrogen or any Sugar chain, word 2 is Fuc, word 3 is Gal, word 4 is G1 cNAc or GalNAc, Xie 5 is Gal, where Glc 6 is the proximal end of the ribosome 2. The sugar chain-modified ribosome according to item 1, which is present in item 1. (Item 21 4 ) From the group consisting of the bond between J 2 iJ 3 , the bond between J 3 ij 4 , the bond between J 4 ^ J 5 and the bond between J 5 and Glc 6 At least one selected sugar chain bond is defined, where the bond between Xie 2 ^ J 3 is an a 1, 2 bond and the bond between Xie 3 ^ J 4 is β Item 213, which is a 1,3 bond, a bond between Xie 4 ^ J 5 is a β 1,3 bond, and a bond between Xie 5 and Glc 6 is a β 1,4 bond. The sugar chain-modified ribosome listed. (Item 215) Bonds between J 2 ^ J 3 , bonds between J 3 ^ J 4 , bonds between J 4 tJ 5 and bonds between J 5 and Glc 6 At least two selected sugar chain bonds are defined, where the bond between Xie 23 and 3 is an ex 1,2 bond and the bond between m 3 ij 4 is a β 1,3 bond The sugar chain according to Item 213, wherein the bond between Xie 4 ^ J 5 is a β 1,3 bond, and the bond between J 5 and Glc 6 is a 13 1,4 bond. Modified ribosome . (Item 216) coupled between J¾J 3, coupling between the J 3 iJ 4, at least selected from the binding force becomes the group between the coupling and J 5 and Glc 6 between the J 4 iJ 5 Three sugar chain bonds are defined, where the bond between Xie 2 ^ J 3 is ex 1, 2 bond and the bond between Xie 3 ^ J 4 is β 1, 3 bond The sugar chain-modified ribosome according to Item 213, wherein the bond between Xie 4 ^ J 5 is a β 1, 3 bond, and the bond between Xie 5 and Glc 6 is a j8 1,4 bond . (Item 217) From the group consisting of a bond between J 2 ^ J 3 , a bond between J 3 ^ J 4 , a bond between J 4 iJ 5 and a bond between J 5 and Glc 6 All of the selected sugar chain bonds are defined, where the bond between Xie 2 ^ J 3 is ex 1, 2 bond and the bond between Xie 3 ^ J 4 is β 1, 3 is a bond, a bond is beta 1, 3 bond between Xie 4 ^ J 5, and the bond between the Xie 5 and Glc 6 is beta 1, 4 bonds, according to item 2 13 Sugar chain-modified ribosome. (Item 218) The sugar chain-modified liposome according to item 213, which has a structure of ribosome proximal end force Fuc-Gal-GlcNAc-Gal-Glc of the sugar chain. (Item 219) The sugar chain-modified ribosome according to item 218, wherein the sugar chain has a structure of ribosome proximal end force Fucal, 2Gal j81, 3GlcNAc β1, 3Gal | 81, 4Glc. (Item 220) Ribosome proximal end force of the sugar chain having the following structure: R 1 — K 2 — Man 3 wherein R 1 is independently hydrogen or any sugar 2. The sugar chain-modified liposome according to Item 1, wherein the K 2 is a chain, and Man 3 is present at the most proximal end of the ribosome. (Item 221) The sugar chain-modified ribosome according to Item 220, wherein the bond between K 2 and Man 3 is selected from the group consisting of α,, 2 bond, α ΐ, 3 bond and α 1, 4 bond force. . (Item 22) The sugar chain-modified ribosome according to Item 220, which has a structure of ribosome proximal end force Man-Man of the sugar chain. (Item 223) The sugar chain-modified ribosome according to item 222, which has a structure selected from the group consisting of ribosome proximal end force Man «1, 2Man, Man al, 3Man and Man α 1, 4Man of the sugar chain . (Item 224) The ribosome proximal end of the sugar chain has the following structure: R 1 — L 2 — Cer 3 , wherein R 1 is independently hydrogen or optional The sugar chain-modified ribosome according to Item 1, wherein L 2 is Glc, and Cer 3 is present at the most proximal position of the ribosome. (Item 225) The sugar chain-modified ribosome according to Item 224, wherein the bond between L 2 and Cer 3 is a j81,1 bond. (Item 226) The sugar chain-modified ribosome according to Item 224, which has a structure of ribosome proximal end force Glc-Cer of the aforementioned sugar chain. (Item 227) Ribosome proximal end force of the sugar chain Glc | 8 1, ICer structure 226. The sugar chain-modified ribosome according to item 226. (Item 228) The ribosome proximal end of the sugar chain has the following structure: R 1 — L 2 — L 3 — Cer 4 , wherein R 1 is independently hydrogen, or 2. The sugar chain-modified ribosome according to item 1, wherein L 2 is Gal, L 3 is Glc, and Cer 4 is present at the most proximal end of the ribosome. (Item 229) At least one sugar chain bond selected from the group consisting of a bond between L 2 and L 3 and a binding force between L 3 and Cer 4 is defined, wherein the L 2 and the bond between L 3, a beta 1, 4 bond, the bond between the L 3 and Cer 4 are beta 1, 1 binding, glycosylation ribosome of claim 228. (Item 230) All of the sugar chain bonds selected from the group consisting of a bond between L 2 and L 3 and a bond between L 3 and Cer 4 are defined, where L 2 and the bond between L 3, a j8 1, 4 bond, the bond between the L 3 and Cer 4 is | 8 1, 1 is a bond, glycosylation ribosome of claim 228. (Item 231) The ribosome proximal end of the sugar chain has a structure of Gal-Glc-Cer,

項目 228に記載の糖鎖修飾リボソーム。（項目 232)前記糖鎖のリボソーム近位端が 、 Gal jS l, 4G1C J8 1, ICerの構造を有する、項目 231に記載の糖鎖修飾リボソーム 。 （項目 233)前記糖鎖のリボソーム近位端が、以下の構造: R1— L2— L3— L4— Cer 5を有し、ここで該 R1は、独立して、水素であるか、または任意の糖鎖であり、そして該 L2は、 GalNAcまたは Neu5Acであり、該 L3は、 Galであり、該 L4は、 Glcであり、ここ で Cer5はリボソームの最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム。 ( 項目 234) L2と L3との間の結合、 L3と L4との間の結合および L4と Cer5との間の結合か らなる群より選択される少なくとも 1つの糖鎖結合が規定されており、ここで、該 L2と L3 との間の結合が、 α 2、 3結合または β 1, 4結合であり、該 L3と L4との間の結合が β 1 , 4結合であり、該 L4と Cer5との間の結合が β 1, 1結合である、項目 233に記載の糖 鎖修飾リボソーム。（項目 235) L2と L3との間の結合、 L3と L4との間の結合および L4と Cer5との間の結合力 なる群より選択される少なくとも 2つの糖鎖結合が規定されて おり、ここで、該 L2と L3との間の結合が、 《2、 3結合または 1, 4結合であり、該 L3と L4との間の結合が β 1, 4結合であり、該 L4と Cer5との間の結合が β 1, 1結合である 、項目 233に記載の糖鎖修飾リボソーム。（項目 236) L2と L3との間の結合、 L3と L4と の間の結合および L4と Cer5との間の結合力 なる群より選択される糖鎖結合のすべ てが規定されており、ここで、該 L2と L3との間の結合力 《2、 3結合または 1, 4結 合であり、該 L3と L4との間の結合が /3 1, 4結合であり、該 L4と Cer5との間の結合が /3 1, 1結合である、項目 233に記載の糖鎖修飾リボソーム。 （項目 237)前記糖鎖のリ ポソ一ム近位端が、 GalNAc - Gal-Glc - Cerおよび Neu5Ac - Gal-Glu - Cer 力もなる群より選択される構造を有する、項目 233に記載の糖鎖修飾リボソーム。（項 目 238)前記糖鎖のリボソーム近位端力 GalNAc j8 1, 4Gal j8 1, 4GlC j8 1, ICer および Neu5Ac α 2、 3Gal j8 1, 4GlU j8 1, ICerからなる群より選択される構造の構 造を有する、項目 237に記載の糖鎖修飾リボソーム。（項目 239)前記糖鎖のリポソ 一ム近位端力 以下の構造: R1— L2— L3— L4— L5— Cer6を有し、ここで該 R1は、独 立して、水素であるか、または任意の糖鎖であり、該 L2は、 Galであり、該 L3は、 GalN Acであり、該 L4は、 Galであり、該 L5は、 Glcであり、ここで Cer6はリボソームの最近位 端に存在する、項目 1に記載の糖鎖修飾リボソーム。（項目 240) L2と L3との間の結 合、 L3と L4との間の結合、 L4と L5との間の結合および L5と Cer6との間の結合力 なる 群より選択される少なくとも 1つの糖鎖結合が規定されており、ここで、該 L2と L3との 間の結合が β 1、 3結合であり、該 L3と L4との間の結合が β 1, 4結合であり、該 L4と L 5との間の結合が β 1, 4結合であり、該 L5と Cer6との間の結合とが β 1, 1結合である 、項目 239に記載の糖鎖修飾リボソーム。（項目 241) L2と L3との間の結合、 L3と L4と の間の結合、 L4と L5との間の結合および L5と Cer6との間の結合力 なる群より選択さ れる少なくとも 2つの糖鎖結合が規定されており、ここで、該 L2と L3との間の結合が /3 1、 3結合であり、該 L3と L4との間の結合が /3 1, 4結合であり、該 L4と L5との間の結合 が β 1, 4結合であり、該 L5と Cer6との間の結合とが β 1, 1結合である、項目 239に 記載の糖鎖修飾リボソーム。 （項目 242) L2と L3との間の結合、 L3と L4との間の結合、 L4と L5との間の結合および L5と Cer6との間の結合力 なる群より選択される少なくとも 3つの糖鎖結合が規定されており、ここで、該 L2と L3との間の結合が β 1、 3結合であ り、該 L3と L4との間の結合が /3 1, 4結合であり、該 L4と L5との間の結合が /3 1, 4結合 であり、該 L5と Cer6との間の結合とが /3 1, 1結合である、項目 239に記載の糖鎖修 飾リボソーム。（項目 243) L2と L3との間の結合、 L3と L4との間の結合、 L4と L5との間 の結合および L5と Cer6との間の結合力 なる群より選択される糖鎖結合のすべてが 規定されており、ここで、該 L2と L3との間の結合が β 1、 3結合であり、該 L3と L4との間 の結合が β 1, 4結合であり、該 L4と L5との間の結合が β 1, 4結合であり、該 L5と Cer 6との間の結合とが j8 1, 1結合である、項目 239に記載の糖鎖修飾リボソーム。（項目 244)前記糖鎖のリボソーム近位端が、 Gal— GalNAc Gal Glc Cerの構造を 有する、項目 239に記載の糖鎖修飾リボソーム。（項目 245)前記糖鎖のリボソーム 近位端が、 Gal jS 1、 3GalNAc β 1, 4Gal j8 1, 4Glc β 1, lCerの構造を有する、項 目 244に記載の糖鎖修飾リボソーム。（項目 246)前記糖鎖のリボソーム近位端が、 以下の構造:!^ーし2—1 ーし4ー1 1 ーじ61：7を有し、ここで該 R1は、独立して、水 素であるか、または任意の糖鎖であり、該 L2は、 Neu5Acであり、該 L3は、 Galであり 、該 L4は、 GalNacであり、該 L5は、 Galであり、該 L6は、 Glcであり、ここで Cer7はリポ ノームの最近位端に存在する、項目 1に記載の糖鎖修飾リボソーム。 （項目 247) L2と L3との間の結合、 L3と L4との間の結合、 L4と L5との間の結合、 L5と L6との間の結合お よび L6と Cer7との間の結合力 なる群より選択される少なくとも 1つの糖鎖結合が規 定されており、ここで、該 L2と L3との間の結合が α 2, 3結合であり、該 L3と L4との間の 結合が j8 1, 3結合であり、該 L4と L5との間の結合が /3 1, 4結合であり、該 L5と L6との 間の結合が β 1, 4であり、該 L6と Cer7との間の結合とが β 1, 1結合である、項目 24 6に記載の糖鎖修飾リボソーム。（項目 248) L2と L3との間の結合、 L3と L4との間の結 合、 L4と L5との間の結合、 L5と L6との間の結合および L6と Cer7との間の結合力 なる 群より選択される少なくとも 2つの糖鎖結合が規定されており、ここで、該 L2と L3との 間の結合が a 2, 3結合であり、該 L3と L4との間の結合が /3 1, 3結合であり、該 L4と L 5との間の結合が j8 1, 4結合であり、該 L5と L6との間の結合が /3 1, 4であり、該 L6と C er7との間の結合とが |8 1, 1結合である、項目 246に記載の糖鎖修飾リボソーム。（項 目 249) L2と L3との間の結合、 L3と L4との間の結合、 L4と L5との間の結合、 L5と L6との 間の結合および L6と Cer7との間の結合力 なる群より選択される少なくとも 3つの糖 鎖結合が規定されており、ここで、該 L2と L3との間の結合が α 2, 3結合であり、該 L3 と L4との間の結合が 1, 3結合であり、該 L4と L5との間の結合が 1, 4結合であり、 該 L5と L6との間の結合が β 1, 4であり、該 L6と Cer7との間の結合とが β 1, 1結合で ある、項目 246に記載の糖鎖修飾リボソーム。（項目 250) L2と L3との間の結合、 L3と L4との間の結合、 L4と L5との間の結合、 L5と L6との間の結合および L6と Cer7との間の 結合力 なる群より選択される少なくとも 4つの糖鎖結合が規定されており、ここで、該 L2と L3との間の結合が α 2, 3結合であり、該 L3と L4との間の結合が β 1, 3結合であ り、該 L4と L5との間の結合が /3 1, 4結合であり、該 L5と L6との間の結合が /3 1, 4であ り、該 L6と Cer7との間の結合とが /3 1, 1結合である、項目 246に記載の糖鎖修飾リポ ノーム。 （項目 251) L2と L3との間の結合、 L3と L4との間の結合、 L4と L5との間の結合 、L5と L6との間の結合および L6と Cer7との間の結合力 なる群より選択される少なくと も 4つの糖鎖結合が規定されており、ここで、該 L2と L3との間の結合がひ 2, 3結合で あり、該 L3と L4との間の結合が /3 1, 3結合であり、該 L4と L5との間の結合が /3 1, 4結 合であり、該 L5と L6との間の結合が /3 1, 4であり、該 L6と Cer7との間の結合とが /3 1, 1結合である、項目 246に記載の糖鎖修飾リボソーム。（項目 252) L2と L3との間の結 合、 L3と L4との間の結合、 L4と L5との間の結合、 L5と L6との間の結合および L6と Cer7 との間の結合力 なる群より選択される糖鎖結合のすべてが規定されており、ここで、 該 L2と L3との間の結合が α 2, 3結合であり、該 L3と L4との間の結合が β 1, 3結合で あり、該 L4と L Item 228. A sugar chain-modified ribosome. (Item 232) The sugar chain-modified ribosome according to Item 231, wherein the ribosome proximal end of the sugar chain has a structure of Gal jSl, 4G1 CJ 81, ICer. (Item 233) The ribosome proximal end of the sugar chain has the following structure: R 1 — L 2 — L 3 — L 4 — Cer 5 where R 1 is independently hydrogen Or any sugar chain, and the L 2 is GalNAc or Neu5Ac, the L 3 is Gal, and the L 4 is Glc, where Cer 5 is the proximal end of the ribosome 2. The sugar chain-modified ribosome according to item 1, which is present in item 1. (Item 234) At least one sugar chain bond selected from the group consisting of a bond between L 2 and L 3 , a bond between L 3 and L 4, and a bond between L 4 and Cer 5 Where the bond between L 2 and L 3 is an α 2,3 bond or β 1,4 bond, and the bond between L 3 and L 4 is β 1 The sugar chain-modified ribosome according to Item 233, wherein the bond between L 4 and Cer 5 is a β 1,1 bond. (Item 235) At least two sugar chain bonds selected from the group consisting of a bond between L 2 and L 3 , a bond between L 3 and L 4, and a bond force between L 4 and Cer 5 Where the bond between L 2 and L 3 is a << 2, 3 bond or 1, 4 bond, and the bond between L 3 and L 4 is β 1, 4 209. The sugar chain-modified ribosome according to Item 233, which is a bond, and the bond between L 4 and Cer 5 is a β1,1 bond. (Item 236) Binding between L 2 and L 3 , binding between L 3 and L 4 and binding force between L 4 and Cer 5 Where the binding force between L 2 and L 3 is << 2, 3 or 1, 4 bond, and the bond between L 3 and L 4 is / 3 1, 4 is a bond, the bond between the L 4 and Cer 5 is / 3 1, 1 binding, glycosylation ribosome of claim 233. (Item 237) The sugar according to item 233, wherein the liposomal proximal end of the sugar chain has a structure selected from the group consisting of GalNAc-Gal-Glc-Cer and Neu5Ac-Gal-Glu-Cer force. Strand-modified ribosome. (Item 238) Ribosome proximal end force of the sugar chain selected from the group consisting of GalNAc j8 1, 4Gal j8 1, 4Gl C j 8 1, ICer and Neu5Ac α2, 3Gal j8 1, 4Gl U j 8 1, ICer 209. The sugar chain-modified ribosome according to Item 237, which has the structure of: (Item 239) Liposome proximal end force of the sugar chain The following structure: R 1 — L 2 — L 3 — L 4 — L 5 — Cer 6 where R 1 is independent Or L 2 is Gal, L 3 is GalN Ac, L 4 is Gal, and L 5 is Glc. Yes, wherein Cer 6 is present at the most proximal position of the ribosome, the sugar chain-modified ribosome according to item 1. (Item 240) Bond between L 2 and L 3 , bond between L 3 and L 4 , bond between L 4 and L 5 and bond force between L 5 and Cer 6 At least one sugar chain bond selected from the group is defined, wherein the bond between the L 2 and L 3 is a β 1,3 bond, and between the L 3 and L 4 The bond is β 1,4 bond, the bond between L 4 and L 5 is β 1,4 bond, and the bond between L 5 and Cer 6 is β 1,1 bond. The sugar chain-modified ribosome according to Item 239. (Item 241) The bond between L 2 and L 3 , the bond between L 3 and L 4 , the bond between L 4 and L 5 and the bond force between L 5 and Cer 6 And at least two sugar chain bonds are defined, wherein the bond between the L 2 and L 3 is a / 3 1,3 bond, and between the L 3 and L 4 The bond is / 3 1, 4 bond, the bond between L 4 and L 5 is β 1, 4 bond, and the bond between L 5 and Cer 6 is β 1, 1 bond. The sugar chain-modified ribosome according to Item 239, wherein (Item 242) The bond between L 2 and L 3 , the bond between L 3 and L 4 , the bond between L 4 and L 5 and the bond force between L 5 and Cer 6 And at least three sugar chain bonds selected from the above, wherein the bond between L 2 and L 3 is a β 1,3 bond, and between L 3 and L 4 The bond is / 3 1, 4 bond, the bond between L 4 and L 5 is / 3 1, 4 bond, and the bond between L 5 and Cer 6 is / 3 1, 1 241. The sugar chain-modified ribosome according to Item 239, which is a bond. (Item 243) Bonds between L 2 and L 3 , bonds between L 3 and L 4 , bonds between L 4 and L 5 and bonds between L 5 and Cer 6 All of the glycan bonds selected Where the bond between the L 2 and L 3 is a β 1,3 bond, the bond between the L 3 and L 4 is a β 1,4 bond, and the L 240. The sugar chain-modified ribosome according to Item 239, wherein the bond between 4 and L 5 is a β 1,4 bond, and the bond between L 5 and Cer 6 is a j8 1,1 bond. (Item 244) The sugar chain-modified ribosome according to item 239, wherein the ribosome proximal end of the sugar chain has a structure of Gal-GalNAc Gal Glc Cer. (Item 245) The sugar chain-modified ribosome according to item 244, wherein the ribosome proximal end of the sugar chain has a structure of Gal jS1, 3GalNAc β1, 4Gal j81, 4Glc β1, lCer. (Item 246) ribosomal proximal end of the sugar chain, the following structure:! ^ Over 2 -1 over 4 - 1 1 over Ji 61: 7 has, wherein said R 1 is independently , Hydrogen or any sugar chain, the L 2 is Neu5Ac, the L 3 is Gal, the L 4 is GalNac, and the L 5 is Gal The sugar chain-modified ribosome according to Item 1, wherein L 6 is Glc, and Cer 7 is present at the most proximal end of the liposome. (Item 247) Bond between L 2 and L 3 , bond between L 3 and L 4 , bond between L 4 and L 5 , bond between L 5 and L 6 and L At least one sugar chain bond selected from the group consisting of the binding force between 6 and Cer 7 is defined, and the bond between L 2 and L 3 is α 2, 3 bond. The bond between L 3 and L 4 is a j8 1,3 bond, the bond between L 4 and L 5 is a / 3 1,4 bond, and the bond between L 5 and L 6 27. The sugar chain-modified ribosome according to Item 246, wherein the bond between is β 1, 4 and the bond between L 6 and Cer 7 is a β 1, 1 bond. (Item 248) Bond between L 2 and L 3 , Bond between L 3 and L 4 , Bond between L 4 and L 5 , Bond between L 5 and L 6 and L At least two sugar chain bonds selected from the group consisting of the binding force between 6 and Cer 7 are defined, where the bond between the L 2 and L 3 is a 2, 3 bond The bond between L 3 and L 4 is a / 3 1,3 bond, the bond between L 4 and L 5 is a j8 1,4 bond, and the bond between L 5 and L 6 247. The sugar chain-modified ribosome according to Item 246, wherein the bond between is / 3 1, 4 and the bond between L 6 and Cer 7 is | 8 1, 1 bond. (Item 249) The bond between L 2 and L 3 , the bond between L 3 and L 4 , the bond between L 4 and L 5 , the bond between L 5 and L 6 and L There are at least three glycan bonds selected from the group consisting of the binding forces between 6 and Cer 7 , where the bond between L 2 and L 3 is an α 2,3 bond. The bond between L 3 and L 4 is 1, 3 bond, the bond between L 4 and L 5 is 1, 4 bond, and the bond between L 5 and L 6 247. The sugar chain-modified ribosome according to Item 246, wherein is β 1,4 and the bond between L 6 and Cer 7 is a β 1,1 bond. (Item 250) Coupling between L 2 and L 3, and L 3 A bond between L 4 , a bond between L 4 and L 5 , a bond between L 5 and L 6 and a bond force between L 6 and Cer 7 A sugar chain bond is defined, where the bond between L 2 and L 3 is an α 2,3 bond, and the bond between L 3 and L 4 is a β 1,3 bond. The bond between L 4 and L 5 is / 3 1, 4 bond, and the bond between L 5 and L 6 is / 3 1, 4, and the bond between L 6 and Cer 247. The sugar chain-modified liposome according to Item 246, wherein the bond with 7 is a / 31,1 bond. (Item 251) The bond between L 2 and L 3 , the bond between L 3 and L 4 , the bond between L 4 and L 5 , the bond between L 5 and L 6 and L 6 and Cer 7 4 single glycosylation also less selected from the binding force becomes a group are defined between, wherein a bond Gahi 2, 3 coupled between said L 2 and L 3 The bond between L 3 and L 4 is a / 3 1,3 bond, the bond between L 4 and L 5 is a / 3 1,4 bond, and L 5 and L 247. The sugar chain-modified ribosome according to Item 246, wherein the bond between 6 is / 3 1, 4 and the bond between L 6 and Cer 7 is a / 3 1, 1 bond. (Item 252) Bond between L 2 and L 3 , Bond between L 3 and L 4 , Bond between L 4 and L 5 , Bond between L 5 and L 6 and L All of the sugar chain bonds selected from the group consisting of the binding force between 6 and Cer 7 are defined, where the bond between L 2 and L 3 is an α 2,3 bond, The bond between L 3 and L 4 is β 1,3 bond, and L 4 and L 4

5との間の結合が j8 1, 4結合であり、該 L5と L6との間の結合が /3 1, 4であり、該 L6と C er7との間の結合とが |8 1, 1結合である、項目 246に記載の糖鎖修飾リボソーム。（項 目 253)前記糖鎖のリボソーム近位端が、 Neu5Ac— Gal— GalNAc— Gal— Glc— Cerの構造を有する、項目 246に記載の糖鎖修飾リボソーム。（項目 254)前記糖鎖 のリボソーム近位端力 Neu5Ac a 2、 3Gal β 1、 3GalNAc β 1, 4Gal β 1, 4Glc β 1, ICerの構造を有する、項目 253に記載の糖鎖修飾リボソーム。（項目 255)前記 糖鎖のリボソーム最近位端の糖力 Glcまたは GlcNAcであり、かつ前記糖鎖のリポ ソーム最遠位端の糖力 SGaほたは Fucである、項目 1に記載の糖鎖修飾リボソーム。 ( 項目 256)前記糖鎖のリボソーム最近位端の糖が、 GlcNAcであり、かつ前記糖鎖の リボソーム最遠位端の糖が Manである、項目 1に記載の糖鎖修飾リボソーム。 （項目 2 57)以下： Fuc a l, 2Gal j8 1, 3GlcNAC j8 1, 3Gal j8 1, 4Glc、Fuc a l, 2Gal j8 1, 4 (Fuc a 1, 3) GlcNAc, Gal a 1, 3 (Fuc a 1, 2) Gal, Gal jS 1, 3 (Fuc a 1, 4) GlcNAc, Gal jS 1, 3 (Fuc a l, 4) GlcNAc j8 1, 3Gal j8 1, 4Glc、 Gal jS 1, 4 (Fu cal, 3)GlcNAcゝ GaljSl, 4Glc、 Neu5Ac a 2, 6GalNAc a l— 0— L— Ser、 3 '— (O— SO H) Gal β 1, 3 (Fuc a 1, 4)GlcNAc、 Fucal, 2Galj81, 4 (Fuc a Bond between 5 is j8 1, 4 bond, bond / 3 1, 4 between the L 5 and L 6, and the coupling between said L 6 and C er 7 | 246. The sugar chain-modified ribosome according to Item 246, which is an 8 1,1 bond. (Item 253) The sugar chain-modified ribosome according to item 246, wherein the ribosome proximal end of the sugar chain has a structure of Neu5Ac-Gal-GalNAc-Gal-Glc-Cer. (Item 254) The sugar chain-modified ribosome according to item 253, wherein the sugar chain has a structure of ribosome proximal end force Neu5Ac a 2, 3Gal β1, 3GalNAc β1, 4Gal β1, 4Glc β1, ICer. (Item 255) A sugar chain according to item 1, which is a sugar force Glc or GlcNAc at the most proximal end of the ribosome of the sugar chain and a sugar force SGa or Fuc at the most distal end of the liposome of the sugar chain. Modified ribosome. (Item 256) The sugar chain-modified ribosome according to item 1, wherein the sugar at the most proximal end of the ribosome of the sugar chain is GlcNAc and the sugar at the most distal end of the ribosome of the sugar chain is Man. (Item 2 57) Following: Fuc al, 2Gal j8 1, 3GlcNA C j 8 1, 3Gal j8 1, 4Glc, Fuc al, 2Gal j8 1, 4 (Fuc a 1, 3) GlcNAc, Gal a 1, 3 (Fuc a 1, 2) Gal, Gal jS 1, 3 (Fuc a 1, 4) GlcNAc, Gal jS 1, 3 (Fuc al, 4) GlcNAc j8 1, 3Gal j8 1, 4Glc, Gal jS 1, 4 (Fu cal, 3) GlcNAc ゝ GaljSl, 4Glc, Neu5Ac a 2, 6GalNAc al— 0— L— Ser, 3 '— (O— SO H) Gal β 1, 3 (Fuc a 1, 4) GlcNAc, Fucal, 2Galj81, 4 (Fuc a

3  Three

1, 3)Glc、 GaljS 1, 3GlcNAC j81, 3Galj81, 4Glc、 GaljS 1, 6GlcNAcゝ GalN Aca 1-O-L-Ser, Neu5Ac a 2, 3Galj81, 3 (Fuc a 1, 4)GlcNAc、 Neu5A ca2, 3Galj81, 4(Fuca 1, 3) GlcNAc, Neu5Ac a 2, 3Gal j81, 4Glc、 Gala 1, 3Gal、 Fuca 1, 2Gal、 GaljS 1, 3GalNAc、 GaljS 1, 4 (Fuc a 1, 3)Glc、 Gal β 1, 4GlcNAc、 GalNAc al, 3 (Fuc al, 2) Gal, GaljS 1, 3GalNAc β 1, 4Gal β 1, 4Glcj81, lCer+Neu5Aca2, 3Galj81, 3GalNAcj81, 4 (Neu5Ac a 2 , 3)Galj81, 4Glcj81, ICerゝ Mana 1, 2Man、 Mana 1, 2Mana 1, 6 (Man a 1, 2Mana 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 2Mana 1, 3)Manj81, 4G1 cNAcjS 1, 4GlcNAcゝ Mana 1, 2Mana 1, 6 (Man a 1, 3) Man a 1, 6 (Man 1, 2Mana 1, 2Mana 1, 3)Manj81, 4GlcNAcj81, 4GlcNAc、 Mana 1, 3M an、 Mana 1, 4Man、 Mana 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 2Mana 1, 3)Manj81, 4GlcNAcj81, 4GlcNAc, Mana 1, 6 (Man a 1, 3) Mana 1, 6 (Man a 1, 2Mana 1, 3)Manj81, 4GlcNAcj81, 4GlcNAc、 Man a 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 3)Manj81, 4GlcNAcj81, 4GlcN Acおよび Man a 1, 6 (Man a 1, 3)Manj81, 4GlcNAcj81, 4GlcNAcならびに それらの 2つ以上の組み合わせ力 なる群より選択される糖鎖が結合して 、る、糖鎖 修飾リボソーム。（項目 258)前記糖鎖が、経口投与につ!ヽて適切な修飾結合密度で 含まれる、項目 1から 257のいずれか 1項に記載の糖鎖修飾リボソーム。（項目 259) 前記修飾結合密度が、少なくとも 0.0075mg糖鎖 Zmg脂質である、項目 258に記 載の糖鎖修飾リボソーム。（項目 260) Fucal, 2Galj81, 3GlcNAC j81, 3Gal β 1 , 4Glc、 Fucal, 2Galj81, 4 (Fuc a 1, 3)GlcNAc、 Gala 1, 3 (Fuc a 1, 2) Gal 、 Galj81, 3 (Fuc a 1 , 4) GlcN Ac , Gal j81 , 3 (Fucal, 4)GlcNACj81, 3Gal j81, 4Glc、 GaljS 1, 4 (Fuc a 1, 3)GlcNAc、 GaljS 1, 4Glc、 Neu5Ac a 2, 6Ga INAcal— O— L— Ser、 3，一（O— SO H)Galj81, 3 (Fucal, 4)GlcNAcゝ Fu 1, 3) Glc, GaljS 1, 3GlcNA C j 81, 3Galj81, 4Glc, GaljS 1, 6GlcNAc ゝ GalN Aca 1-OL-Ser, Neu5Ac a 2, 3Galj81, 3 (Fuc a 1, 4) GlcNAc, Neu5A ca2, 3Galj81, 4 (Fuca 1, 3) GlcNAc, Neu5Ac a 2, 3Gal j81, 4Glc, Gala 1, 3Gal, Fuca 1, 2Gal, GaljS 1, 3GalNAc, GaljS 1, 4 (Fuc a 1, 3) Glc, Gal β 1, 4GlcNAc, GalNAc al, 3 (Fuc al, 2) Gal, GaljS 1, 3GalNAc β 1, 4Gal β 1, 4Glcj81, lCer + Neu5Aca2, 3Galj81, 3GalNAcj81, 4 (Neu5Ac a 2, 3) Galj81, 4Glcj81, ICerゝ Mana 1, 2Man, Mana 1, 2Mana 1, 6 (Man a 1, 2Mana 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 2Mana 1, 3) Manj81, 4G1 cNAcjS 1, 4GlcNAc ゝ Mana 1, 2Mana 1, 6 (Man a 1, 3) Man a 1, 6 (Man 1, 2Mana 1, 2Mana 1, 3) Manj81, 4GlcNAcj81, 4GlcNAc, Mana 1, 3M an, Mana 1, 4Man, Mana 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 2Mana 1, 3) Manj81, 4GlcNAcj81, 4GlcNAc, Mana 1, 6 (Man a 1, 3) Mana 1, 6 (Man a 1, 2Mana 1, 3) Manj81, 4GlcNAcj81, 4GlcNAc, Man a 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 3) Manj81, 4GlcNAcj81, 4GlcN Ac and Man a 1, 6 (Man a 1, 3) A sugar chain-modified ribosome in which sugar chains selected from the group consisting of Manj81, 4GlcNAcj81, 4GlcNAc and combinations of two or more thereof are combined. (Item 258) The sugar chain-modified ribosome according to any one of items 1 to 257, wherein the sugar chain is contained at a modified bond density suitable for oral administration. (Item 259) The sugar chain-modified ribosome according to item 258, wherein the modified binding density is at least 0.0075 mg sugar chain Z mg lipid. (Item 260) Fucal, 2Galj81, 3GlcNA C j 81, 3Gal β1, 4Glc, Fucal, 2Galj81, 4 (Fuc a 1, 3) GlcNAc, Gala 1, 3 (Fuc a 1, 2) Gal, Galj81, 3 ( Fuc a 1, 4) GlcN Ac, Gal j81, 3 (Fucal, 4) GlcNA Cj 81, 3Gal j81, 4Glc, GaljS 1, 4 (Fuc a 1, 3) GlcNAc, GaljS 1, 4Glc, Neu5Ac a 2, 6Ga INAcal— O— L— Ser, 3, 1 (O— SO H) Galj81, 3 (Fucal, 4) GlcNAc ゝ Fu

3  Three

cal, 2Galj81, 4 (Fucal, 3)Glc、 GaljS 1, 3GlcNAC j81, 3Galj81, 4Glc、 G aljSl, 6GlcNAcゝ GalNAca l— O—L—Serゝ Neu5Ac a 2, 3Galj81, 3 (Fuc a 1, 4) GlcNAc、 Neu5Ac a 2, 3Gal βΐ, 4 (Fuc a 1, 3) GlcNAc、 Neu5Ac a 2, 3Galj81, 4Glc、 Gala 1, 3Gal、 Fuca 1, 2Gal、 GaljS 1, 3GalNAc、 GaljS 1 , 4 (Fuc a 1, 3) Glc、 GaljS 1, 4GlcNAc、 GalNAc a 1, 3 (Fuc a 1, 2) Gal、 Gal β 1, 3GalNAC j81, 4Galj81, 4GlC j81, lCer+Neu5Ac a 2, 3Galj81, 3Gal NAc j81, 4 (Neu5Ac a 2, 3)Galj81, 4Glcj81, lCer、 Mana 1, 2Man、 Man 1, 2Mana 1, 6 (Man a 1, 2Mana 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 2 Mana 1, 3)Manj81, 4GlcNAcj81, 4GlcNAcゝ Man a 1, 2Mana 1, 6 (Man 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 2Mana 1, 3)Manj81, 4GlcNAc β 1, 4GlcNAc、 Mana 1, 3Man、 Mana 1, 4Man、 Mana 1, 6 (Man a 1, 3) Ma na 1, 6 (Man a 1, 2Mana 1, 2Mana 1, 3)Manj81, 4GlcNAcj81, 4GlcNA c、 Mana 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 3) Man β 1, 4G1 cNAcjS 1, 4GlcNAcゝ Mana 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 3) Man β 1, 4GlcNAcj81, 4GlcNAcぉょびManQ；l, 6 (Man a 1, 3) Man β 1, 4GlcN Acj81, 4GlcNAcならびにそれらの 2つ以上の組み合わせからなる群より選択され る糖鎖が、少なくとも 0.0075mg糖鎖/ mg脂質の修飾結合密度で含まれる、項目 2 58に記載の糖鎖修飾リボソーム。（項目 261)Manal, 2Man、 Manal, 4Manお よび Mana 1, 3Manからなる群より選択される糖鎖力 約 0.0075mg糖鎖 Zmg脂 質の修飾結合密度で含まれる、項目 258に記載の糖鎖修飾リボソーム。（項目 262) Manal, 6 (Manal, 3)Manj81, 4GlcNAcj81, 4GlcNAc力 約 0.0205mg 糖鎖 Zmg脂質の修飾結合密度で含まれる、項目 258に記載の糖鎖修飾リボソーム 。 （項目 263) Fucal, 2Gal、 Fucal, 2Galj81, 3GlcNACj81, 3Galj81, 4Glc 、 GalNAc a 1, 3 (Fuc a 1, 2) Gal, GaljS 1, 3GalNAc、 Gal j81, 3 (Fuc a 1, 4) GlcNAcjS 1, 3Galj81, 4Glc、 Galal, 3 (Fucal, 2) Gal, GaljS 1, 4Glc、 Gal j81, 4GlcNAc、 GaljS 1, 4 (Fuc a 1, 3)GlcNAc、 Fuca 1, 2Galj81, 4 (Fuc a 1, 3) GlcNAc, Neu5Ac a 2, 6GalNAc a l— 0—L— Ser、 GaljS 1, 4GlcNAc および GaljSl, 3 (Fucal, 4)GlcNAcからなる群より選択される糖鎖力 約 0.02 5mg糖鎖 Zmg脂質の修飾結合密度で含まれる、項目 258に記載の糖鎖修飾リポソ ーム。（項目 264) Man a 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 3) Man β 1, 4 GlcNAciS 1, 4GlcNAc力 約 0.0275mg糖鎖 Zmg脂質の修飾結合密度で含ま れる、項目 258に記載の糖鎖修飾リボソーム。（項目 265)Manal, 6(Manal, 3 )Mana 1, 6(Mana 1, 2Mana 1, 3)Manj81, 4GlcNAcj81, 4GlcNAc力 約 0.03 lmg糖鎖, mg脂質の修飾結合密度で含まれる、項目 258に記載の糖鎖修飾 リボソーム。（項目 266) Man α 1, 6(Mana 1, 3)Mana 1, 6(Mana 1, 2Mana 1, 2Manal, 3)Manj81, 4GlcNAcj81, 4GlcNAc力 約 0.035mg糖鎖 Zmg 脂質の修飾結合密度で含まれる、項目 258に記載の糖鎖修飾リボソーム。（項目 26 7) Mana 1, 2Mana 1, 6(Mana 1, 3)Mana 1, 6(Mana 1, 2Mana 1, 2Ma nal, 3)Manj81, 4GlcNAC j81, 4GlcNAc力 約 0.0385mg糖鎖 Zmg脂質の 修飾結合密度で含まれる、項目 258に記載の糖鎖修飾リボソーム。 （項目 268) Man 1, 2Mana 1, 6(Mana 1, 2Mana 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 2 Mana 1, 3)Manj81, 4GlcNACj81, 4GlcNAc力 約 0.042mg糖鎖 Zmg脂質 の修飾結合密度で含まれる、項目 258に記載の糖鎖修飾リボソーム。（項目 269) Fu ca 1, 2Galj81, 4(Fuca 1, 3)Glc、 Neu5Ac a 2, 3Galj81, 4Glc、 GaljS 1, 3 GalNAc、 GaljS 1, 3GlcNAC j81, 3Galj81, 4Glc、 GaljS 1, 4(Fucal, 3)Glc 、 Fuc a 1 , 2Gal、 GalNAc a 1, 3 (Fuc a 1, 2) Gal、 GalNAc al— O— L— Ser GaljS 1, 6GlcNAcゝ Galal, 3Gal、 3，一（O— SO H)Galj81, 3 (Fuc a 1, 4)G1 cal, 2Galj81, 4 (Fucal, 3) Glc, GaljS 1, 3GlcNA C j 81, 3Galj81, 4Glc, GaljSl, 6GlcNAc ゝ GalNAca l— O—L—Ser ゝ Neu5Ac a 2, 3Galj81, 3 (Fuc a 1, 4) GlcNAc, Neu5Ac a 2, 3Gal βΐ, 4 (Fuc a 1, 3) GlcNAc, Neu5Ac a 2, 3Galj81, 4Glc, Gala 1, 3Gal, Fuca 1, 2Gal, GaljS 1, 3GalNAc, GaljS 1, 4 (Fuc a 1, 3) Glc, GaljS 1, 4GlcNAc, GalNAc a 1, 3 (Fuc a 1, 2) Gal, Gal β 1, 3GalNA C j 81, 4Galj81, 4Gl C j 81, lCer + Neu5Ac a 2 , 3Galj81, 3Gal NAc j81, 4 (Neu5Ac a 2, 3) Galj81, 4Glcj81, lCer, Mana 1, 2Man, Man 1, 2Mana 1, 6 (Man a 1, 2Mana 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 2 Mana 1, 3) Manj81, 4GlcNAcj81, 4GlcNAc ゝ Man a 1, 2Mana 1, 6 (Man 1, 3) Man a 1, 6 (Man a 1, 2Mana 1, 2Mana 1, 3) Manj81, 4GlcNAc β 1, 4GlcNAc, Mana 1, 3Man, Mana 1, 4Man, Mana 1, 6 (Man a 1, 3) Mana 1, 6 (Man a 1, 2Mana 1, 2Mana 1, 3) Manj81, 4GlcNAcj81 , 4GlcNA c, Mana 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 2 Mana 1, 3) Man β 1, 4G1 cNAcjS 1, 4GlcNAc ゝ Mana 1, 6 (Man a 1, 3 ) Man a 1, 6 (Man a 1, 3) Man β 1, 4GlcNAcj81, 4GlcNAc and ManQ; l, 6 (Man a 1, 3) Man β 1, 4GlcN Acj81, 4GlcNAc and two or more of them Set Carbohydrate that will be selected from the group consisting of Align is included in a modified bond density of at least 0.0075mg carbohydrate / mg lipid, sugar chain modification ribosome of claim 2 58. (Item 261) Sugar chain strength selected from the group consisting of Manal, 2Man, Manal, 4Man and Mana 1, 3Man About 0.0075 mg sugar chain Zmg The sugar chain according to item 258, which is included in the modified bond density of the fat Modified ribosome. (Item 262) The sugar chain-modified ribosome according to item 258, comprising Manal, 6 (Manal, 3) Manj81, 4GlcNAcj81, 4GlcNAc force about 0.0205 mg sugar chain Zmg lipid modified binding density. (Item 263) Fucal, 2Gal, Fucal, 2Galj81, 3GlcNA Cj 81, 3Galj81, 4Glc, GalNAc a 1, 3 (Fuc a 1, 2) Gal, GaljS 1, 3GalNAc, Gal j81, 3 (Fuc a 1, 4) GlcNAcjS 1, 3Galj81, 4Glc, Galal, 3 (Fucal, 2) Gal, GaljS 1, 4Glc, Gal j81, 4GlcNAc, GaljS 1, 4 (Fuc a 1, 3) GlcNAc, Fuca 1, 2Galj81, 4 (Fuc a 1 3) GlcNAc, Neu5Ac a 2, 6GalNAc al— 0—L— Sugar chain strength selected from the group consisting of Ser, GaljS 1, 4GlcNAc and GaljSl, 3 (Fucal, 4) GlcNAc About 0.02 5 mg Sugar chain Zmg 258. The sugar chain-modified liposome according to Item 258, which is contained at a modified bond density. (Item 264) Man a 1, 6 (Man a 1, 3) Man a 1, 6 (Man a 1, 3) Man β 1, 4 261. GlcNAciS 1, 4 GlcNAc force Approx. 0.0275 mg Sugar chain The sugar chain-modified ribosome according to Item 258, which is contained at a modified binding density of Zmg lipid. (Item 265) Manal, 6 (Manal, 3) Mana 1, 6 (Mana 1, 2Mana 1, 3) Manj81, 4GlcNAcj81, 4GlcNAc force Approximately 0.03 lmg sugar chain, included in modified binding density of mg lipid, in item 258 The sugar chain-modified ribosome described. (Item 266) Man α 1, 6 (Mana 1, 3) Mana 1, 6 (Mana 1, 2 Mana 1, 2 Manal, 3) Manj81, 4GlcNAcj81, 4GlcNAc force Approx. 0.035 mg Sugar chain Zmg Included in modified binding density of lipid , The sugar chain-modified ribosome according to Item 258. (Item 26 7) Mana 1, 2Mana 1, 6 (Mana 1, 3) Mana 1, 6 (Mana 1, 2Mana 1, 2Manal, 3) Manj81, 4GlcNA C j 81, 4GlcNAc force Approximately 0.0385 mg Sugar chain Zmg lipid 259. The sugar chain-modified ribosome according to Item 258, which is included at the modified bond density of (Item 268) Man 1, 2 Mana 1, 6 (Mana 1, 2 Mana 1, 3) Man a 1, 6 (Man a 1, 2 Mana 1, 2 Mana 1, 3) Manj81, 4GlcNA Cj 81, 4GlcNAc force Approx. 0.042 mg 259. A sugar chain-modified ribosome according to item 258, which is contained at a modified bond density of sugar chain Zmg lipid. (Item 269) Fu ca 1, 2Galj81, 4 (Fuca 1, 3) Glc, Neu5Ac a 2, 3Galj81, 4Glc, GaljS 1, 3 GalNAc, GaljS 1, 3GlcNA C j 81, 3Galj81, 4Glc, GaljS 1, 4 ( Fucal, 3) Glc, Fuc a 1, 2Gal, GalNAc a 1, 3 (Fuc a 1, 2) Gal, GalNAc al— O— L— Ser GaljS 1, 6GlcNAc ゝ Galal, 3Gal, 3, one (O— SO H) Galj81, 3 (Fuc a 1, 4) G1

3  Three

cNAc、 Neu5Ac a 2, 3Galj81, 4 (Fuc a 1, 3) GlcNAcおよび Neu5Ac a 2, 3G aljS 1, 3 (Fuc a 1, 4)GlcNAcからなる群より選択される糖鎖力 約 0. 5mg糖鎖 Z mg脂質の修飾結合密度で含まれる、項目 258に記載の糖鎖修飾リボソーム。 （項目 270)Galj81, 3GalNAC j81, 4Galj81, 4GlCj81, lCer+Neu5Ac α 2, 3Galj8 1, 3GalNAC j81, 4(Neu5Aca2, 3)Galj81, 4GlCj81, ICer力 約 0. 75mg糖 鎖 Zmg脂質の修飾結合密度で含まれる、項目 258に記載の糖鎖修飾リボソーム。 ( 項目 271) Fuc al, 2Gal、 GalNAc al, 3(Fucal, 2) Gal, GaljS 1, 3GalNAc 、 GaljS 1, 4Glcおよび GaljS 1, 4 (Fuc a 1, 3) Glcからなる群より選択される糖鎖が 、約 0.025〜約 0. 5mg糖鎖 Zmg脂質の修飾結合密度で含まれる、項目 258に記 載の糖鎖修飾リボソーム。 （項目 272)前記糖鎖カ^ンカ一を介して前記リボソームの 膜に結合されている、項目 1から 271のいずれ力 1項に記載の糖鎖修飾リボソーム。 ( 項目 273)前記リンカ一が生体由来蛋白質である、項目 272に記載の糖鎖修飾リポ ノーム。 （項目 274)前記リンカ一がヒト由来蛋白質である、項目 273に記載の糖鎖修 飾リボソーム。（項目 275)前記リンカ一がヒト由来血清蛋白質である、項目 274に記 載の糖鎖修飾リボソーム。 （項目 276)前記リンカ一がヒト血清アルブミンまたはゥシ血 清アルブミンである項目 272に記載の糖鎖修飾リボソーム。（項目 277)前記糖鎖修 飾リボソームが、リボソーム膜またはリンカ一の少なくとも一方に親水性ィ匕合物を結合 させることにより親水性ィ匕されている、項目 1から 276のいずれか 1項に記載の糖鎖 修飾リボソーム。（項目 278)前記リボソームと前記糖鎖が、ペプチド結合により結合し ている、項目 1から 271のいずれか 1項に記載の糖鎖修飾リボソーム。（項目 279)前 記リボソームの膜上にあるガンダリオシドと前記リンカ一が共有結合により結合し、該 リンカ一の末端力 ペプチド結合により結合している、項目 2 Sugar chain strength selected from the group consisting of cNAc, Neu5Ac a 2, 3Galj81, 4 (Fuc a 1, 3) GlcNAc and Neu5Ac a 2, 3G aljS 1, 3 (Fuc a 1, 4) GlcNAc About 0.5 mg sugar 259. Sugar chain-modified ribosome according to item 258, which is included at a modified bond density of chain Z mg lipid. (Item 270) Galj81, 3GalNA C j 81, 4Galj81, 4Gl Cj 81, lCer + Neu5Ac α 2, 3Galj8 1, 3GalNA C j 81, 4 (Neu5Aca2, 3) Galj81, 4Gl Cj 81, ICer force approx. 258. Sugar chain-modified ribosome according to item 258, which is included in the modified binding density of chain Zmg lipid. (Item 271) Sugar selected from the group consisting of Fuc al, 2Gal, GalNAc al, 3 (Fucal, 2) Gal, GaljS 1, 3GalNAc, GaljS 1, 4Glc and GaljS 1, 4 (Fuc a 1, 3) Glc The sugar chain-modified ribosome according to item 258, wherein the chain is contained at a modified bond density of about 0.025 to about 0.5 mg sugar chain Zmg lipid. (Item 272) The sugar chain-modified ribosome according to any one of items 1 to 271, wherein the sugar chain-modified ribosome is bound to the membrane of the ribosome via the sugar chain handler. ( Item 273) The sugar chain-modified liposome according to Item 272, wherein the linker is a biological protein. (Item 274) The sugar chain-modified ribosome according to Item 273, wherein the linker is a human-derived protein. (Item 275) The sugar chain-modified ribosome according to item 274, wherein the linker is a human-derived serum protein. (Item 276) The sugar chain-modified ribosome according to item 272, wherein the linker is human serum albumin or urine serum albumin. (Item 277) In any one of items 1 to 276, the sugar chain-modified ribosome is made hydrophilic by binding a hydrophilic compound to at least one of the ribosome membrane or the linker. The sugar chain-modified ribosome described. (Item 278) The sugar chain-modified ribosome according to any one of items 1 to 271, wherein the ribosome and the sugar chain are bound by a peptide bond. (Item 279) The above-mentioned linker gandioside on the ribosome membrane and the linker are bound by a covalent bond, and the terminal force of the linker is bound by a peptide bond.

72に記載の糖鎖修飾リボソーム。（項目 280)前記親水性ィ匕合物力 トリス (ヒドロキシ アルキル)アミノアルカンである、項目 277に記載の糖鎖修飾リボソーム。（項目 281) リボソーム番号 27、 29、 40、 45、 50、 53、 56、 67、 68、 69、 70、 71、 87、 105、 11 7、 120、 125、 139、 142、 150、 152、 153、 154、 175、 184、 186、 197、 204、 2 24、 225、 230、 237、 240、 273、 285、 288、 290また ίま 301の!ヽずれ力の構造を 有する、糖鎖修飾リボソーム。（項目 282)項目 1から 281のいずれか 1項に記載の糖 鎖修飾リボソームを含む、静脈投与用及び経口投与用薬物送達媒体。（項目 283) 項目 1から 281のいずれ力 1項に記載の糖鎖修飾リボソームと投与が所望される物質 とを含む、静脈投与用及び経口投与用組成物。（項目 284)前記所望される物質が、 診断薬、研究試薬および機能性食品から選択される物質である、項目 283に記載の 静脈投与用及び経口投与用組成物。 （項目 285)  73. The sugar chain-modified ribosome according to 72. (Item 280) The sugar chain-modified ribosome according to Item 277, wherein the hydrophilic property is a tris (hydroxyalkyl) aminoalkane. (Item 281) Ribosome number 27, 29, 40, 45, 50, 53, 56, 67, 68, 69, 70, 71, 87, 105, 11 7, 120, 125, 139, 142, 150, 152, 153 154, 175, 184, 186, 197, 204, 2 24, 225, 230, 237, 240, 273, 285, 288, 290 or 301, a glycosylated ribosome having a structure of shear force. (Item 282) A drug delivery vehicle for intravenous administration and oral administration, comprising the sugar chain-modified ribosome according to any one of items 1 to 281. (Item 283) Any one of Items 1 to 281 A composition for intravenous administration and oral administration comprising the sugar chain-modified ribosome according to Item 1 and a substance desired to be administered. (Item 284) The composition for intravenous administration or oral administration according to item 283, wherein the desired substance is a substance selected from diagnostic agents, research reagents and functional foods. (Item 285)

前記診断薬が、 DNAプローブ診断薬、 X線造影剤、放射性試薬、放射性造影剤、 放射性診断薬、蛍光試薬、蛍光造影剤、蛍光診断薬、 CT用造影剤、 PET用造影剤 、 SPECT用造影剤、 MRI用造影剤、エイズ診断薬、血液学的検査用試薬、機能検 查用試薬、微生物検査用試薬、分子イメージング、インビボイメージング、蛍光ィメー ジング、発光イメージング、セルソーター、 PETおよび SPECTからなる群より選択さ れる診断薬である、項目 284に記載の静脈投与用及び経口投与用組成物。 (項目 286)前記研究試薬が、組換え DNA技術、ィムノアツセィ、ハイブリダィゼーシ ヨン法、酵素アツセィにおいて使用される試薬である、項目 284に記載の静脈投与用 及び経口投与用組成物。（項目 287)前記機能性食品が、ビタミン、ミネラル、ァミノ 酸、炭水化物を含む食品である、項目 284に記載の静脈投与用及び経口投与用組 成物。（項目 288)項目 1から 281のいずれか 1項に記載の糖鎖修飾リボソームと医薬 活性成分をさらに含む、静脈投与用及び経口投与用薬学的組成物。（項目 289)前 記糖鎖修飾リボソーム力 薬剤または遺伝子を封入している力、または結合している 、項目 288に記載の静脈投与用及び経口投与用薬学的組成物。（項目 290) 前記薬剤が、バイオ医薬品またはバイオ治療用物質 (例えば、 siRNA、 shRNA、 siRN A誘導体、 shRNA誘導体、 RNA、 RNA誘導体、 DNA、 DNA誘導体、モノクローナル抗 体、ワクチン、インターフェロン、ホルモン、プロスタグランジン、転写因子、組換えタン パク質、抗体医薬、核酸〉 The diagnostic agent is a DNA probe diagnostic agent, X-ray contrast agent, radioactive reagent, radioactive contrast agent, radioactive diagnostic agent, fluorescent reagent, fluorescent contrast agent, fluorescent diagnostic agent, CT contrast agent, PET contrast agent, SPECT contrast agent Agents, MRI contrast agents, AIDS diagnostic agents, hematology testing reagents, functional testing reagents, microbial testing reagents, molecular imaging, in vivo imaging, fluorescence imaging, luminescence imaging, cell sorter, PET and SPECT 284. A composition for intravenous administration and oral administration according to item 284, which is a diagnostic agent selected more. (Item 286) The composition for intravenous administration and oral administration according to Item 284, wherein the research reagent is a reagent used in recombinant DNA technology, immunoassay, hybridization method, enzyme assay. (Item 287) The composition for intravenous and oral administration according to item 284, wherein the functional food is a food containing vitamins, minerals, amino acids, and carbohydrates. (Item 288) A pharmaceutical composition for intravenous administration and oral administration, further comprising the sugar chain-modified ribosome according to any one of items 1 to 281 and a pharmaceutically active ingredient. (Item 289) The pharmaceutical composition for intravenous administration and oral administration according to Item 288, wherein the sugar chain-modified ribosome force is a force encapsulating or binding a drug or a gene. (Item 290) The drug is a biopharmaceutical or biotherapeutic substance (eg, siRNA, shRNA, siRNA derivative, shRNA derivative, RNA, RNA derivative, DNA, DNA derivative, monoclonal antibody, vaccine, interferon, hormone, prosta Glandin, transcription factor, recombinant protein, antibody drug, nucleic acid>

医薬、遺伝子治療薬)、アルキル化系抗癌剤、代謝拮抗剤、植物由来抗癌剤、抗癌 性抗生物質、生物学的応答調節剤（biological response modifiers： BRM) ·サ イト力イン類、白金錯体系抗癌剤、免疫療法剤、ホルモン系抗癌剤、モノクローナル 抗体等の腫瘍用薬剤、中枢神経用薬剤、末梢神経系，感覚器官用薬剤、呼吸器疾 患治療薬剤、循環器用薬剤、消化器官用薬剤、ホルモン系用薬剤、泌尿器'生殖器 用薬剤、ビタミン ·滋養強壮剤、代謝性医薬品、抗生物質 ·化学療法薬剤、検査用薬 剤、抗炎症剤、眼疾患薬剤、中枢神経系薬剤、自己免疫系薬剤、循環器系薬剤、 糖尿病、高脂血症のような生活習慣病薬剤、副腎皮質ホルモン、免疫抑制剤、抗菌 薬、抗ウィルス薬、血管新生抑制剤、サイト力イン、ケモカイン、抗サイト力イン抗体、 抗ケモカイン抗体、抗サイト力イン.ケモカイン受容体抗体、 siRNA、 shRNA、 miR NA、 smRNA、アンチセンス RNAまたは ODNまたは DNAのような遺伝子治療関連 の核酸製剤、神経保護因子、抗体医薬、分子標的薬、骨粗鬆症，骨代謝改善薬、神 経ペプチド、生理活性ペプチド ·蛋白質力 なる群より選択される項目 289に記載の 静脈投与用及び経口投与用薬学的組成物。 Pharmaceuticals, gene therapy agents), alkylated anticancer agents, antimetabolites, plant-derived anticancer agents, anticancer antibiotics, biological response modifiers (BRM) · site force-ins, platinum complex anticancer agents , Immunotherapeutic agents, hormonal anticancer agents, tumor drugs such as monoclonal antibodies, central nervous system drugs, peripheral nervous system, sensory organ drugs, respiratory disease drugs, cardiovascular drugs, digestive organ drugs, hormonal drugs Drugs, urogenital drugs, vitamins, nourishing tonics, metabolic drugs, antibiotics, chemotherapeutic drugs, test drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, autoimmune drugs, cardiovascular system Drugs, lifestyle diseases such as diabetes mellitus, hyperlipidemia, corticosteroids, immunosuppressants, antibacterial agents, antiviral agents, angiogenesis inhibitors, cytoforce-in, chemokines, anti-site-force-in antibodies, anti Ke Gene therapy-related nucleic acid preparations, neuroprotective factors, antibody drugs, molecular targeting drugs, chemokine receptor antibodies, chemokine receptor antibodies, siRNA, shRNA, miRNA, smRNA, antisense RNA or ODN or DNA, 289. A pharmaceutical composition for intravenous and oral administration according to item 289, selected from the group consisting of osteoporosis, bone metabolism-improving drug, neuropeptide, bioactive peptide / protein power.

(項目 291)前記静脈投与用及び経口投与用組成物が、生物学的因子を必要とする 被験体に該生物学的因子を腫瘍内に送達するためのものであり、前記物質が該生 物学的因子を含む、項目 290に記載の静脈投与用及び経口投与用薬学的組成物。 (項目 292)呼吸器系、循環器系、消化器系、泌尿器，生殖器系、中枢神経系または 末梢神経系の障害を有する哺乳動物を処置するための静脈投与用及び経口投与 用薬物送達媒体であって、該静脈投与用及び経口投与用薬物送達媒体は項目 1に 記載の糖鎖修飾リボソームおよび薬学的に受容可能なキャリアを含み、該糖鎖修飾 リボソームは該障害を処置するのに有効な量の薬剤を含有する、静脈投与用及び経 口投与用薬学的組成物。（項目 293)静脈投与用及び経口投与用組成物の製造の ための、項目 1に記載の糖鎖修飾リボソームの使用。（項目 294)前記静脈投与用及 び経口投与用組成物が、呼吸器系、循環器系、消化器系、泌尿器 ·生殖器系、中枢 神経系または末梢神経系の障害を処置するための医薬を含む、項目 293に記載の 使用。（項目 295)呼吸器系、循環器系、消化器系、泌尿器，生殖器系、中枢神経系 または末梢神経系の障害を有する被験体を処置するための方法であって、該被験 体に、該障害を処置するための静脈投与用及び経口投与用薬学的組成物を投与す る工程を包含し、該静脈投与用及び経口投与用薬学的組成物は糖鎖修飾リポソ一 ムおよび薬学的受容可能なキャリアを含み、該糖鎖修飾リボソームは該障害を処置 するのに有効な量の薬剤を含有する、方法。（項目 296)生物学的因子を必要とする 被験体において、標的部位に該生物学的因子を送達するための方法であって、該 方法は、項目 1に記載の糖鎖修飾リボソームを投与する工程を包含し、該糖鎖修飾リ ポソ一ムは該生物学的因子の有効量を含有する、方法。（項目 297)糖鎖修飾リポソ ームを製造する方法であって、該方法は、以下： （a)リボソームを提供する工程； ( b)必要に応じて、該リボソームを親水性化処理する工程； （c)必要に応じて、該親 水性ィ匕処理されたリボソームにリンカ一を結合させて、リンカ一結合リボソームを生成 する工程;および （d)該リボソームに、糖鎖を結合させて糖鎖修飾リボソームを生成 する工程を包含する、方法。（項目 298)項目 297に記載の糖鎖修飾リボソームを製 造する方法であって、 工程 (b)のリボソームを親水性ィ匕処理する工程力 リボソーム の脂質膜上またはリンカ一上に、直接または間接的に低分子量の親水性ィ匕合物を 結合することによって実施され、 工程 (c)において使用されるリンカ一が、ヒト由来の タンパク質であり、かつ 工程 (d)において、該リボソームに、直接または間接的に糖 鎖を結合させる条件下で、糖鎖を結合させて糖鎖修飾リボソームを生成する工程を 包含する、方法。（項目 299)項目 297に記載の糖鎖修飾リボソームを製造する方法 であって、 工程 (d)において、前記糖鎖と前記リボソームを、経口投与に適切な条 件で結合させる、方法。（項目 300)前記糖鎖が、項目 1〜257のいずれ力 1項に記 載の糖鎖である、項目 297に記載の糖鎖修飾リボソームを製造する方法。（項目 301 )目的の送達部位に薬物を送達するための糖鎖修飾リボソームの製造方法であって 、該方法は、以下： （a)種々の糖鎖密度を有する、該目的の送達部位への送達を 達成する糖鎖修飾リボソームを提供する工程； （b)該糖鎖修飾リボソーム上の糖鎖 密度について、該送達部位への最適な送達を達成する密度を決定する工程;および (c)該薬物を決定された最適な糖鎖修飾リボソームに組み込んで薬物含有リポソ一 ムを生成する工程を包含する、方法。 (Item 291) The composition for intravenous administration and oral administration is for delivering a biological factor into a tumor to a subject in need of the biological factor, and the substance is the living agent. 290. A pharmaceutical composition for intravenous and oral administration according to item 290, comprising physical factors. (Item 292) Intravenous and oral drug delivery vehicles for treating mammals with respiratory, circulatory, digestive, urinary, genital, central or peripheral nervous system disorders The drug delivery vehicle for intravenous administration and oral administration comprises the sugar chain-modified ribosome according to Item 1 and a pharmaceutically acceptable carrier, and the sugar chain-modified ribosome is effective for treating the disorder. A pharmaceutical composition for intravenous and oral administration, comprising an amount of the drug. (Item 293) Use of the sugar chain-modified ribosome according to item 1 for the production of a composition for intravenous administration and oral administration. (Item 294) The composition for intravenous administration and oral administration is a medicament for treating disorders of the respiratory system, circulatory system, digestive system, urinary / genital system, central nervous system or peripheral nervous system. Including use of item 293. (Item 295) A method for treating a subject having a disorder of the respiratory system, the circulatory system, the digestive system, the urinary organs, the genital system, the central nervous system, or the peripheral nervous system, the subject comprising Including a step of administering a pharmaceutical composition for intravenous administration and oral administration for treating a disorder, the pharmaceutical composition for intravenous administration and oral administration comprising a sugar chain-modified liposome and a pharmaceutically acceptable A method wherein the glycosylated ribosome contains an amount of an agent effective to treat the disorder. (Item 296) A method for delivering a biological agent to a target site in a subject in need of the biological agent, the method administering the sugar chain-modified ribosome according to item 1. A method wherein the glycosylated liposome contains an effective amount of the biological agent. (Item 297) A method for producing a sugar chain-modified liposome, which comprises the following steps: (a) a step of providing a ribosome; (b) a step of hydrophilizing the ribosome if necessary (C) if necessary, a step of binding a linker to the lyosomally treated ribosome to form a linker-bound ribosome; and (d) binding a sugar chain to the ribosome to form a sugar. Producing a chain-modified ribosome. (Item 298) A method for producing a sugar chain-modified ribosome according to Item 297, wherein the ribosome of step (b) is treated with a hydrophilic treatment, directly or directly on the lipid membrane or linker of the ribosome. The linker is used by indirectly binding a low molecular weight hydrophilic compound and used in step (c) is a human-derived protein, and in step (d), Sugar directly or indirectly A method comprising a step of binding a sugar chain to produce a sugar chain-modified ribosome under conditions for binding the chain. (Item 299) A method for producing the sugar chain-modified ribosome according to item 297, wherein in the step (d), the sugar chain and the ribosome are bound under conditions suitable for oral administration. (Item 300) A method for producing a sugar chain-modified ribosome according to item 297, wherein the sugar chain is the sugar chain described in any one of items 1 to 257. (Item 301) A method for producing a sugar chain-modified ribosome for delivering a drug to a target delivery site, the method comprising the following: (a) having various sugar chain densities to the target delivery site Providing a sugar chain-modified ribosome that achieves delivery; (b) determining, for the sugar chain density on the sugar chain-modified ribosome, a density that achieves optimal delivery to the delivery site; and (c) the A method comprising the step of incorporating a drug into the determined optimal sugar chain-modified ribosome to produce a drug-containing liposome.

[0186] 以上のように、本発明の好ましい実施形態を用いて本発明を例示してきた力 本発 明は、この実施形態に限定して解釈されるべきものではない。本発明は、特許請求 の範囲によってのみその範囲が解釈されるべきであることが理解される。当業者は、 本発明の具体的な好ましい実施形態の記載から、本発明の記載および技術常識に 基づいて等価な範囲を実施することができることが理解される。本明細書において引 用した特許、特許出願および文献は、その内容自体が具体的に本明細書に記載さ れているのと同様にその内容が本明細書に対する参考として援用されるべきであるこ とが理解される。 [0186] As described above, the power that has exemplified the present invention using the preferred embodiment of the present invention. The present invention should not be construed as being limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range based on the description of the present invention and the common general technical knowledge from the description of specific preferred embodiments of the present invention. Patents, patent applications, and literature references cited in this specification should be incorporated by reference as if the contents themselves were specifically described in the present specification. Is understood.

[0187] 以下、実施例により、本発明の構成をより詳細に説明するが、本発明はこれに限定さ れるものではない。以下において使用した試薬類は、特に言及した場合を除いて、 市販されているものを使用した。  [0187] Hereinafter, the configuration of the present invention will be described in more detail by way of examples, but the present invention is not limited thereto. The reagents used in the following were commercially available unless otherwise specified.

[0188] (実施例 1.リボソームの調製） リボソームは既報の手法 (Yamazaki, N. , Kodama , M. and Gabius, H. —J. (1994) Methods Enzymol. 242, 56— 65)により、 改良型コール酸透析法を用いて調製した。すなわち、ジパルミトイルホスファチジル コリン、コレステロール、ジセチルホスフェート、ガンダリオシド及びジパルミトイルホス ファチジルエタノールアミンをモル比でそれぞれ 35 : 40 : 5 : 15 : 5の割合で合計脂質 量 45. 6mgになるように混合し、コール酸ナトリウム 46. 9mgを添カロし、クロ口ホルム Zメタノール溶液 3mlに溶解した。この溶液を蒸発させ、沈殿物を真空中で乾燥させ ることによって脂質膜を得た。得られた脂質膜を TAPS緩衝液 (pH 8. 4) 3mlに懸 濁、超音波処理して、透明なミセル懸濁液を得た。さらに、ミセル懸濁液を PM10膜（ Amicon Co. , USA)と pH 7. 2のリン酸緩衝液（Phosphate Buffred Saline ( PBS)： Na HPO (25. 55g) /KH PO (2. 72g) /NaN (0. 8g) /NaCl(35. 4 [0188] (Example 1. Preparation of ribosome) Ribosome was improved by a previously reported method (Yamazaki, N., Kodama, M. and Gabius, H. —J. (1994) Methods Enzymol. 242, 56—65). Prepared using a modified cholate dialysis method. In other words, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, gandarioside and dipalmitoyl phosphatidylethanolamine were mixed at a molar ratio of 35: 40: 5: 15: 5 to give a total lipid amount of 45.6 mg. Then add sodium cholate 46.9 mg Z was dissolved in 3 ml of methanol solution. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane. The obtained lipid membrane was suspended in 3 ml of TAPS buffer (pH 8.4) and sonicated to obtain a transparent micelle suspension. In addition, the micelle suspension was mixed with PM10 membrane (Amicon Co., USA) and pH 7.2 phosphate buffer (Phosphate Buffred Saline (PBS): Na HPO (25. 55g) / KH PO (2.72g) / NaN (0.8g) /NaCl(35.4

2 4 2 4 3  2 4 2 4 3

g) )を用いた限外濾過にかけ均一リボソーム（平均粒径 lOOnm) 10mlを調製した。  g) 10 ml of uniform ribosome (average particle size lOOnm) was prepared by ultrafiltration using).

[0189] (実施例 2.リボソーム脂質膜面上の親水性化処理） 実施例 1で調製したリボソーム 溶液 10mlを XM300膜 (Amicon Co. , USA)と CBS緩衝液（pH 8. 5)を用いた 限外濾過にかけ溶液の pHを 8. 5にした。次に、架橋試薬 bis (sulfosuccinimidyl) s liberate (BS 3 ; Pierce Co. , USA) 10mlを加え、 25°Cで 2時間攪拌した。その後 、更に 7°Cでー晚攪拌してリボソーム膜上の脂質ジパルミトイルフォスファチジルエタ ノールァミンと BS3との化学結合反応を完結した。そして、このリボソーム液を XM30 0膜と CBS緩衝液 (pH 8. 5)で限外濾過にかけた。次に、 CBS緩衝液 (pH 8. 5) lmlに溶かしたトリス（ヒドロキシメチル）ァミノメタン 40mgをリボソーム液 10mlに加え て、 25°Cで 2時間攪拌後、 7°Cで一晩攪拌してリボソーム膜上の脂質に結合した BS 3とトリス (ヒドロキシメチル)ァミノメタンとの化学結合反応を完結した。これにより、リポ ソーム膜の脂質ジパルミトイルフォスファチジルエタノールァミン上にトリス（ヒドロキシ メチル)ァミノメタンの水酸基が配位して水和親水性ィ匕された。 [0189] (Example 2. Hydrophilization treatment on ribosome lipid membrane surface) 10 ml of the ribosome solution prepared in Example 1 was used with XM300 membrane (Amicon Co., USA) and CBS buffer (pH 8.5). The solution was subjected to ultrafiltration to a pH of 8.5. Next, 10 ml of a crosslinking reagent bis (sulfosuccinimidyl) s liberate (BS 3; Pierce Co., USA) was added, and the mixture was stirred at 25 ° C. for 2 hours. Thereafter, the mixture was further stirred at 7 ° C to complete the chemical binding reaction between the lipid dipalmitoylphosphatidylethanolamine on the ribosome membrane and BS3. Then, this ribosome solution was subjected to ultrafiltration with XM300 membrane and CBS buffer (pH 8.5). Next, add 40 mg of tris (hydroxymethyl) aminomethane dissolved in 1 ml of CBS buffer (pH 8.5) to 10 ml of ribosome solution, stir at 25 ° C for 2 hours, and then stir at 7 ° C overnight. The chemical coupling reaction between BS 3 bound to lipid on the membrane and tris (hydroxymethyl) aminomethane was completed. As a result, the hydroxyl group of tris (hydroxymethyl) aminomethane was coordinated on the lipid dipalmitoylphosphatidylethanolamine of the liposomal membrane to make it hydrated and hydrophilic.

[0190] (実施例 3.リボソーム膜面上へのヒト血清アルブミン (HSA)の結合） リボソーム膜 面上へのヒト血清アルブミン（HSA)の結合は、既報の手法 (Yamazaki, N. , Koda ma, M. and Gabius, H. —J. (1994) MethodsEnzymol. 242, 56— 65)によ り、カップリング反応法を用いて行った。すなわち、この反応は 2段階ィ匕学反応で行い 、はじめに、実施例 2で得られた 10mlのリボソーム膜面上に存在するガンダリオシド 丄 mlの TAPs (N― Tris (hydroxymethyl) metnyl— 3— ammopropanesulfoni c acid)緩衝液 (pH 8. 4)に溶かしたメタ過ヨウ素酸ナトリウム 43mgを加えて室温 で 2時間攪拌して過ヨウ素酸酸ィ匕した後、 XM300膜と PBS緩衝液 (pH 8. 0)で限 外濾過することにより酸ィ匕されたリボソーム 10mlを得た。このリボソーム液に、 20mg のヒト血清アルブミン（HSA)をカ卩えて 25°Cで 2時間攪拌し、次に PBS (pH 8. 0)に 2M NaBH CN 100 1を加えて 10°Cでー晚攪拌してリボソーム上のガングリオシ[0190] (Example 3. Binding of human serum albumin (HSA) to the surface of the ribosome membrane) The binding of human serum albumin (HSA) to the surface of the ribosome membrane was determined by a previously reported method (Yamazaki, N., Koda ma , M. and Gabius, H. —J. (1994) Methods Enzymol. 242, 56—65), using the coupling reaction method. In other words, this reaction was carried out in a two-step chemical reaction. First, ganlioside 丄 ml of TAPs (N-Tris (hydroxymethyl) metnyl- 3-ammopropanesulfoni c) present on the 10 ml ribosome membrane surface obtained in Example 2 was used. acid) buffer solution (pH 8.4) dissolved in sodium metaperiodate (43 mg), stirred at room temperature for 2 hours, and then periodate acidified, XM300 membrane and PBS buffer solution (pH 8.0) 10 ml of ribosome that was acidified was obtained by ultrafiltration. To this ribosome solution, add 20 mg of human serum albumin (HSA), stir at 25 ° C for 2 hours, and then add PBS (pH 8.0). Add 2M NaBH CN 100 1 and stir at 10 ° C for ganglios on the ribosome.

3 Three

ドと HSAとのカップリング反応で HSAを結合した。そして、 XM300膜と CBS緩衝液 (pH 8. 5)で限外濾過をした後、 HSA結合リボソーム液 10mlを得た。  HSA was bound by a coupling reaction between the HSA and HSA. After ultrafiltration with XM300 membrane and CBS buffer (pH 8.5), 10 ml of HSA-binding ribosome solution was obtained.

[0191] (実施例 4.糖鎖の調製） 以下の表 4に示される糖鎖を使用した。 (Example 4. Preparation of sugar chain) [0191] The sugar chains shown in Table 4 below were used.

[0192] 各糖鎖の質量を計測し、以下の実施例 5において使用するための前処理をした。 2 つ以上の糖鎖の組み合せを使用する場合、各糖鎖を混合した。 [0192] The mass of each sugar chain was measured and pretreated for use in Example 5 below. When using a combination of two or more sugar chains, each sugar chain was mixed.

[0193] [表 4] [0193] [Table 4]

Figure imgf000104_0001
Figure imgf000104_0001

(実施例 5.リボソーム膜面結合ヒト血清アルブミン (HSA)上への糖鎖の結合） 実 施例 4において調製した各糖鎖 50 gを、 0. 25gの NH HCOを溶かした 0. 5ml水 溶液に加え、 37°Cで 3日間攪拌した後、 0. 45 mのフィルターで濾過して糖鎖の還 元末端のアミノ化反応を完結して、各糖鎖のグリコシルァミンィ匕合物 50 gを得た。 次に、実施例 3で得たリボソーム液の一部分 lmlに架橋試薬 3, 3，—ジチォビス (ス ルホスクシ-ミジルプロピオネート）（DTSSP ; Pierce Co. , USA) lmgを加えて 2 5°Cで 2時間、続いて 7°Cでー晚攪拌し、 XM300膜と CBS緩衝液 (pH 8. 5)で限 外濾過して DTSSPがリボソーム上の HSAに結合したリボソーム lmlを得た。次に、 このリボソーム液に上記のグリコシルァミン化合物 50 gを加えて、 25°Cで 2時間攪 拌し、その後 7°Cで一晩攪拌し、 XM300膜と PBS緩衝液 (pH 7. 2)で限外濾過し てリボソーム膜面結合ヒト血清アルブミン上の DTSSPにグリコシル化ァミン化合物の 結合を行った。その結果、表 2に示される糖鎖とヒト血清アルブミンとリボソームとが結 合したリボソーム各 2ml (総脂質量 2mg、総蛋白量 200 μ g、平均粒径 lOOnm)が得 られた。 (Example 5. Binding of sugar chain to ribosome membrane surface-bound human serum albumin (HSA)) 50 g of each sugar chain prepared in Example 4 was dissolved in 0.25 g NH 4 HCO 0.5 ml water In addition to the solution, after stirring at 37 ° C for 3 days, filtration through a 0.45 m filter completes the amination reaction of the sugar chain's reducing end, and the glycosamine amine compound of each sugar chain. 50 g was obtained. Next, 1 mg of the cross-linking reagent 3, 3, -dithiobis (sulfos-midylpropionate) (DTSSP; Pierce Co., USA) was added to a part of 1 ml of the ribosome solution obtained in Example 3 at 25 ° C. And then stirred at 7 ° C for 2 hours, and ultrafiltered with XM300 membrane and CBS buffer (pH 8.5) to obtain 1 ml of ribosome with DTSSP bound to HSA on ribosome. Next, add 50 g of the above glycosylamine compound to the ribosome solution, stir at 25 ° C for 2 hours, then at 7 ° C overnight, and add XM300 membrane and PBS buffer (pH 7.2). ), And glycosylated amine compound was bound to DTSSP on ribosome membrane-bound human serum albumin. As a result, 2 ml of each ribosome in which the sugar chain shown in Table 2 was bound with human serum albumin and ribosome (total lipid amount 2 mg, total protein amount 200 μg, average particle size lOOnm) was obtained.

[0194] 以下の表 5に、各糖鎖を用いた場合のリボソーム膜面結合ヒト血清アルブミン (HSA) 上への結合の結果を示す。特に明記しない限り、これらの糖鎖のリボソーム膜面結合 ヒト血清アルブミンへの結合は、実施例 5と同様の方法および条件で行った。 表 5に おいて、化合物（1)は各糖鎖のダルコシルァミンィ匕合物を示す。  [0194] Table 5 below shows the results of binding to ribosome membrane surface-bound human serum albumin (HSA) when each sugar chain is used. Unless otherwise specified, these sugar chains were bound to ribosome membrane surface bound human serum albumin by the same method and conditions as in Example 5. In Table 5, compound (1) represents a darcosylamine compound of each sugar chain.

[0195] [表 5] [0195] [Table 5]

O0ZAV7:.Z8S.0/900z<K>d z88£ SO O0ZAV7: Z8S.0 / 900z <K> d z88 £ SO

Figure imgf000106_0001
Figure imgf000106_0001

(調製例 1.リボソーム膜面結合ヒト血清アルブミン (HSA)上へのトリス (ヒドロキシメチ ル)ァミノメタンの結合） 比較試料としてのリボソームを調製するために、実施例 3で 得たリボソーム液の一部分 lmlに架橋試薬 3, 3' ジチォビス (スルホスクシンイミジ ルプロピオネート（DTSSP ;Pierce Co. , USA) lmgをカ卩えて 25°Cで 2時間、続い て 7°Cでー晚攪拌し、 XM300膜と CBS緩衝液 (pH 8. 5)で限外濾過して DTSSP 力 Sリボソーム上の HSAに結合したリボソーム lmlを得た。次に、このリボソーム液にト リス（ヒドロキシメチル）ァミノメタン (Wako Co. , Japan) 13mgをカ卩えて、 25°Cで 2時 間攪拌し、その後 7°Cで一晩攪拌し、 XM300膜と PBS緩衝液 (pH 7. 2)で限外濾 過してリボソーム膜面結合ヒト血清アルブミン上の DTSSPにトリス（ヒドロキシメチル） ァミノメタンの結合を行った。この工程で既に大過剰である 13mgのトリス（ヒドロキシメ チル）ァミノメタンが存在するのでリボソーム膜面結合ヒト血清アルブミン (HSA)上の 親水性化処理も同時に完結した。その結果、最終産物である親水性化処理されたト リス (ヒドロキシメチル)ァミノメタンとヒト血清アルブミンとリボソームとが結合した比較試 料としてのリボソーム（略称: TRIS) 2ml (総脂質量 2mg、総蛋白量 200 g、平均粒 径 lOOnm)が得られた。 (Preparation Example 1. Binding of tris (hydroxymethyl) aminomethane onto ribosome membrane-bound human serum albumin (HSA)) To prepare ribosome as a comparative sample, a portion of the ribosome fluid obtained in Example 3 Add 1 mg of cross-linking reagent 3, 3 'dithiobis (sulfosuccinimidyl propionate (DTSSP; Pierce Co., USA) 1 mg at 25 ° C for 2 hours, then stir at 7 ° C, and mix with XM300 membrane and CBS. Ultrafiltration with a buffer solution (pH 8.5) yielded 1 ml of ribosome bound to HSA on DTSSP-powered S ribosome, which was then added to tris (hydroxymethyl) aminomethane (Wako Co., Japan). ) Add 13 mg, stir at 25 ° C for 2 hours, then stir overnight at 7 ° C, and ultrafilter with XM300 membrane and PBS buffer (pH 7.2) to bind to the ribosome membrane surface. Binding of tris (hydroxymethyl) aminomethane to DTSSP on human serum albumin Since there was already 13 mg of tris (hydroxymethyl) aminomethane in large excess in this process, the hydrophilic treatment on ribosome membrane-bound human serum albumin (HSA) was completed at the same time. 2 ml of ribosome (abbreviation: TRIS) as a comparative sample in which tris (hydroxymethyl) aminomethane, which has been hydrophilized, human serum albumin, and ribosome are bound to each other (2 mg of total lipid, 200 g of total protein, Average particle diameter lOOnm) was obtained.

[0196] (実施例 6.リボソーム膜面結合ヒト血清アルブミン (HSA)上の親水性ィ匕処理） 実施 例 5の手段により [Example 6: Hydrophilic treatment on ribosome membrane-bound human serum albumin (HSA)] By the means of Example 5

調製された糖鎖が結合したリボソームについて、それぞれ別々に以下の手順によりリ ポソーム上の HSAタンパク質表面の親水性ィ匕処理を行った。糖鎖結合リボソーム 2 mlに、別々に、トリス（ヒドロキシメチル）ァミノメタン 13mgをカ卩えて、 25°Cで 2時間、そ の後 7°Cで一晩攪拌した後、 XM300膜と PBS緩衝液 (pH 7. 2)で限外濾過し未反 応物を除去して、最終産物である親水性化処理された糖鎖結合リボソーム複合体各 2ml (総脂質量 2mg、総蛋白量 200 μ g、平均粒径 lOOnm)を得た。  The prepared ribosomes to which sugar chains were bound were each subjected to hydrophilic treatment on the surface of the HSA protein on the liposome by the following procedure. Separately, 13 ml of tris (hydroxymethyl) aminomethane was separately added to 2 ml of sugar chain-bound ribosome, stirred at 25 ° C for 2 hours, and then at 7 ° C overnight, and then XM300 membrane and PBS buffer ( Unfiltered to remove the unreacted product by pH 7.2), 2 ml each of the glycosylated ribosome complex hydrophilized as the final product (total lipid amount 2 mg, total protein amount 200 μg, average Particle size lOOnm) was obtained.

[0197] (実施例 7.各種の糖鎖結合リボソーム複合体によるレクチン結合活性阻害効果の測 定） 調製例 1および実施例 6の手段により調製した各糖鎖結合リボソーム複合体の インビトロでのレクチン結合活性は、常法（Yamazaki, N. (1999) Drug Delivery System, 14, 498— 505)に従いレクチン固定化マイクロプレートを用いた阻害実 験で測定した。すなわち、レクチン（E— selectin;R&D Systems Co. , USA)を 96穴マイクロプレートに固定ィ匕した。このレクチン固定ィ匕プレートに、比較リガンドで あるピオチンィ匕したフコシルイ匕フエチュイン 0. 1 μ gとともに、濃度の異なる各種の糖 鎖結合リボソーム複合体（蛋白質量として、0. Ol ^ g, 0. 04 /^、0. 11 、0. 33 g、 1 g)を加え、 4°Cで 2時間インキュベートした。 PBS (pH 7. 2)で 3回洗浄し た後、西洋ヮサビペルォキシダーゼ (HRPO)結合ストレプトアビジンを添カ卩した。さら に 4°Cで 1時間インキュベートし、 PBS (pH 7. 2)で 3回洗浄した。次いでペルォキ シダーゼ基質を添カ卩して室温で静置、 405nmの吸光度をマイクロプレートリーダー（ Molecular Devices Corp. , USA)で測定した。フコシル化フエチュインのビォチ ン化は、 sulfo— NHS— biotin reagent (Pierce Co. , USA)処理後、 Centrico n- 30 (Amicon Co. , USA)により精製した。 HRPO結合ストレプトアビジンは、 H RPOの酸化と NaBH CNを用いた還元アミノ化法によるストレプトアビジンの結合に (Example 7. Measurement of lectin-binding activity inhibition effect by various sugar chain-bound ribosome complexes) [0197] In vitro lectins of each sugar chain-bound ribosome complex prepared by the means of Preparation Example 1 and Example 6 The binding activity was measured by an inhibition experiment using a lectin-immobilized microplate according to a conventional method (Yamazaki, N. (1999) Drug Delivery System, 14, 498-505). That is, lectin (E-selectin; R & D Systems Co., USA) Fixed to a 96-well microplate. On this lectin-fixed plate, 0.1 μg of fucosyl pheotuine, which is a comparative ligand, was added to various glycan-binding ribosome complexes with different concentrations (as protein mass, 0. Ol ^ g, 0.04). / ^, 0.11, 0.33 g, 1 g) was added and incubated at 4 ° C for 2 hours. After washing 3 times with PBS (pH 7.2), horse radish peroxidase (HRPO) -conjugated streptavidin was added. The plate was further incubated at 4 ° C for 1 hour and washed 3 times with PBS (pH 7.2). Next, the peroxidase substrate was added and left at room temperature, and the absorbance at 405 nm was measured with a microplate reader (Molecular Devices Corp., USA). Biotinylation of fucosylated pheutains was purified by Centricon 30 (Amicon Co., USA) after treatment with sulfo-NHS-biotin reagent (Pierce Co., USA). HRPO-conjugated streptavidin is used to bind streptavidin by oxidation of HRPO and reductive amination using NaBHCN.

3  Three

より調製した。この測定結果を次のように処理して計算した結果を以下の表に示す。  More prepared. The results obtained by processing the measurement results as follows are shown in the following table.

[0198] [表 6] [0198] [Table 6]

各 Concentrat i onにおけるサンプル LY-1 と I C50の値

Figure imgf000108_0001
Sample LY-1 and I C50 values at each Concentrat i on
Figure imgf000108_0001

の値の差を して比率であらわしたものである。  The difference between the values is expressed as a ratio.

[0199] [表 7]  [0199] [Table 7]

Contro l Contro l

Figure imgf000108_0002
Figure imgf000108_0002

従って、サンプル LY— 1の平均値の比を Wとすると、サンプル LY— 1の平均値を Xと し、 hotを Y、 coldを Ζとしたときの計算式は、 Therefore, if the ratio of the average value of sample LY-1 is W, the average value of sample LY-1 is X, hot is Y, and cold is Ζ

W= (X-Z) / (Y-Z) X 100  W = (X-Z) / (Y-Z) X 100

と表すことができる。  It can be expressed as.

表 6、表 7をもとに作成したサンプル LY— 1と系列 IC50のグラフ 1を図 6に示す。 グラフ 1は表 6をもとに作成したものである。 X軸は対数メモリになっている。折れ線グ ラフ上の各点はサンプル LY— 1の各濃度（横軸)における測定値の平均の比を示す 。サンプルによってコントロールの値が異なるので比較しやすいようにグラフの縦軸を hotと coldの差を 1としてその比で表す。 Sample LY— 1のグラフと系列 IC50のグラ フの交点の X座標が IC の値である。交点は座標 1(0. 11,0. 562)と座標 2 (0. 33,0 Fig. 6 shows graph 1 of sample LY-1 and series IC50 created based on Tables 6 and 7. Graph 1 is based on Table 6. The X axis is a logarithmic memory. Each point on the line graph represents the average ratio of the measured values at each concentration (horizontal axis) of sample LY-1. Since the control value varies depending on the sample, the vertical axis of the graph is expressed as a ratio with the difference between hot and cold as 1, for easy comparison. The X coordinate of the intersection of the Sample LY—1 graph and the series IC50 graph is the IC value. The intersection is at coordinate 1 (0.11, 562) and coordinate 2 (0.33,0)

50  50

. 414)を含む直線上にありその式は y=—0. 673x+  414) and its formula is y = —0.673x +

0. 636となる。 y=0. 5 (系列 IC50の式）の 2本の直線の交点の x座標は 0. 202と なる。この値を蛋白質の分子量 69000で割り、さらにリボソーム 1個あたりの蛋白質の 個数 300で害ると 9. 76E— 09となる。  0. 636. The x coordinate of the intersection of two straight lines with y = 0.5 (series IC50 formula) is 0.202. Dividing this value by the molecular weight of the protein, 69000, and harming by the number of proteins per ribosome, 300, gives 9.76E-09.

これらの計算は、コンピュータプログラムを用いて自動化することができる。 These calculations can be automated using a computer program.

[表 8] [Table 8]

Figure imgf000110_0001
Figure imgf000110_0001

(実施例 8.クロラミン T法による各種糖鎖結合リボソームの1^標識） クロラミン T ( Wako Pure Chemical Co. , Japan)溶液並びに二亜硫酸ナトリウム溶液をそれ ぞれ 3mgZmlならびに 5mgZmlとなるように用時調製して用いた。実施例 6により調 製した糖鎖結合リボソームならびにトリス (ヒドロキシメチル)ァミノメタン結合リボソーム を各 50 /z lずつ別々にエツペンチューブに入れ、続いて125I— NaI (NEN Life Sci ence Product, Inc. USA)を 15 1、クロラミン T溶液を 10 μ 1加え反応させた。 5 分ごとにクロラミン Τ溶液 10 1を加え、この操作を 2回繰り返した後 15分後に還元剤 として二亜硫酸ナトリウム 100 1をカ卩え、反応を停止させた。次に、 Sephadex G— 50 (Phramacia Biotech. Sweden)カラムクロマト上に乗せ、 PBSで溶出、標識体 を精製した。最後に、非標識—リボソーム複合体を添加して比活性 (4 X 106 BqZ mg protein)を調整して1251標識リボソーム液を得た。 (Example 8. 1 ^ labeling of various sugar chain-bound ribosomes by the chloramine T method) Chloramine T (Wako Pure Chemical Co., Japan) solution and sodium disulfite solution were prepared at the time of use to be 3 mgZml and 5 mgZml, respectively. Used. The sugar chain-bound ribosome and the tris (hydroxymethyl) aminomethane-bound ribosome prepared according to Example 6 were separately placed in an Eppendorf tube at a rate of 50 / zl, followed by 125 I—NaI (NEN Life Science Product, Inc. USA). ) And 15 μl of chloramine T solution were added and reacted. Chloramine solution 101 was added every 5 minutes, and this operation was repeated twice. After 15 minutes, sodium disulfite 1001 was added as a reducing agent to stop the reaction. Next, Sephadex G— It was placed on 50 (Phramacia Biotech. Sweden) column chromatography, eluted with PBS, and the labeled product was purified. Finally, a non-labeled-ribosome complex was added to adjust the specific activity (4 × 10 6 BqZ mg protein) to obtain a 125 1-labeled ribosome solution.

[0201] (実施例 9.各種の糖鎖結合リボソーム複合体のマウスでの腸管力 血中への移行量 の測定） 一昼夜水分以外絶食した雄性 ddYマウス（7週齢）に、実施例 8により1251標 識された糖鎖結合ならびにトリス（ヒドロキシメチル)ァミノメタン結合リボソーム複合体 0. 2mlを蛋白質量として 3 gZ—匹の割合になるように、マウス用経口ゾンデで腸 管内に強制投与した後、 10分後にネンブタール麻酔下で下大動脈より血液 lmlを 採血した。そして、血中の1251放射能をガンマ一カウンター（Alola ARC300)で測 定した。さらに、各種のリボソーム複合体の生体内安定性を調べる目的で、各血液の 血清を Sephadex G— 50で再クロマトした力 いずれも大半の放射能が高分子量 のボイドフラクションにみられ、各種のリボソーム複合体は生体内においても安定性を 有していた。なお、腸管力も血中への放射能移行量は、投与全放射能に対する血液 lml当たりの放射能の割合（％投与量 Zml血液)で表示した。糖鎖修飾リボソームは 、用いた糖鎖の種類によって、腸管力も血中に移行するものと移行しないものが存在 した。この結果を以下の表に示す。表 9において、標的指向性の評価（+ +、 +)の 定義は、以下のとおりである。また、評価（一）はネガティブな結果を表し、 NAは未測 定を表す。この結果に基づいて、経口投与に最適な糖鎖の種類及び結合密度を決 定することが可能となる。 [0201] (Example 9. Measurement of intestinal force blood translocation in mice of various sugar chain-linked ribosome complexes) In male ddY mice (7 weeks old) fasted except for water all day and night, according to Example 8. 125 1 Labeled glycosylation and tris (hydroxymethyl) aminomethane-binding ribosome complex 0.2 g of protein is forced to enter the intestinal tract with an oral sonde for mice so that the amount of protein is 3 gZ-rat Ten minutes later, lml blood was collected from the lower aorta under Nembutal anesthesia. Then, 125 1 radioactivity in blood was measured with a gamma counter (Alola ARC300). Furthermore, for the purpose of investigating the in vivo stability of various ribosome complexes, the power of re-chromatizing each blood serum with Sephadex G-50 was found in most high-molecular-weight void fractions. The complex was also stable in vivo. The amount of radioactivity transferred into the blood of the intestinal tract was also expressed as the ratio of radioactivity per ml of blood relative to the total radioactivity administered (% dose Zml blood). Depending on the type of sugar chain used, there were sugar chain-modified ribosomes that migrated into the blood and those that did not. The results are shown in the following table. In Table 9, the definitions of target-directed evaluation (++, +) are as follows. Evaluation (1) indicates a negative result, and NA indicates unmeasured. Based on this result, it is possible to determine the sugar chain type and bond density that are optimal for oral administration.

[0202] [表 9]  [0202] [Table 9]

標的指向性の評価 （+十、 +) の定義

Figure imgf000111_0001
Definition of target orientation evaluation (+ ten, +)
Figure imgf000111_0001

[0203] [表 10]

Figure imgf000112_0001
[0203] [Table 10]
Figure imgf000112_0001

(実施例 10.糖鎖修飾リボソームの生体内動態検討） 実験は、正常マウス、ならび に、担癌マウスに対して行った。その手順は以下のとおりである。各種の糖鎖修飾リ ポソーム、ならびに、糖鎖修飾無しのリボソームの各組織への分布量の測定は、正常 マウス、ならびに、 Ehrlich ascites tumor (EAT)細胞（約 2 X 107個）を雄性 ddY マウス（7週齢)大腿部皮下に移植し、癌組織が 0. 3〜0. 6gに発育 (6〜8日後）した ものを本実験に用いた。これらのマウスに実施例 8により1251標識した各種リボソーム 0 . 2mlを蛋白質量として —匹の割合となるように経口投与、または、尾静脈に 注入投与し、 10分、または、 5分後に組織 (血液、肝臓、心臓、肺、脾臓、脳、癌組織 、癌の周囲の炎症組織、小腸、大腸、リンパ節、骨髄、腎臓、脾臓、胸腺、筋肉）を摘 出、各組織の放射能をガンマカウンタ (Aloka ARC 300)で測定した。なお、各組 織への放射能分布量は、投与全放射能に対する各組織 lg当たりの放射能の割合（ %投与量 Zg組織)を計測した。そして、糖鎖修飾リボソーム、ならびに基準リポソ一 ムとして糖鎖の代わりにトリス (ヒドロキシメチル)ァミノメタンを結合させたリボソームを 静脈投与 5分後に、血中または各組織に送達された糖鎖修飾リボソームでの 4匹の 計測平均値および基準リボソームでの 4匹の計測平均値の倍率を計算した。この計 算結果により、経口投与後の血中への移行性、ならびに各臓器への標的指向性を、 基準リボソームとしてトリス (ヒドロキシメチル)ァミノメタンを結合させたリボソームを用 いて評価した。この結果を以下の表に示す。経口投与した場合の臓器への送達につ いても、経口投与により血中に移行した媒体は静脈注射と同様の傾向を示す。以下 の表に示す結果より、本発明の糖鎖修飾リボソームは、腫瘍部位及び炎症部位に集 積し、これらの部位への指向性を有することがわ力つた。表 11において、標的指向性 の評価（+ +、 +)の定義は、以下のとおりである。また、評価（-)はネガティブな結 果を表し、 NAは未測定を表す。 (Example 10. Examination of in vivo kinetics of sugar chain-modified ribosome) Experiments were performed on normal mice and tumor-bearing mice. The procedure is as follows. Various sugar chain modifications Measurement of the distribution of posomes and ribosomes without glycosylation in each tissue was performed using normal mice and Ehrlich ascites tumor (EAT) cells (approximately 2 X 10 7 cells) in male ddY mice (7 weeks old). Transplanted subcutaneously in the thigh, and cancer tissue grown to 0.3 to 0.6 g (6 to 8 days later) was used in this experiment. These mice were orally administered at 0.2 ml of various ribosomes labeled with 125 1 according to Example 8 as a protein amount—or injected into the tail vein, and the tissue was collected 10 minutes or 5 minutes later. (Blood, liver, heart, lung, spleen, brain, cancer tissue, inflamed tissue surrounding the cancer, small intestine, large intestine, lymph node, bone marrow, kidney, spleen, thymus, muscle) Measured with a gamma counter (Aloka ARC 300). The amount of radioactivity distributed to each tissue was measured by the ratio of radioactivity per lg of each tissue to the total radioactivity administered (% dose Zg tissue). Then, the sugar chain-modified ribosome and the ribosome bound with tris (hydroxymethyl) aminomethane instead of the sugar chain as a reference liposome were intravenously administered 5 minutes later, and the sugar chain-modified ribosome delivered to the blood or each tissue The magnification of the 4 measured averages and the 4 measured averages on the reference ribosome was calculated. Based on this calculation result, the transferability to blood after oral administration and the target directivity to each organ were evaluated using a ribosome combined with tris (hydroxymethyl) aminomethane as a reference ribosome. The results are shown in the following table. Regarding delivery to organs after oral administration, the medium that has been transferred into the blood by oral administration shows the same tendency as intravenous injection. From the results shown in the following table, it was proved that the sugar chain-modified ribosome of the present invention accumulates at a tumor site and an inflammation site and has directivity to these sites. In Table 11, the definition of target directivity evaluation (++, +) is as follows. Evaluation (-) indicates a negative result, and NA indicates not measured.

[0204] [表 11] [0204] [Table 11]

Figure imgf000113_0001
Figure imgf000113_0001

[0205] [表 12]

Figure imgf000114_0001
表 10並びに表 12は、各種の放射性糖鎖修飾リボソームの経口投与並びに静注投 与でのマウスにおける各組織への放射性糖鎖リボソームの集積効果を示す評価結 果である。これらの結果は、この糖鎖修飾リボソームがリガンドとしての糖鎖の機能を 活用して、疾患患部や各種臓器へ薬物や蛍光物質や放射標識物質などをァクティ ブターゲティングにより高効率に集積.送達することを示すものである。従って、本発 明の糖鎖修飾リボソームは、腫瘍などの標的組織での集積を可視化できるので、治 療用薬剤送達媒体としての利用とともに、研究試薬や診断薬などとしての利用への 送達媒体をも提供する。 [0205] [Table 12]
Figure imgf000114_0001
Tables 10 and 12 show the evaluation results showing the accumulation effect of various types of radioactive sugar chain-modified ribosomes on each tissue in mice after oral administration and intravenous administration. It is fruit. These results show that this sugar chain-modified ribosome utilizes the function of the sugar chain as a ligand to efficiently accumulate and deliver drugs, fluorescent substances, radiolabeled substances, etc. to diseased areas and various organs by active targeting. It shows that. Therefore, since the sugar chain-modified ribosome of the present invention can visualize the accumulation in target tissues such as tumors, it can be used not only as a therapeutic drug delivery vehicle but also as a research reagent or diagnostic drug. Also provide.

[0207] (実施例 11.抗癌剤ドキソルビシン封入リボソームの調製） リボソームは既報の手法  (Example 11. Preparation of anticancer drug doxorubicin-encapsulated ribosome) Ribosome is a previously reported technique

(Yamazaki, N. , Kodama, M. and Gabius, H. —J. (1994) Methods Enzy mol. 242, 56— 65)により、改良型コール酸透析法を用いて調製した。すなわち、 ジパルミトイルホスファチジルコリン、コレステロール、ジセチルホスフェート、ガンダリ オシド及びジパルミトイルホスファチジルエタノールアミンをモル比でそれぞれ 35： 40 : 5 : 15 : 5の割合で合計脂質量 45. 6mgになるように混合し、コール酸ナトリウム 46. 9mgを添カ卩し、クロ口ホルム Zメタノール溶液 3mlに溶解した。この溶液を蒸発させ、 沈殿物を真空中で乾燥させることによって脂質膜を得た。得られた脂質膜を TAPS 緩衝生理食塩液 (pH8. 4) 10mlに懸濁、超音波処理し、透明なミセル懸濁液 10ml を得た。このミセル懸濁液に TAPS緩衝液 (pH8. 4)で 3mg/lmlになるよう完全に 溶解した抗癌剤ドキソルビシンを撹拌しながらゆっくりと滴下して均一に混合した後、 このドキソルビシン入りミセル懸濁液を PM10膜 (Amicon Co. , USA)と TAPS緩 衝生理食塩液 (pH8. 4)を用いた限外濾過にかけ均一な抗癌剤ドキソルビシン封入 リポソーム粒子懸濁液 1 Omlを調製した。  (Yamazaki, N., Kodama, M. and Gabius, H. —J. (1994) Methods Enzy mol. 242, 56—65). That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, gandarioside and dipalmitoyl phosphatidylethanolamine were mixed in a molar ratio of 35: 40: 5: 15: 5 to give a total lipid content of 45.6 mg, 46.9 mg of sodium cholate was added and dissolved in 3 ml of Kuroguchi Form Z methanol solution. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane. The obtained lipid membrane was suspended in 10 ml of TAPS buffered physiological saline (pH 8.4) and sonicated to obtain 10 ml of a transparent micelle suspension. To this micelle suspension, the anticancer drug doxorubicin completely dissolved in TAPS buffer (pH 8.4) to 3 mg / lml was slowly added dropwise with stirring, and then mixed uniformly, and then this micelle suspension containing doxorubicin was added. Uniform anticancer drug doxorubicin-encapsulated liposome particle suspension 1 Oml was prepared by ultrafiltration using PM10 membrane (Amicon Co., USA) and TAPS buffered saline (pH 8.4).

[0208] 得られた生理食塩懸濁液中（37°C)の抗癌剤ドキソルビシン封入リボソーム粒子の粒 子径とゼータ電位をゼータ電位 ·粒子径 ·分子量測定装置（Model Nano ZS, Ma lvernlnstruments Ltd, , UK)により測定した結果、粒子径は 50〜350nm、ゼー タ電位は 30〜一 10mVであった。  [0208] The particle size and zeta potential of the anticancer drug doxorubicin-encapsulated ribosome particles in the obtained physiological saline suspension (37 ° C) were determined by measuring the zeta potential · particle size · molecular weight measuring device (Model Nano ZS, Malvernlnstruments Ltd,, (UK), the particle size was 50 to 350 nm, and the zeta potential was 30 to 10 mV.

[0209] (実施例 12.抗癌剤ドキソルビシン封入リボソーム脂質膜面上の親水性化処理） 実 施例 11で調製した抗癌剤ドキソルビシン封入リボソーム溶液 1 Omlを XM300膜 (A micon Co. , USA)と CBS緩衝液 (ρΗ8. 5)を用いた限外濾過にかけ溶液の ρΗ を 8. 5にした。次に、架橋試薬ビス（スルホスクシンィミジル)スべレート（BS3 ; Pierce Co. , USA) 10mlを加え、 25°Cで 2時間攪拌した。その後、更に 7°Cで一晩撹拌 してリボソーム膜上の脂質ジパルミトイルホスファチジルエタノールァミンと BS3との化 学結合反応を完結した。そして、このリボソーム液を XM300膜と CBS緩衝液 (pH8. 5)で限外濾過にかけた。次に、 CBS緩衝液 (pH8. 5) lmlに溶かしたトリス（ヒドロキ シメチル)ァミノメタン 40mgをリボソーム液 10mlに加えて、 25°Cで 2時間撹拌後、 7 °Cで一晩撹拌してリボソーム膜上の脂質に結合した BS3とトリス (ヒドロキシメチル)ァ ミノメタンとの化学結合反応を完結した。これにより、抗癌剤ドキソルビシン封入リポソ ーム膜の脂質ジパルミトイルホスファチジルエタノールァミン上にトリス（ヒドロキシメチ ル)ァミノメタンの水酸基が配位して水和親水性ィ匕された。 (Example 12. Hydrophilization treatment on anticancer drug doxorubicin-encapsulated ribosome lipid membrane surface) [0209] 1 ml of anticancer drug doxorubicin-encapsulated ribosome solution prepared in Example 11 was added to XM300 membrane (A micon Co., USA) and CBS buffer The solution was subjected to ultrafiltration using a liquid (ρ 58.5) to make the solution ρΗ 8.5. Next, the crosslinking reagent bis (sulfosuccinimidyl) suberate (BS3; Pierce (Co., USA) 10 ml was added and stirred at 25 ° C. for 2 hours. Thereafter, the mixture was further stirred overnight at 7 ° C to complete the chemical binding reaction between the lipid dipalmitoylphosphatidylethanolamine on the ribosome membrane and BS3. Then, this ribosome solution was subjected to ultrafiltration using an XM300 membrane and a CBS buffer (pH 8.5). Next, add 40 mg of tris (hydroxymethyl) aminomethane dissolved in 1 ml of CBS buffer (pH 8.5) to 10 ml of ribosome solution, stir at 25 ° C for 2 hours, and then stir overnight at 7 ° C to ribosome membrane. The chemical coupling reaction between BS3 bound to the above lipid and tris (hydroxymethyl) aminomethane was completed. As a result, the hydroxyl group of tris (hydroxymethyl) aminomethane was coordinated on the lipid dipalmitoyl phosphatidylethanolamine of the liposomal membrane encapsulating the anticancer drug doxorubicin to make it hydrated and hydrophilic.

[0210] (実施例 13.抗癌剤ドキソルビシン封入リボソーム膜面上へのヒト血清アルブミン (H SA)の結合） リボソーム膜面上へのヒト血清アルブミン (HSA)の結合は、既報の手 法（Yamazaki, N. , Kodama, M. and Gabius, H. —J. (1994) MethodsEnz ymol. 242, 56— 65)により、カップリング反応法を用いて行った。すなわち、この反 応は 2段階ィ匕学反応で行い、まずはじめに、実施例 2で得られた 10mlのリボソーム 膜面上に存在するガンダリオシドを lmlの TAPS緩衝液 (pH8. 4)に溶力したメタ過 ヨウ素酸ナトリウム 43mgを加えて室温で 2時間撹拌して過ヨウ素酸酸ィ匕した後、 XM 300膜と PBS緩衝液 (pH8. 0)で限外濾過することにより酸ィ匕されたリボソーム 10ml を得た。このリボソーム液に、 20mgのヒト血清アルブミン（HSA)を加えて 25°Cで 2時 間撹拌し、次に PBS (pH8. 0)に 2M NaBH CN 100 1をカ卩えて 10 [0210] (Example 13. Binding of human serum albumin (HSA) to ribosome membrane surface encapsulated with anticancer drug doxorubicin) Binding of human serum albumin (HSA) to the surface of ribosome membrane has been reported (Yamazaki, N., Kodama, M. and Gabius, H. —J. (1994) Methods Enzym. 242, 56—65), using the coupling reaction method. That is, this reaction was carried out by a two-step chemical reaction. First, the gandarioside present on the 10 ml ribosome membrane surface obtained in Example 2 was dissolved in 1 ml TAPS buffer (pH 8.4). Sodium metaperiodate (43 mg) was added, stirred at room temperature for 2 hours, and acidified with periodate, followed by ultrafiltration with XM 300 membrane and PBS buffer (pH 8.0). 10ml was obtained. To this ribosome solution, add 20 mg of human serum albumin (HSA), stir at 25 ° C for 2 hours, and then add 2M NaBH CN 100 1 to PBS (pH 8.0).

3 。Cでー晚撹 拌してリボソーム上のガンダリオシドと HSAとのカップリング反応で HSAを結合した。 そして、 XM300膜と CBS緩衝液 (pH8. 5)で限外濾過をした後、 HSA結合抗癌剤 ドキソルビシン封入リボソーム液 10mlを得た。  3. The mixture was agitated with C and HSA was bound by a coupling reaction between Gandarioside on the ribosome and HSA. Then, after ultrafiltration with XM300 membrane and CBS buffer (pH 8.5), 10 ml of ribosome solution encapsulating HSA-conjugated anticancer drug doxorubicin was obtained.

[0211] (実施例 14.糖鎖の調製） 実施例 4と同様の手順により糖鎖を調製した。 (Example 14. Preparation of sugar chain) [0211] A sugar chain was prepared in the same manner as in Example 4.

[0212] (実施例 15.抗癌剤ドキソルビシン封入リボソーム膜面結合ヒト血清アルブミン (HSA )上への糖鎖の結合とリンカ一蛋白質 (HSA)の親水性化処理） 実施例 14にお 、て 調製した各糖鎖 50 gを 0. 25gの NH HCOを溶かした 0. 5ml水溶液に加え、 37 (Example 15. Anticancer drug doxorubicin-encapsulated ribosome membrane surface bound human serum albumin (HSA) binding to sugar chain and linker protein (HSA) hydrophilization) Prepared in Example 14 Add 50 g of each sugar chain to a 0.5 ml aqueous solution in which 0.25 g NH 4 HCO is dissolved.

4 3  4 3

°Cで 3日間攪拌した後、 0. 45 μ mのフィルターで濾過して糖鎖の還元末端のァミノ 化反応を完結して各糖鎖のグリコシルァミンィ匕合物 50 gを得た。次に、実施例 13 で得た抗癌剤ドキソルビシン封入リボソーム液の一部分 lmlに架橋試薬 3, 3，—ジチ ォビス（スルホスクシ-ミジルプロピオネート）（DTSSP ; Pierce Co. , USA) lmgを 加えて 25°Cで 2時間、続いて 7°Cでー晚撹拌し、 XM300膜と CBS緩衝液 (pH8. 5) で限外濾過して DTSSPがリボソーム上の HSAに結合したリボソーム lmlを得た。次 に、このリボソーム液に上記の糖鎖のグリコシルァミン化合物 50 gを加えて、 25°C で 2時間攪拌し、その後 7°Cで一晩撹拌し、 XM300膜と PBS緩衝液 (pH7. 2)で限 外濾過してリボソーム膜面結合ヒト血清アルブミン上の DTSSPに各糖鎖の結合を行 つた。次に、このリボソーム液にトリス（ヒドロキシメチル）ァミノメタン（Wako Co. , Jap an) 13mgをカ卩えて、 25°Cで 2時間攪拌し、その後 7°Cでー晚撹拌し、 XM300膜と P BS緩衝液 (pH7. 2)で限外濾過してリボソーム膜面結合ヒト血清アルブミン上の DT SSPにグリコシルイ匕アミンィ匕合物の結合を行った。その結果、トリス（ヒドロキシメチル） ァミノメタンとヒト血清アルブミンとリボソームとが結合したリンカ一蛋白質 (HSA)の親 水性ィ匕処理をしたリボソームを得た。その結果、各糖鎖とヒト血清アルブミンとリポソ一 ムとが結合したリンカ一蛋白質 (HSA)の親水性ィ匕処理をした抗癌剤ドキソルビシン 封入リボソーム 2ml (総脂質量 2mg、総蛋白量 200 μ g)が得られた。 After stirring at ° C for 3 days, the mixture was filtered through a 0.45 μm filter to complete the amination reaction of the reducing end of the sugar chain, thereby obtaining 50 g of a glycosamine amine compound of each sugar chain. Next, Example 13 Add 1 mg of cross-linking reagent 3, 3, -dithiobis (sulfosucci-midylpropionate) (DTSSP; Pierce Co., USA) to 1 ml of a part of ribosome solution encapsulated with anticancer drug doxorubicin obtained in 2 hours at 25 ° C, Subsequently, the mixture was stirred at 7 ° C and ultrafiltered with XM300 membrane and CBS buffer (pH 8.5) to obtain 1 ml of ribosome with DTSSP bound to HSA on ribosome. Next, add 50 g of the glycosylamine compound of the above-mentioned sugar chain to the ribosome solution, stir at 25 ° C for 2 hours, and then at 7 ° C overnight, then add XM300 membrane and PBS buffer (pH 7. After ultrafiltration in 2), each sugar chain was bound to DTSSP on ribosome membrane surface-bound human serum albumin. Next, 13 mg of tris (hydroxymethyl) aminomethane (Wako Co., Japan) was added to this ribosome solution, stirred at 25 ° C for 2 hours, and then stirred at 7 ° C. The glycosylamine amine compound was bound to DT SSP on ribosome membrane surface-bound human serum albumin by ultrafiltration with BS buffer (pH 7.2). As a result, a ribosome was obtained that was treated with a hydrophilic protein of linker protein (HSA) in which tris (hydroxymethyl) aminomethane, human serum albumin and ribosome were bound. As a result, 2 ml of anticancer drug doxorubicin encapsulated ribosome treated with a hydrophilic protein of linker protein (HSA) in which each sugar chain, human serum albumin and liposome were bound (total lipid amount 2 mg, total protein amount 200 μg) was gotten.

[0213] 得られた生理食塩懸濁液中（37°C)の抗癌剤ドキソルビシン封入リボソーム粒子の粒 子径とゼータ電位をゼータ電位 ·粒子径 ·分子量測定装置（Model Nano ZS, Ma lvern Instruments Ltd, , UK)により測定した結果、粒子径は 50〜350nm、ゼ ータ電位は 30〜一 10mVであった。  [0213] The particle size and zeta potential of the anticancer drug doxorubicin-encapsulated ribosome particles in the obtained physiological saline suspension (37 ° C) were measured using the zeta potential · particle size · molecular weight measuring device (Model Nano ZS, Malvern Instruments Ltd, , UK), the particle size was 50 to 350 nm, and the zeta potential was 30 to 10 mV.

[0214] (調製例 2 :糖脂質リボソームの調製） 糖脂質リボソーム (FEE, EEで始まるもの、例 えば、リボソーム番号 3、リボソーム番号 37、リボソーム番号 67、リボソーム番号 218 など）は以下のように調製した。  [0214] (Preparation Example 2: Preparation of glycolipid ribosome) Glycolipid ribosomes (starting with FEE, EE, eg, ribosome number 3, ribosome number 37, ribosome number 67, ribosome number 218, etc.) are as follows: Prepared.

[0215] リボソームはコール酸透析法を用いて調製した。すなわち、ジパルミトイルフォスファ チジルコリン、コレステロール、ジセチルフォスフェート、ガンダリオシド (糖脂質糖鎖と して GM1を 100%含むもの）及びジパルミトイルホスファチジルエタノールアミンをモ ル比でそれぞれ 35 :40 : 5 : 15 : 5の割合で合計脂質量 45. 6mgになるように混合し 、コール酸ナトリウム 46. 9mg添加し、クロ口ホルム Zメタノール溶液 3ml〖こ溶解した。 この溶液を蒸発させ、沈殿物を真空中で乾燥させることによって脂質膜を得た。得ら れた脂質膜を TAPS緩衝液 (pH8. 4) 3mlに懸濁、超音波処理し、透明なミセル懸 濁液 3mlを得た。このミセル懸濁液に PBS緩衝液 (pH7. 2)をカ卩えて 10mlにしてか ら、このミセル懸濁液を PM10膜 (Amicon Co. , USA)と TAPS緩衝液（pH8. 4 )を用いた限外濾過にかけ均一な親水性ィ匕処理をしてな 、リボソーム粒子懸濁液 10 mlを調製した。このリボソーム液にボルトンハンター試薬（BHR ； Pierce Co. , USA) 5mgを加えて、 25°Cで 2時間、その後 7°Cで 4時間反応させジパルミトイルホ スファチジルエタノールアミンを BH化した後、 PBS緩衝液（PH7. 2)で限外濾過に 力けた。その結果、比較試料としてのリボソーム（略称: EEGMl— BH) 10ml (総脂 質量 45. 6mg、平均粒子径 lOOnm)が得られた。 [0215] Ribosomes were prepared using the cholate dialysis method. That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, gandarioside (containing 100% GM1 as a glycolipid sugar chain) and dipalmitoyl phosphatidylethanolamine in a molar ratio of 35: 40: 5: 15 : Mixed to a total lipid content of 45.6 mg at a ratio of 5, 46.9 mg of sodium cholate was added, and 3 ml of black mouth form Z methanol solution was dissolved. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane. Obtained The obtained lipid membrane was suspended in 3 ml of TAPS buffer (pH 8.4) and sonicated to obtain 3 ml of a clear micelle suspension. Add PBS buffer (pH 7.2) to this micelle suspension to make 10 ml, and use PM10 membrane (Amicon Co., USA) and TAPS buffer (pH 8.4) for this micelle suspension. 10 ml of a ribosome particle suspension was prepared without subjecting it to ultrafiltration and carrying out a uniform hydrophilic treatment. After adding 5 mg of Bolton Hunter's reagent (BHR; Pierce Co., USA) to this ribosome solution and reacting at 25 ° C for 2 hours and then at 7 ° C for 4 hours, dipalmitoylphosphatidylethanolamine was converted to BH. PBS buffer (PH7.2) was used for ultrafiltration. As a result, 10 ml of ribosome (abbreviation: EEGMl-BH) (total fat mass 45.6 mg, average particle diameter lOOnm) as a comparative sample was obtained.

[0216] 得られた生理食塩懸濁液中（37°C)の抗癌剤ドキソルビシン封入リボソーム粒子の粒 子径とゼータ電位をゼータ電位 ·粒子径 ·分子量測定装置（Model Nano ZS, Ma lvern Instruments Ltd. , UK)により測定した結果、粒子径は 50〜350nm、ゼ ータ電位は 30〜一 10mVであった。  [0216] The particle size and zeta potential of the anticancer drug doxorubicin-encapsulated ribosome particles in the obtained physiological saline suspension (37 ° C) were converted into zeta potential, particle size, molecular weight measuring device (Model Nano ZS, Malvern Instruments Ltd. , UK), the particle size was 50 to 350 nm, and the zeta potential was 30 to 10 mV.

[0217] (実施例 16.リボソーム膜面結合ヒト血清アルブミン (HSA)上の親水性ィ匕処理） 実 施例 15の手段により調製された糖鎖が結合したリボソームについて、以下の手順に よりリボソーム上の HSA蛋白質表面の親水性ィ匕処理を行った。糖鎖結合リボソーム 2 mlに、別々に、トリス（ヒドロキシメチル）ァミノメタン 13mgをカ卩えて、 25°Cで 2時間、そ の後 7°Cで一晩攪拌した後、 XM300膜と PBS緩衝液 (pH 7. 2)で限外濾過し未反 応物を除去して、最終産物である親水性化処理された糖鎖結合リボソーム複合体各 2ml (総脂質量 2mg、総蛋白量 200 μ g、平均粒径 lOOnm)を得た。  (Example 16. Hydrophilic treatment on ribosome membrane surface-bound human serum albumin (HSA)) [0217] The ribosome to which the sugar chain prepared by the means of Example 15 was bound was obtained by the following procedure. The surface of the above HSA protein was subjected to hydrophilic treatment. Separately, 13 ml of tris (hydroxymethyl) aminomethane was separately added to 2 ml of sugar chain-bound ribosome, stirred at 25 ° C for 2 hours, and then at 7 ° C overnight, and then XM300 membrane and PBS buffer ( Unfiltered to remove the unreacted product by pH 7.2), 2 ml each of the glycosylated ribosome complex hydrophilized as the final product (total lipid amount 2 mg, total protein amount 200 μg, average Particle size lOOnm) was obtained.

[0218] (実施例 17.各種の糖鎖結合リボソーム複合体によるレクチン結合活性阻害効果の 測定） 実施例 16の手段により調製した各糖鎖結合リボソーム複合体のインビトロで のレクチン結合活性は、常法（Yamazaki, N. (1999) Drug Delivery System, 14, 498- 505)に従いレクチン固定ィ匕マイクロプレートを用いた阻害実験で測定し た。すなわち、レクチン（E— selectin;R&D Systems Co. , USA)を 96穴マイク 口プレートに固定ィ匕した。このレクチン固定ィ匕プレートに、比較リガンドであるピオチン 化したフコシルイ匕フエチュイン 0. 1 μ gとともに、濃度の異なる各種の糖鎖結合リポソ ーム複合体 (蛋白質量として、 0. 01 g、 0. 04 g、 0. 11 g、 0. 33 g、 1 g)を 加え、 4°Cで 2時間インキュベートした。 PBS (pH 7. 2)で 3回洗浄した後、西洋ヮサ ビペルォキシダーゼ（HRPO)結合ストレプトアビジンを添カ卩し、さらに 4°Cで 1時間ィ ンキュベート、 PBS (pH 7. 2)で 3回洗浄し、ペルォキシダーゼ基質を添カ卩して室 温で静置、 405nmの吸光度をマイクロプレートリーダー（Molecular Devices Co rp. , USA)で測定した。フコシル化フエチュインのピオチン化は、 sulfo— NHS—bi otin reagent (Pierce Co. , USA)処理後、 Centricon— 30 (Amicon Co. , U SA)により精製した。 HRPO結合ストレプトアビジンは、 HRPOの酸化と NaBH CN (Example 17. Measurement of lectin binding activity inhibition effect by various sugar chain-binding ribosome complexes) [0218] In vitro lectin binding activity of each sugar chain-binding ribosome complex prepared by the means of Example 16 According to the method (Yamazaki, N. (1999) Drug Delivery System, 14, 498-505), it was measured in an inhibition experiment using a lectin-fixed microplate. That is, lectin (E-selectin; R & D Systems Co., USA) was immobilized on a 96-well microphone opening plate. To this lectin-immobilized plate, 0.1 μg of fucosyl pheotuine, which is a ligated ligand, and various sugar chain-binding liposome complexes with different concentrations (0.01 g, 0. 04 g, 0.11 g, 0.33 g, 1 g) In addition, it was incubated at 4 ° C for 2 hours. After washing 3 times with PBS (pH 7.2), add horseradish peroxidase (HRPO) -conjugated streptavidin, and incubate at 4 ° C for 1 hour, PBS (pH 7.2) The plate was washed three times with a peroxidase substrate, allowed to stand at room temperature, and the absorbance at 405 nm was measured with a microplate reader (Molecular Devices Corp., USA). Piotination of fucosylated pheutains was purified by Centricon-30 (Amicon Co., USA) after treatment with sulfo-NHS-biotin reagent (Pierce Co., USA). HRPO-conjugated streptavidin oxidizes HRPO and NaBH CN

3 を用いた還元アミノ化法によるストレプトアビジンの結合により調製した。 IC50を上記と 同様にして測定した結果を以下の表に示す。  Prepared by conjugation of streptavidin by the reductive amination method using 3. The results of measuring IC50 as described above are shown in the following table.

[表 13] [Table 13]

Figure imgf000120_0001
Figure imgf000120_0001

(実施例 18.クロラミン Τ法による各種糖鎖結合リボソームの125Ι標識） クロラミン Τ ( Wako Pure Chemical Co. , Japan)溶液並びに二亜硫酸ナトリウム溶液をそれ ぞれ 3mgZmlならびに 5mgZmlとなるように用時調製して用いた。実施例 16により 調製した糖鎖結合リボソームならびにトリス (ヒドロキシメチル)ァミノメタン結合リポソ一 ムを各 ずつ別々にエツペンチューブに入れ、続いて1251— NaI (NEN Life S cience Product, Inc. USA)を 15 ^ 1、クロラミン T溶液を 10 μ 1カ卩ぇ反応させた。 5分ごとにクロラミン Τ溶液 10 1を加え、この操作を 2回繰り返し Before use so that the (Example 18. chloramine 125 iota labeling of various sugar chain binding ribosomes by T method) chloramine Τ (Wako Pure Chemical Co., Japan ) solution and a sodium disulfite solution, respectively it 3mgZml and 5mgZml prepared Used. The sugar chain-linked ribosome and tris (hydroxymethyl) aminomethane-linked liposome prepared according to Example 16 were separately placed in an Eppendorf tube, followed by 125 1-NaI (NEN Life Science Product, Inc. USA). 15 ^ 1, 10 μl of chloramine T solution was reacted. Add Chloramine ク ロ solution 10 1 every 5 minutes and repeat this procedure twice.

た後 15分後に還元剤として二亜硫酸ナトリウム 100 1を加え、反応を停止させた。 次に、 Sephadex G— 50 (Phramacia Biotech. Sweden)カラムクロマト上に乗 せ、 PBSで溶出、標識体を精製した。最後に、非標識—リボソーム複合体を添加して 比活性 (4 X 106 Bq/mg protein)を調整して1251標識リボソーム液を得た。 15 minutes later, sodium disulfite 100 1 was added as a reducing agent to stop the reaction. Next, it was placed on a column chromatography on Sephadex G-50 (Phramacia Biotech. Sweden), eluted with PBS, and the labeled product was purified. Finally, a non-labeled ribosome complex was added to adjust the specific activity (4 × 10 6 Bq / mg protein) to obtain a 125 1-labeled ribosome solution.

[0220] (実施例 19.各種の糖鎖結合リボソーム複合体のマウスでの腸管力 血中への移行 量の測定） 一昼夜水分以外絶食した雄性 ddYマウス（7週齢）に、実施例 17により12 51標識された糖鎖結合ならびにトリス (ヒドロキシメチル)ァミノメタン結合リボソーム複 合体 0. 2mlを蛋白質量として 3 gZ—匹の割合になるように、マウス用経口ゾンデ で腸管内に強制投与した後、 10分後にネンブタール麻酔下で下大動脈より血液 lm 1を採血した。そして、血中の1251放射能をガンマ一カウンター（Alola ARC300)で 測定した。さらに、各種のリボソーム複合体の生体内安定性を調べる目的で、各血液 の血清を Sephadex G— 50で再クロマトした力 いずれも大半の放射能が高分子 量のボイドフラクションにみられ、各種のリボソーム複合体は生体内においても安定 性を有していた。なお、腸管力も血中への放射能移行量は、投与全放射能に対する 血液 lml当たりの放射能の割合（％投与量 Zml血液)で表示した。用いた糖鎖の種 類によって、腸管から血中に移行するものと移行しないものが存在した。この結果を 以下の表に示す。 [0220] (Example 19. Measurement of the amount of intestinal force blood translocation in mice of various sugar chain-binding ribosome complexes) In male ddY mice (7 weeks old) fasted except for water overnight, according to Example 17. 12 5 1 Labeled sugar chain bond and tris (hydroxymethyl) aminomethane-linked ribosome complex 0.2 mg of protein was forced into the intestine with an oral sonde so that the amount of protein was 3 gZ—in the ratio of 3 animals. Ten minutes later, blood lm 1 was collected from the lower aorta under Nembutal anesthesia. Then, 125 1 radioactivity in blood was measured with a gamma counter (Alola ARC300). Furthermore, for the purpose of investigating the in vivo stability of various ribosome complexes, the power of rechromatography of blood serum with Sephadex G-50 was found in most high-molecular-weight void fractions. The ribosome complex was also stable in vivo. The amount of radioactivity transferred into the blood of the intestinal tract was also expressed as the ratio of radioactivity per ml of blood to the total radioactivity administered (% dose of Zml blood). Depending on the type of sugar chain used, there were those that migrated from the intestinal tract into the blood and those that did not migrate. The results are shown in the table below.

[0221] [表 14] [0221] [Table 14]

番号 略称 経口投与 Number Abbreviation Oral administration

+  +

+  +

++  ++

+  +

+  +

+  +

++  ++

++  ++

+  +

++  ++

++  ++

+ +

++ ++

- -

--

+ +

+  +

++  ++

++ ++

- -

++ ++

+  +

++  ++

- -

++ ++

- -

++ ++

++  ++

++  ++

++  ++

-  -

++ ++

++  ++

++  ++

- -

--

++ ++

++  ++

+  +

++  ++

+  +

++  ++

++  ++

- -

- (実施例 20.各種の糖鎖結合リボソーム複合体の尾静注投与による腫瘍を有するマ ウスでの処置効果） (1)腫瘍を有するマウスにおける尾静注投与による処置効果 線維肉腫、筋肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、脊索腫、血管肉腫、リンパ 管肉腫、骨膜腫、中皮腫、平滑筋肉腫、横紋筋肉腫、胃癌、食道癌、直腸癌、脾臓 癌、卵巣癌、前立腺癌、子宮癌、頭部および頸部の癌、皮膚癌、脳の癌、扁平上皮 癌、脂腺癌腫、乳頭状癌、嚢胞腺癌、髄様癌、気管支原生癌、腎細胞癌、肝細胞癌 、胆管癌腫、絨毛上皮癌、セミノーマ、胎生期癌、ウィルムス腫瘍、子宮頸癌、精巣癌 、小細胞性肺癌腫、非小細胞性肺癌種、膀胱癌腫、上皮細胞癌腫、ダリオ一マ、星 状細胞腫、髄芽腫、頭蓋咽頭腫、脳室上衣腫、松果体腫、血管芽腫、聴神経腫、乏 突起神経膠腫、髄膜腫、黒色腫、神経芽腫、網膜芽腫、白血病、リンパ腫および力 ポジ肉腫からなる群より選択される腫瘍のモデルとなるマウスを、 10日間程飼育'観 察し、以下の実験に用いる。これらのマウスを、対象となる疾患の治療に使用可能な 薬剤を封入した糖鎖修飾リボソーム投与群およびコントロールとしての生理食塩水投 与群の 2群に分ける。これらのマウスに、薬剤を封入した糖鎖修飾リボソームまたは生 理食塩水を尾静脈投与により、週 4回、 2週間投与する。週 2回の頻度で、 4週間、疾 患部位を観察する。薬剤封入糖鎖修飾リボソーム投与群および生理食塩水投与群 の疾患部位の変化を比較した結果、薬剤封入糖鎖修飾リボソーム投与群は、極めて 少ない投与量にもかかわらず、投与開始から良好な処置効果を示し、一方、生理食 塩水投与群の疾患部位には変化が見られない。薬剤封入糖鎖修飾リボソームは、尾 静脈投与により有意な処置効果を有することを示す。 -(Example 20. Treatment effect in mice with tumors by intravenous injection of various sugar chain-linked ribosome complexes) (1) Treatment effects of intravenous tail administration in tumor-bearing mice Fibrosarcoma, myoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, hemangiosarcoma, lymphangiosarcoma, periosteum, mesothelioma, smooth Myoma, rhabdomyosarcoma, stomach cancer, esophageal cancer, rectal cancer, spleen cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, brain cancer, squamous cell carcinoma, sebaceous carcinoma , Papillary carcinoma, cystadenocarcinoma, medullary carcinoma, primary bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, cervical cancer, testicular cancer, small cell Lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelial cell carcinoma, Dariooma, astrocytoma, medulloblastoma, craniopharyngioma, ventricular ependymoma, pineal tumor, hemangioblastoma, auditory nerve From glioma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma and force positive sarcoma That tumor model consisting of mouse selected from the group, guess rearing 'views about 10 days, used in the following experiments. These mice are divided into two groups: a sugar chain-modified ribosome administration group encapsulating a drug that can be used to treat the target disease, and a physiological saline administration group as a control. In these mice, sugar chain-modified ribosomes encapsulating drugs or physiological saline are administered 4 times a week for 2 weeks by tail vein administration. Observe the disease site twice a week for 4 weeks. As a result of comparing changes in disease sites in the drug-encapsulated sugar chain-modified ribosome-administered group and the physiological saline-administered group, the drug-encapsulated sugar chain-modified ribosome-administered group showed a good treatment effect from the start of administration despite the extremely small dose. On the other hand, there is no change in the diseased part of the physiological saline administration group. It is shown that drug-encapsulated sugar chain-modified ribosome has a significant therapeutic effect by tail vein administration.

(2)蛍光顕微鏡を用いた尾静注投与での腫瘍への薬剤移行の観察  (2) Observation of drug transfer to the tumor by tail vein injection using a fluorescence microscope

蛍光顕微鏡による観察は、以下のとおり行う。腫瘍を有するマウスの癌部位の皮膚 を切除し、腫瘍部位を露出させスライドガラスに固定する。蛍光顕微鏡のステージ上 にマウスを乗せて腫瘍患部位周囲の血管を探索し、血管像が明瞭に観察できる位置 を決定する。上記（1)と同じ薬剤封入糖鎖修飾リボソームを 0. 2ml尾静脈内に投与 する。投与直後からの疾患部位への薬剤集積を蛍光顕微鏡で観察する。修飾糖前 投与による阻害実験については、薬剤封入糖鎖修飾リボソームの投与 5分前に修飾 糖鎖溶液 (60mM)を 0. 2mL投与し、上記と同様な方法により観察を行う。薬剤封 入糖鎖修飾リボソームの投与後、直ちに疾患部位周辺の血管において薬剤の蛍光 力 S観察される。投与後 5分では血管壁部に薬剤蛍光が観察される。その後、時間の 経過と共に疾患部位への薬剤移行が観察され、 2時間後には、疾患部位の血管周 囲の組織内部に薬剤の蛍光がみられる。修飾糖鎖の前投与により、薬剤封入リポソ ームの疾患部位への集積が完全にブロックされて、薬剤封入糖鎖修飾リボソーム投 与直後からの、血管壁力 の蛍光は見られない。これらの結果は、この糖鎖修飾リポ ノームがリガンドとしての糖鎖の機能を活用して、疾患部位に薬物をアクティブターゲ ティングにより高効率に集積'送達していることを示す。 Observation with a fluorescence microscope is performed as follows. The skin at the cancer site of a mouse with a tumor is excised, and the tumor site is exposed and fixed to a glass slide. Place the mouse on the stage of the fluorescence microscope, search for blood vessels around the tumor site, and determine the position where the blood vessel image can be clearly observed. The same drug-encapsulated sugar chain-modified ribosome as in (1) above is administered into the 0.2 ml tail vein. Drug accumulation at the diseased site immediately after administration is observed with a fluorescence microscope. For the inhibition experiment by pre-administration of the modified sugar, 0.2 mL of the modified sugar chain solution (60 mM) is administered 5 minutes before administration of the drug-encapsulated sugar chain-modified ribosome, and observation is performed in the same manner as described above. Immediately after administration of the drug-encapsulated sugar chain-modified ribosome, the fluorescence of the drug in the blood vessels around the disease site Force S observed. Drug fluorescence is observed in the blood vessel wall 5 minutes after administration. Thereafter, drug transfer to the diseased site is observed over time, and after 2 hours, fluorescence of the drug is seen inside the tissue surrounding the blood vessel of the diseased site. Pre-administration of the modified sugar chain completely blocks the accumulation of the drug-encapsulated liposome at the disease site, and no fluorescence of the vascular wall force is observed immediately after administration of the drug-encapsulated sugar chain-modified ribosome. These results indicate that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand and accumulates and delivers the drug to the disease site by active targeting with high efficiency.

(実施例 21.各種の糖鎖結合リボソーム複合体の経口投与による腫瘍を有するマ ウスでの処置効果）  (Example 21. Treatment effect in mice with tumors by oral administration of various sugar chain-linked ribosome complexes)

(1)腫瘍を有するマウスにおける経口投与による処置効果  (1) Treatment effect by oral administration in tumor-bearing mice

線維肉腫、筋肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、脊索腫、血管肉腫、リンパ 管肉腫、骨膜腫、中皮腫、平滑筋肉腫、横紋筋肉腫、胃癌、食道癌、直腸癌、脾臓 癌、卵巣癌、前立腺癌、子宮癌、頭部および頸部の癌、皮膚癌、脳の癌、扁平上皮 癌、脂腺癌腫、乳頭状癌、嚢胞腺癌、髄様癌、気管支原生癌、腎細胞癌、肝細胞癌 、胆管癌腫、絨毛上皮癌、セミノーマ、胎生期癌、ウィルムス腫瘍、子宮頸癌、精巣癌 、小細胞性肺癌腫、非小細胞性肺癌種、膀胱癌腫、上皮細胞癌腫、ダリオ一マ、星 状細胞腫、髄芽腫、頭蓋咽頭腫、脳室上衣腫、松果体腫、血管芽腫、聴神経腫、乏 突起神経膠腫、髄膜腫、黒色腫、神経芽腫、網膜芽腫、白血病、リンパ腫および力 ポジ肉腫からなる群より選択される腫瘍のモデルとなるマウスを、 10日間程飼育'観 察し、以下の実験に用いる。これらのマウスを、対象となる疾患の治療に使用可能な 薬剤を封入した糖鎖修飾リボソーム投与群およびコントロールとしての生理食塩水投 与群の 2群に分ける。これらのマウスに、薬剤を封入した糖鎖修飾リボソームまたは生 理食塩水を経口投与により、週 4回、 2週間投与する。週 2回の頻度で、 4週間、疾患 部位を観察する。薬剤封入糖鎖修飾リボソーム投与群および生理食塩水投与群の 疾患部位の変化を比較した結果、薬剤封入糖鎖修飾リボソーム投与群は、極めて少 ない投与量にもかかわらず、投与開始から良好な処置効果を示し、一方、生理食塩 水投与群の疾患部位には変化が見られない。薬剤封入糖鎖修飾リボソームは、経口 投与により有意な処置効果を有することを示す。 [0225] (2)蛍光顕微鏡を用いた経口投与での腫瘍部位への薬剤移行の観察 蛍光顕微鏡による観察は、以下のとおり行う。腫瘍を有するマウスの癌部位の皮膚 を切除し、腫瘍部位を露出させスライドガラスに固定する。蛍光顕微鏡のステージ上 にマウスを乗せて腫瘍部位周囲の血管を探索し、血管像が明瞭に観察できる位置を 決定する。上記（1)と同じ薬剤封入糖鎖修飾リボソームを 0. 2ml経口投与する。投 与直後からの疾患部位への薬剤集積を蛍光顕微鏡で観察する。修飾糖前投与によ る阻害実験については、薬剤封入糖鎖修飾リボソームの投与 5分前に修飾糖鎖溶液 (60mM)を 0. 2mL投与し、上記と同様な方法により観察を行う。薬剤封入糖鎖修 飾リボソームの投与後、直ちに疾患部位周辺の血管において薬剤の蛍光が観察さ れる。投与後 5分では血管壁部に薬剤蛍光が観察される。その後、時間の経過と共 に疾患部位への薬剤移行が観察され、 2時間後には、疾患部位の血管周囲の組織 内部に薬剤の蛍光がみられる。修飾糖鎖の前投与により、薬剤封入リボソームの疾 患部位への集積が完全にブロックされて、薬剤封入糖鎖修飾リボソーム投与直後か らの、血管壁からの蛍光は見られない。これらの結果は、この糖鎖修飾リボソームがリ ガンドとしての糖鎖の機能を活用して、疾患部位に薬物をアクティブターゲテイングに より高効率に集積'送達していることを示す。 Fibrosarcoma, muscle sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, lymphangiosarcoma, periosteum, mesothelioma, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, rectal cancer , Spleen cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, brain cancer, squamous cell carcinoma, sebaceous carcinoma, papillary carcinoma, cystadenocarcinoma, medullary cancer, bronchial progenitor Cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, cervical cancer, testicular cancer, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelium Cell carcinoma, Darioma, astrocytoma, medulloblastoma, craniopharyngioma, ventricular ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, A mouse model of a tumor selected from the group consisting of neuroblastoma, retinoblastoma, leukemia, lymphoma and force positive sarcoma, 10 days Guess extent breeding 'view, used in the following experiment. These mice are divided into two groups: a sugar chain-modified ribosome administration group encapsulating a drug that can be used to treat the target disease, and a physiological saline administration group as a control. These mice are orally administered sugar-modified ribosome encapsulating the drug or physiological saline 4 times a week for 2 weeks. Observe the disease site twice a week for 4 weeks. As a result of comparing changes in disease sites in the drug-encapsulated sugar chain-modified ribosome-administered group and the physiological saline-administered group, the drug-encapsulated sugar chain-modified ribosome-administered group showed good treatment from the start of administration despite the extremely small dose. On the other hand, there is no change in the disease site of the saline administration group. Drug-encapsulated sugar chain-modified ribosomes have a significant therapeutic effect by oral administration. (2) Observation of drug transfer to the tumor site by oral administration using a fluorescence microscope Observation using a fluorescence microscope is performed as follows. The skin at the cancer site of a mouse with a tumor is excised, and the tumor site is exposed and fixed to a glass slide. Place the mouse on the stage of the fluorescence microscope, search for blood vessels around the tumor site, and determine the position where the blood vessel image can be clearly observed. Orally administer 0.2 ml of the same drug-encapsulated sugar chain-modified ribosome as in (1) above. Drug accumulation at the site of disease immediately after administration is observed with a fluorescence microscope. For the inhibition experiment with the modified sugar pre-administration, 0.2 mL of the modified sugar chain solution (60 mM) is administered 5 minutes before administration of the drug-encapsulated sugar chain-modified ribosome, and observation is performed in the same manner as described above. Immediately after administration of the drug-encapsulated sugar chain-modified ribosome, fluorescence of the drug is observed in the blood vessels around the disease site. Drug fluorescence is observed in the blood vessel wall 5 minutes after administration. Thereafter, drug transfer to the diseased site is observed over time, and after 2 hours, fluorescence of the drug is seen inside the tissue around the blood vessel at the diseased site. Pre-administration of the modified sugar chain completely blocks the accumulation of the drug-encapsulated ribosome at the disease site, and no fluorescence from the blood vessel wall is observed immediately after administration of the drug-encapsulated sugar chain-modified ribosome. These results indicate that this sugar chain-modified ribosome utilizes the function of the sugar chain as a ligand and accumulates and delivers the drug to the disease site with high efficiency by active targeting.

[0226] 糖鎖修飾リボソームの標的指向性は、糖鎖の種類によって制御される。さらに糖鎖 の結合密度を考慮することにより、より適切な腫瘍指向性糖鎖修飾リボソームを選択 することができる。この標的指向性は、糖鎖修飾リボソームが薬物を含んでいても、含 んで 、なくても変更されな 、。  [0226] The target directivity of the sugar chain-modified ribosome is controlled by the type of sugar chain. Furthermore, considering the binding density of sugar chains, more appropriate tumor-directed sugar chain-modified ribosomes can be selected. This targeting is not altered whether or not the glycosylated ribosome contains or does contain a drug.

[0227] (実施例 22.ビタミン A封入リボソームの調製と封入薬物定量と保存安定性）  (Example 22. Preparation of vitamin A-encapsulated ribosome, quantification of encapsulated drug, and storage stability)

リボソームはコール酸透析法を用いて調製した。すなわち、ジパルミトイルホスファ チジルコリン、コレステロール、ジセチルホスフェート、ガンダリオシド及びジパルミトイ ルホスファチジルエタノールアミンをモル比でそれぞれ 35 :40 : 5 : 15 : 5の割合で合 計脂質量 45. 6mgになるように混合し、コール酸ナトリウム 46. 9mg添加し、クロロホ ルム Zメタノール溶液 3mlに溶解した。この溶液を蒸発させ、沈殿物を真空中で乾燥 させることによって脂質膜を得た。得られた脂質膜を TAPS緩衝生理食塩液 (pH8. 4) 3mlに懸濁、超音波処理し、透明なミセル懸濁液 10mlを得た。このミセル懸濁液 に TAPS緩衝液 (pH8. 4)で 3mg/lmlになるよう完全に溶解したビタミン Aを撹拌 しながらゆっくりと滴下して均一に混合した後、このビタミン A入りミセル懸濁液を PM 10膜 (AmiconCo. , USA)と TAPS緩衝生理食塩液 (pH8. 4)を用いた限外濾過 にかけ均一なビタミン A封入リボソーム粒子懸濁液 10mlを調製した。得られた生理 食塩懸濁液中（37°C)のビタミン A封入リボソーム粒子の粒子径とゼータ電位をゼー タ電位'粒子径 '分子量測定装置（ModelNanoZS, Malvern InstrumentsLtd, , UK)により測定した結果、粒子径は 50〜350nm、ゼータ電位は— 30〜一 10mV であった。このリボソームの封入薬物量を吸光度 260nmで測定するとおよそ 280 g /mlの濃度でビタミン Aが封入されていることがわかった。このビタミン A封入リポソ ームは、冷蔵庫中に 1年間保存した後にも沈殿や凝集を起こすことなく安定であった Ribosomes were prepared using the cholate dialysis method. In other words, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, gandarioside and dipalmitoyl phosphatidylethanolamine were mixed in a molar ratio of 35: 40: 5: 15: 5 to give a total lipid amount of 45.6 mg. 46.9 mg of sodium cholate was added and dissolved in 3 ml of chloroform Z methanol solution. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane. The obtained lipid membrane was suspended in 3 ml of TAPS buffered physiological saline (pH 8.4) and sonicated to obtain 10 ml of a transparent micelle suspension. This micelle suspension Vitamin A completely dissolved in TAPS buffer (pH 8.4) to 3 mg / lml is slowly added dropwise with stirring and mixed uniformly, and this micelle suspension containing vitamin A is added to a PM 10 membrane ( AmiconCo., USA) and ultrafiltration using TAPS buffered saline (pH 8.4) to prepare 10 ml of a uniform suspension of ribosome particles encapsulating vitamin A. Results of measuring the particle size and zeta potential of vitamin A-encapsulated ribosome particles in the physiological saline suspension (37 ° C) using a zeta potential 'particle size' molecular weight measuring device (ModelNanoZS, Malvern Instruments Ltd,, UK) The particle size was 50 to 350 nm, and the zeta potential was -30 to 1-10 mV. When the amount of drug contained in the ribosome was measured at an absorbance of 260 nm, it was found that vitamin A was encapsulated at a concentration of about 280 g / ml. This vitamin A-encapsulated liposome was stable without precipitation or aggregation even after storage for 1 year in a refrigerator.

[0228] (実施例 23.ガンダリオシドを含まない糖鎖修飾リボソームの調製） (Example 23. Preparation of a sugar chain-modified ribosome containing no gandarioside)

(1.リボソームの調製）  (1. Preparation of ribosome)

リボソームは既報の手法（Yamazaki, N. , Kodama, M. and Gabius, H. —J. (1994) Methods Enzymol. 242, 56— 65)により、改良型コール酸透析法を用 いて調製した。すなわち、ジパルミトイルホスファチジルコリン、コレステロール、ジセ チルホスフェート、及びジパルミトイルホスファチジルエタノールアミンを合計脂質量 4 5. 6mgになるように混合し、コール酸ナトリウム 46. 9mgを添カロし、クロ口ホルム Zメ タノール溶液 3mlに溶解させる。この溶液を蒸発させ、沈殿物を真空中で乾燥させる ことによって脂質膜を得る。得られた脂質膜を TAPS緩衝液 (pH 8. 4) 3mlに懸濁 、超音波処理して、透明なミセル懸濁液を得る。さらに、ミセル懸濁液を PM 10膜 ( A micon Co. , USA)と PBS緩衝液 (pH 7. 2)を用いた限外濾過にかけ均一リポソ ーム（平均粒径 lOOnm) 10mlを調製する。  Ribosomes were prepared according to a previously reported method (Yamazaki, N., Kodama, M. and Gabius, H. —J. (1994) Methods Enzymol. 242, 56-65) using an improved cholate dialysis method. That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, and dipalmitoyl phosphatidylethanolamine were mixed so that the total lipid amount was 45.6 mg, and sodium cholate 46.9 mg was added to the mixture, followed by Kuroguchi Form Z methanol. Dissolve in 3 ml of solution. The solution is evaporated and the precipitate is dried in vacuo to obtain a lipid membrane. The obtained lipid membrane is suspended in 3 ml of TAPS buffer (pH 8.4) and sonicated to obtain a transparent micelle suspension. Furthermore, the micelle suspension is subjected to ultrafiltration using a PM 10 membrane (A micon Co., USA) and PBS buffer (pH 7.2) to prepare 10 ml of a uniform liposome (average particle size lOOnm).

[0229] (2.リボソーム脂質膜面上の親水性化処理） [0229] (2. Hydrophilization treatment on ribosomal lipid membrane surface)

上記 1.において調製したリボソーム溶液 10mlを XM300膜 (Amicon Co. , US A)と CBS緩衝液 (pH 8. 5)を用いた限外濾過にかけ溶液の pHを 8. 5にする。次 に、架橋試薬 bis (sulfosuccinimidyl) suberate (BS3 ;Pierce Co. , USA) 10ml を加え、 25°Cで 2時間攪拌する。その後、更に 7°Cで一晩攪拌してリボソーム膜上の 脂質ジパルミトイルフォスファチジルエタノールァミンと BS3との化学結合反応を完結 させる。そして、このリボソーム液を XM300膜と CBS緩衝液 (pH 8. 5)で限外濾過 にかける。次に、 CBS緩衝液 (pH 8. 5) lmlに溶力したトリス（ヒドロキシメチル)アミ ノメタン 40mgをリボソーム液 10mlに加えて、 25°Cで 2時間攪拌後、 7°Cで一晩攪拌 してリボソーム膜上の脂質に結合した BS3とトリス (ヒドロキシメチル)ァミノメタンとの化 学結合反応を完結させる。これにより、リボソーム膜の脂質ジパルミトイルフォスファチ ジルエタノールァミン上にトリス（ヒドロキシメチル）ァミノメタンの水酸基が配位して水 和親水性化される。 10 ml of the ribosome solution prepared in 1 above is subjected to ultrafiltration using XM300 membrane (Amicon Co., USA) and CBS buffer (pH 8.5) to adjust the pH of the solution to 8.5. Next, add 10 ml of the crosslinking reagent bis (sulfosuccinimidyl) suberate (BS3; Pierce Co., USA), and stir at 25 ° C for 2 hours. Then, stir overnight at 7 ° C on the ribosome membrane. Completes the chemical binding reaction between the lipid dipalmitoylphosphatidylethanolamine and BS3. The ribosome solution is then ultrafiltered with XM300 membrane and CBS buffer (pH 8.5). Next, 40 mg of tris (hydroxymethyl) aminomethane dissolved in 1 ml of CBS buffer (pH 8.5) was added to 10 ml of ribosome solution, stirred at 25 ° C for 2 hours, and then stirred at 7 ° C overnight. Thus, the chemical binding reaction between BS3 bound to lipid on the ribosome membrane and tris (hydroxymethyl) aminomethane is completed. As a result, the hydroxyl group of tris (hydroxymethyl) aminomethane is coordinated on the lipid dipalmitoylphosphatidylethanolamine of the ribosome membrane to make it hydrated.

[0230] (3.リボソーム膜面上へのヒト血清アルブミン（HSA)の結合） [0230] (3. Binding of human serum albumin (HSA) to ribosome membrane surface)

実施例 3と同様の手法によりリボソーム膜面上ヘヒト血清アルブミン (HSA)を結合さ せる処理を行う。その結果、ヒト血清アルブミン (HSA)は、リボソーム膜面上に結合し ないという結果を得る。  In the same manner as in Example 3, treatment to bind human serum albumin (HSA) on the ribosome membrane surface is performed. As a result, human serum albumin (HSA) does not bind on the ribosome membrane surface.

[0231] (実施例 24.各種の糖鎖結合リボソーム複合体の尾静注投与による担癌マウスで の制癌効果の測定）  [Example 24. Measurement of anticancer effect in tumor-bearing mice by intravenous injection of various sugar chain-binding ribosome complexes]

(1)担癌マウスにおける尾静注投与による制癌効果  (1) Anticancer effect of tail vein injection in tumor-bearing mice

担癌マウスの作成は、 ddY系 7週齢マウス (雄性、体重 35〜40g)の背部毛髪を電動バ リカンで剃り、皮下に Ehrlich Ascites Tumor (細胞約 5xl06個/匹）を移殖した。 10日間 程飼育'観察を行い、癌細胞の生着したものを選び実験に用いた。薬物投与並びに 癌の体積測定は、投与薬剤として封入されたドキソルビシン濃度を 0.0625mgZkgに 調製したドキソルビシン封入リボソーム番号 155投与群とコントロールとして生理食塩 水投与群の 2種類とし、担癌マウスに尾静脈投与を週 4回、 2週間投与した。癌細胞 移植後 10日目から、週 2回の頻度で、 4週間、ノギスを用いて癌の長径と短径を測定 し、以下の式より癌の増殖体積を算出した。癌体積 (mm3) = (長径 +短径 2) Z2 この 結果を図 1に示す。ドキソルビシン封入リボソーム番号 155投与群とコントロールとして 生理食塩水投与群の腫瘍の増殖体積の変化を各群で比較した結果、極めて少な!/、 投与量にもかかわらず、ドキソルビシン封入リボソーム番号 155投与群の癌の増殖抑 制効果は、顕著で投与開始力 癌の増殖が抑えられた。最終測定日である移植 34 日目における癌組織の大きさ（体積)を比較すると、ドキソルビシン封入リボソーム番 号 155投与群は生理食塩水投与群と比較し有意な抑制作用がみられた。これらの結 果は、この制癌剤封入'糖鎖修飾リボソームが、極めて少ない薬剤投与量で強い制 癌効果を有することを示すものである（図 2)。 The tumor-bearing mice were prepared by shaving the back hair of a ddY 7-week-old mouse (male, body weight 35-40 g) with an electric hair clipper and transplanting Ehrlich Ascites Tumor (approximately 5xl0 6 cells / mouse) subcutaneously. They were kept for about 10 days and observed, and those with cancer cells engrafted were selected and used for the experiment. For drug administration and cancer volume measurement, the doxorubicin-encapsulated ribosome number 155 prepared in 0.0625 mgZkg encapsulated as the drug to be administered, and the physiological saline group as a control were administered to the tumor-bearing mice via the tail vein. Was administered 4 times a week for 2 weeks. From the 10th day after cancer cell transplantation, the major axis and minor axis of the cancer were measured with calipers at a frequency of twice a week for 4 weeks, and the growth volume of the cancer was calculated from the following formula. Cancer volume (mm 3 ) = (major axis + minor axis 2 ) Z2 The results are shown in FIG. Comparison of changes in tumor growth volume between the doxorubicin-encapsulated ribosome No. 155 administration group and the physiological saline administration group as a result of each group showed extremely little! /, Despite the dose, the doxorubicin-encapsulated ribosome no. 155 administration group The suppressive effect on cancer growth was remarkable, and the ability to start administration was suppressed. Comparing the size (volume) of cancer tissue on the 34th day of transplantation, which is the final measurement day, the number of ribosomes encapsulating doxorubicin The No. 155 administration group showed a significant inhibitory effect compared to the saline administration group. These results indicate that this anticancer drug-encapsulated 'glycan-modified ribosome has a strong anticancer effect at a very small drug dose (Fig. 2).

[0232] 図 2は、ドキソルビシン封入リボソーム番号 155の尾静注投与での担癌マウスにおけ る制癌効果を示す図である。 [0232] Fig. 2 is a diagram showing the anticancer effect in tumor-bearing mice after intravenous administration of doxorubicin-encapsulated ribosome # 155 to the tail.

(2)蛍光顕微鏡を用いた尾静注投与での癌組織へのドキソルビシンの移行の観察 蛍光顕微鏡による観察は、担癌マウスの癌部位の皮膚を切除し、癌組織を露出させ スライドガラスに癌部位を固定させた。蛍光顕微鏡のステージ上にマウスを乗せて癌 組織周囲血管の探索を行い、血管像が明瞭に観察できる位置を決定した。脂質濃 度として 2mg/mL、ドキソルビシン濃度として 0.025mg/mLとしたドキソルビシン封入リポ ソーム番号 155を 0.2ml尾静脈内に投与した。投与直後からの癌糸且織へのドキソルビ シンの集積を蛍光顕微鏡で観察した。修飾糖前投与による阻害実験については、ド キソルビシン封入リボソーム番号 155投与 5分前に修飾糖鎖 1-6マンノビオース） 溶液 (60mM)を 0.2mL投与し、上記と同様な方法により観察を行った。その結果を写 真 1に示す。ドキソルビシン封入リボソーム番号 155投与後、直ちに癌組織周辺血管 でのドキソルビシンの蛍光が観察された。投与後 5分では血管壁部にドキソルビシン の赤色蛍光が観察された。その後、時間の経過と共に組織へのドキソルビシンの移 行が観察され、 2時間後には、癌血管周囲の腫瘍組織内部にドキソルビシンの蛍光 がみられた。修飾糖鎖の前投与により、ドキソルビシン封入リボソーム番号 155の腫瘍 組織への集積が完全にブロックされて、ドキソルビシン封入リボソーム番号 155投与直 後からの血管壁からの蛍光は見られな力つた。これらの結果は、この糖鎖修飾リポソ ームがリガンドとしての糖鎖の機能を活用して、疾患患部や各種臓器へ薬物や蛍光 物質や放射標識物質などをアクティブターゲティングにより高効率に集積 '送達する ことを示すものである（図 3)。  (2) Observation of doxorubicin transfer to cancer tissue by intravenous tail vein administration using a fluorescence microscope Observation with a fluorescence microscope is performed by removing the skin of the cancer site of a tumor-bearing mouse and exposing the cancer tissue to the slide glass. The site was fixed. The mouse was placed on the stage of a fluorescence microscope to search for blood vessels surrounding the cancer tissue, and the position where the blood vessel image could be clearly observed was determined. 0.2 ml of doxorubicin-encapsulated liposome No. 155 with a lipid concentration of 2 mg / mL and a doxorubicin concentration of 0.025 mg / mL was administered into the tail vein. Accumulation of doxorubicin on the cancer yarn and tissue immediately after administration was observed with a fluorescence microscope. In the inhibition experiment by the pre-administration of modified sugar, 0.2 mL of the modified sugar chain 1-6 mannobiose) solution (60 mM) was administered 5 minutes before administration of doxorubicin-encapsulated ribosome No. 155, and observation was performed in the same manner as described above. The result is shown in Photo 1. Immediately after administration of doxorubicin-encapsulated ribosome No. 155, fluorescence of doxorubicin was observed in the blood vessels surrounding the cancer tissue. Five minutes after administration, red fluorescence of doxorubicin was observed in the blood vessel wall. Thereafter, the transfer of doxorubicin to the tissue was observed over time, and after 2 hours, fluorescence of doxorubicin was observed inside the tumor tissue around the cancer blood vessels. Pre-administration of the modified sugar chain completely blocked the accumulation of doxorubicin-encapsulated ribosome # 155 in the tumor tissue, and the fluorescence from the blood vessel wall immediately after administration of doxorubicin-encapsulated ribosome # 155 was strong. These results show that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand to efficiently integrate drugs, fluorescent substances, radiolabeled substances, etc. into diseased areas and various organs through active targeting. (Figure 3).

[0233] 図 3は、ドキソルビシン封入リボソーム番号 155の尾静注投与での担癌マウスにお ける腫瘍血管力 腫瘍組織並びに細胞へのドキソルビシンの集積効果を示す蛍光 顕微鏡写真である。左側並びに右側の画像は、同一腫瘍組織'細胞のそれぞれ緑 色並びに赤色の蛍光顕微鏡写真であって、緑色 (左側の画像）は、血管、組織並び に細胞の自然蛍光を示し、赤色 (右側の画像）は、蛍光物質であるドキソルビシンの 腫瘍組織並びに癌細胞中での蛍光を示す。これらの結果は、この糖鎖修飾リポソ一 ムがリガンドとしての糖鎖の機能を活用して、疾患患部や各種臓器へ薬物や蛍光物 質や放射標識物質などをアクティブターゲティングにより高効率に集積'送達すること を示すものである。従って、本発明の糖鎖修飾リボソームは、腫瘍などの標的組織で の集積を可視化できるので、治療用薬剤送達媒体としての利用とともに、研究試薬 や診断薬などとしての利用への送達媒体をも提供する。 [0233] Fig. 3 is a fluorescence micrograph showing the accumulation effect of doxorubicin on tumor tissue and cells in tumor-bearing mice after intravenous injection of doxorubicin-encapsulated ribosome # 155. The left and right images are green and red fluorescence micrographs of the same tumor tissue 'cell, respectively. Green (left image) shows blood vessels and tissues. The red fluorescence (right image) shows the fluorescence of doxorubicin, a fluorescent substance, in tumor tissues and cancer cells. These results show that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand to efficiently accumulate drugs, fluorescent substances, radiolabeled substances, etc. in diseased areas and various organs through active targeting. Indicates delivery. Therefore, since the sugar chain-modified ribosome of the present invention can visualize accumulation in a target tissue such as a tumor, it also provides a delivery medium for use as a research drug or a diagnostic agent as well as a therapeutic drug delivery medium. To do.

[0234] (実施例 25.各種の糖鎖結合リボソーム複合体の経口投与による担癌マウスでの制 癌効果の測定）  [Example 25. Measurement of anticancer effect in cancer-bearing mice by oral administration of various sugar chain-binding ribosome complexes]

(1)担癌マウスにおける経口投与による制癌効果  (1) Anticancer effect by oral administration in cancer-bearing mice

担癌マウスの作成は、 ddY系 7週齢マウス (雄性、体重 35〜40g)の背部毛髪を電動バ リカンで剃り、皮下に Ehrlich Ascites Tumor (細胞約 5xl06個/匹）を移殖した。 10日間 程飼育'観察を行い、癌細胞の生着したものを選び実験に用いた。薬物投与並びに 癌の体積測定は、投与薬剤として封入されたドキソルビシン濃度を 0.375mgZkgに調 製したドキソルビシン封入リボソーム番号 237投与群とコントロールとして生理食塩水 投与群の 2種類とし、担癌マウスに経口投与を週 4回、 2週間投与した。癌細胞移植 後 10日目から、週 2回の頻度で、 4週間、ノギスを用いて癌の長径と短径を測定し、以 下の式より癌の増殖体積を算出した。癌体積 (mm3) = (長径 +短径 2) Z2 この結果 を図 1に示す。ドキソルビシン封入リボソーム番号 237投与群とコントロールとして生理 食塩水投与群の腫瘍の増殖体積の変化を各群で比較した結果、極めて少な!、投与 量にもかかわらず、ドキソルビシン封入リボソーム番号 237投与群の癌の増殖抑制効 果は、顕著で投与開始力 癌の増殖が抑えられた。最終測定日である移植 34日目 における癌組織の大きさ（体積)を比較すると、ドキソルビシン封入リボソーム番号 237 投与群は生理食塩水投与群と比較し有意な抑制作用がみられた。これらの結果は、 この制癌剤封入'糖鎖修飾リボソームが、極めて少ない薬剤投与量で強い制癌効果 を有することを示すものである（図 4)。 The tumor-bearing mice were prepared by shaving the back hair of a ddY 7-week-old mouse (male, body weight 35-40 g) with an electric hair clipper and transplanting Ehrlich Ascites Tumor (approximately 5xl0 6 cells / mouse) subcutaneously. They were kept for about 10 days and observed, and those with cancer cells engrafted were selected and used for the experiment. For drug administration and cancer volume measurement, the doxorubicin-encapsulated ribosome number 237 administration group prepared at 0.375 mgZkg encapsulated as the drug to be administered and the physiological saline administration group as a control were administered orally to tumor-bearing mice. Was administered 4 times a week for 2 weeks. From the 10th day after cancer cell transplantation, the major axis and minor axis of the cancer were measured with calipers at a frequency of twice a week for 4 weeks, and the growth volume of the cancer was calculated from the following formula. Cancer volume (mm 3 ) = (major axis + minor axis 2 ) Z2 The results are shown in FIG. Comparison of changes in tumor growth volume between the doxorubicin-encapsulated ribosome No. 237 administration group and the physiological saline as a control group was extremely small. The growth-suppressing effect was remarkable, and the ability to start administration was suppressed. Comparing the size (volume) of cancer tissue on the 34th day of transplantation, which was the last measurement day, the doxorubicin-encapsulated ribosome No. 237 administration group showed a significant inhibitory effect compared to the physiological saline administration group. These results indicate that this anticancer drug-encapsulated 'glycan-modified ribosome has a strong anticancer effect at a very small dose of drug (Fig. 4).

[0235] 図 4は、ドキソルビシン封入リボソーム番号 237の経口投与での担癌マウスにおける 制癌効果を示す図である。 (2)蛍光顕微鏡を用いた経口投与での癌組織へのドキソルビシンの移行の観察 蛍光顕微鏡による観察は、担癌マウスの癌部位の皮膚を切除し、癌組織を露出さ せスライドガラスに癌部位を固定させた。蛍光顕微鏡のステージ上にマウスを乗せて 癌組織周囲血管の探索を行い、血管像が明瞭に観察できる位置を決定した。脂質 濃度として 4mg/mL、ドキソルビシン濃度として 0.050mg/mLとしたドキソルビシン封入 リボソーム番号 237を 0.3ml経口投与した。投与直後からの癌組織へのドキソルビシン の集積を蛍光顕微鏡で観察した。修飾糖前投与による阻害実験については、ドキソ ルビシン封入リボソーム番号 237投与 5分前に修飾糖鎖 1-3マンノビオース)溶液 ( 60mM)を 0.3mL投与し、上記と同様な方法により観察を行った。その結果を写真 1に 示す。ドキソルビシン封入リボソーム番号 237投与後、時間の経過と共に組織へのド キソルビシンの移行が観察され、 6時間後には、癌血管周囲の腫瘍組織内部にドキ ソルビシンの蛍光がみられた。修飾糖鎖の前投与により、ドキソルビシン封入リポソ一 ム番号 237の腫瘍組織への集積が完全にブロックされて、ドキソルビシン封入リポソ一 ム番号 237投与直後力もの血管壁力もの蛍光は見られな力つた。これらの結果は、こ の糖鎖修飾リボソームがリガンドとしての糖鎖の機能を活用して、疾患患部や各種臓 器へ薬物や蛍光物質や放射標識物質などをアクティブターゲティングにより高効率 に集積'送達することを示すものである（図 5)。 [0235] Fig. 4 is a graph showing the anticancer effect in tumor-bearing mice after oral administration of doxorubicin-encapsulated ribosome number 237. (2) Observation of transfer of doxorubicin to cancer tissue by oral administration using a fluorescence microscope The observation with a fluorescence microscope is performed by removing the skin of the cancer site of a tumor-bearing mouse and exposing the cancer tissue to the slide glass. Was fixed. A mouse was placed on the stage of a fluorescence microscope to search for blood vessels surrounding the cancer tissue, and a position where a blood vessel image could be clearly observed was determined. 0.3 ml of doxorubicin-encapsulated ribosome No. 237 at a lipid concentration of 4 mg / mL and a doxorubicin concentration of 0.050 mg / mL was orally administered. Accumulation of doxorubicin in the cancer tissue immediately after administration was observed with a fluorescence microscope. In the inhibition experiment by the pre-administration of modified sugar, 0.3 mL of the modified sugar chain 1-3 mannobiose) solution (60 mM) was administered 5 minutes before administration of ribosome No. 237 encapsulated with doxorubicin, and observation was performed in the same manner as described above. The result is shown in Photo 1. After administration of doxorubicin-encapsulated ribosome No. 237, transfer of doxorubicin to the tissue was observed over time, and 6 hours later, doxorubicin fluorescence was observed inside the tumor tissue around the cancer blood vessels. Pre-administration of the modified sugar chain completely blocked the accumulation of doxorubicin-encapsulated liposome number 237 in the tumor tissue, and the fluorescence of the vascular wall force was strong as soon as doxorubicin-encapsulated liposome number 237 was administered. . These results show that this sugar chain-modified ribosome utilizes the function of the sugar chain as a ligand to efficiently integrate and deliver drugs, fluorescent substances, radiolabeled substances, etc. to diseased affected areas and various organs through active targeting. (Figure 5).

図 5は、ドキソルビシン封入リボソーム番号 237の経口投与での担癌マウスにおける 腫瘍血管から腫瘍組織並びに細胞へのドキソルビシン集積効果を示す蛍光顕微鏡 写真である。左側並びに右側の画像は、同一腫瘍組織 ·細胞のそれぞれ緑色並び に赤色の蛍光顕微鏡写真であって、緑色 (左側の画像）は、血管、組織並びに細胞 の自然蛍光を示し、赤色 (右側の画像）は、蛍光物質であるドキソルビシンの腫瘍組 織並びに癌細胞中での蛍光を示す。これらの結果は、この糖鎖修飾リボソームがリガ ンドとしての糖鎖の機能を活用して、疾患患部や各種臓器へ薬物や蛍光物質や放 射標識物質などをアクティブターゲティングにより高効率に集積 '送達することを示す ものである。従って、本発明の糖鎖修飾リボソームは、腫瘍などの標的組織での集積 を可視化できるので、治療用薬剤送達媒体としての利用とともに、研究試薬や診断 薬などとしての利用への送達媒体をも提供する。 [0237] 以上のように、本発明の好ましい実施形態を用いて本発明を例示してきた力 本発 明は、この実施形態に限定して解釈されるべきものではない。本発明は、特許請求 の範囲によってのみその範囲が解釈されるべきであることが理解される。当業者は、 本発明の具体的な好ましい実施形態の記載から、本発明の記載および技術常識に 基づいて等価な範囲を実施することができることが理解される。本明細書において引 用した特許、特許出願および文献は、その内容自体が具体的に本明細書に記載さ れているのと同様にその内容が本明細書に対する参考として援用されるべきであるこ とが理解される。 FIG. 5 is a fluorescence micrograph showing the effect of doxorubicin accumulation from tumor blood vessels to tumor tissues and cells in tumor-bearing mice after oral administration of doxorubicin-encapsulated ribosome No. 237. The left and right images are fluorescent micrographs of the same tumor tissue and cells, respectively, in green and red. Green (left image) shows the natural fluorescence of blood vessels, tissues and cells, and red (right image). ) Shows the fluorescence of doxorubicin, a fluorescent substance, in tumor tissues and cancer cells. These results show that this sugar chain-modified ribosome utilizes the function of the sugar chain as a ligand to efficiently integrate drugs, fluorescent substances, radiolabeled substances, etc. into diseased areas and various organs through active targeting. It shows what to do. Therefore, since the sugar chain-modified ribosome of the present invention can visualize accumulation in target tissues such as tumors, it also provides a delivery medium for use as a therapeutic drug delivery medium as well as a research reagent or a diagnostic drug. To do. [0237] As described above, the power that has exemplified the present invention using the preferred embodiment of the present invention. The present invention should not be construed as being limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range based on the description of the present invention and the common general technical knowledge from the description of specific preferred embodiments of the present invention. Patents, patent applications and literature references cited in this specification should be incorporated by reference as if the contents themselves were specifically described in the present specification. Is understood.

産業上の利用可能性  Industrial applicability

[0238] 本発明は、目的の送達部位に薬物を経口投与又は静脈投与によって送達すること ができるという有用性を有する。従って、本発明は、糖鎖修飾リボソームに薬剤や遺 伝子を封入した薬剤送達組成物及びこれに関連する有用性を提供する。 [0238] The present invention has utility that a drug can be delivered to a target delivery site by oral administration or intravenous administration. Therefore, the present invention provides a drug delivery composition in which a drug or gene is encapsulated in a sugar chain-modified ribosome and utility related thereto.

Claims

IBUB M IBUB M 、。VN。IOS'I O ,. VN. IOS'I O 、。VN。IO ' iq。VN。IO iqus^(s' ^UBWS' ^UB^)9' ^UB^(S' ^UB^)9' ^UB^ ,. VN. IO 'iq. VN. IO iqus ^ (s' ^ UBWS '^ UB ^) 9 ' ^ UB ^ (S '^ UB ^) 9 ' ^ UB ^ 、。VN。I09'I 0 ,. VN. I09'I 0 、。VN。IO ' iq。VN。IO iqus^(s' UB^S' ^UBWS' ^UB^)9' ^UB^(S' ^UB^)9' ^UB^ ,. VN. IO 'iq. VN. IO iqus ^ (s 'UB ^ S' ^ UBWS '^ UB ^) 9' ^ UB ^ (S '^ UB ^) 9' ^ UB ^ 、。VN。io 'iq。v,. VN. io 'iq. v N°10^' i u^ CS' ΐ^ ζ' ΐ^ ζ' ΐ^ )9' TBUB (S' ΐΏυΏ 2' ΐΏυΏ )9' ΐΏυΏ 2' TBUB N ° 10 ^ 'iu ^ CS ' ΐ ^ ζ 'ΐ ^ ζ' ΐ ^) 9 'T BUB (S' ΐ ΏυΏ 2 'ΐ ΏυΏ) 9' ΐ ΏυΏ 2 'T BUB 、。VN。IO,. VN. IO ^VN^lOCS'T^Wiqpo^eOS-O)-^^ VN ^ lOCS'T ^ Wiqpo ^ eOS-O)-^ FO(2'TBont[)S'T∞VNFO 、。VN。 ΐ 0FO (2'T Bon t [) S'T∞VNFO VN. ΐ 0 、おつ ΐ ' ΐ q。IO ' ΐ PO(S'2BOVen9N8 ' ^。VSn。N) ΐ q^VNPOS'T qpo , Otsu ΐ 'ΐ q. IO 'ΐ PO (S'2 BO Ven9N8' ^ .VSn.N) ΐ q ^ VNPOS'T qpo iq OS' 。 VSnsN
Figure imgf000132_0001
iq OS '. VSnsN
Figure imgf000132_0001
 ：マ一 ^ fi¾潘讓 っ^ ^^藤 "^; >¾ ^ $ li 止 «  ： Maichi ^ fi¾ 潘 讓 っ ^ ^^ 藤 "^;> ¾ ^ $ li« Z88STC/900Zdf/X3d 。マ一 ^ ίί¾翁簾 n 襍 ¾コ) i^^
Figure imgf000133_0001
Z88STC / 900Zdf / X3d . Ma ^^ ίί¾ 翁 簾 n ¾¾) i ^^
Figure imgf000133_0001
 °。VN。IO( ^。  °. VN. IO (^. 、。VN。IO 'ITOW)s'iqiB3(HsoS— o)— 'ε 、。VN。IO0'IB。ntI)S'iq OS'SB。VSn3N ，,. VN. IO 'I TO W) s'iqiB3 ( H soS— o) —' ε,. VN. IO0'I B. ntI) S'iq OS'S B. VSn3N, 、。VN。IO ' iq。VN3I0 iqus^(s' ^UB^)9' ^UB^(S' ^UB^)9' ^UB^ ,. VN. IO 'iq. VN3I0 iqus ^ (s '^ UB ^) 9 ' ^ UB ^ (S '^ UB ^) 9 ' ^ UB ^ 、。10 iq 09' 。 VSnsN 9uu9S-i-o-T B。 ' S。VSn。N,. 10 iq 09 '. VSnsN 9uu9S-i-o-T B. 'S. VSn. N 、UB附' imre^M , UB attached 'imre ^ M 、。VN。IO ' iq。VN。IO
Figure imgf000133_0002
,. VN. IO 'iq. VN. IO
Figure imgf000133_0002
 9uu9S- -o-TBovNF09'2BOVen9N ΐ 0 °VN310(S' ΐ¾3¾)^' iqpos'iBonj
Figure imgf000133_0003
9uu9S- -o-TBovNF09'2 BO Ven9N ΐ 0 ° VN310 (S 'ΐ¾3¾) ^'iqpos'iBonj
Figure imgf000133_0003
 auuss-q-o-T ^oyNFO  auuss-q-o-T ^ oyNFO 、。VN。IO ' iq。VN。IO
Figure imgf000133_0004
,. VN. IO 'iq. VN. IO
Figure imgf000133_0004
 Z88STC/900Zdf/X3d [4] 前記リンカ一が生体由来蛋白質であることを特徴とする請求項 3に記載の糖鎖修飾リ ポソーム。 Z88STC / 900Zdf / X3d 4. The sugar chain-modified liposome according to claim 3, wherein the linker is a biological protein. [5] 前記リンカ一がヒト血清アルブミンまたはゥシ血清アルブミンであることを特徴とする請 求項 4に記載の糖鎖修飾リボソーム。  [5] The sugar chain-modified ribosome according to claim 4, wherein the linker is human serum albumin or ushi serum albumin. [6] 前記糖鎖修飾リボソームが、リボソーム膜またはリンカ一の少なくとも一方に親水性ィ匕 合物を結合させることにより親水性ィ匕されて 、ることを特徴とする請求項 1〜5の ヽず れかに記載の糖鎖修飾リボソーム。 [6] The sugar chain-modified ribosome is hydrophilicized by binding a hydrophilic compound to at least one of a ribosome membrane or a linker. The sugar chain-modified ribosome according to any one of the above. [7] 前記リボソームと前記糖鎖が、ペプチド結合により結合していることを特徴とする請求 項 1〜6のいずれかに記載の糖鎖修飾リボソーム。 7. The sugar chain-modified ribosome according to any one of claims 1 to 6, wherein the ribosome and the sugar chain are bound by a peptide bond. [8] 前記リボソームの膜上にあるガンダリオシドと前記リンカ一が共有結合により結合し、 該リンカ一の末端がペプチド結合により結合していることを特徴とする請求項 3に記 載の糖鎖修飾リボソーム。 [8] The sugar chain modification according to [3], wherein the gandioside on the ribosome membrane and the linker are bound by a covalent bond, and the end of the linker is bound by a peptide bond. Ribosome. [9] 前記親水性化合物が、低分子の親水性化合物、好ましくは少なくとも 1つの OH基を 有する低分子の親水性化合物、さらに好ましくは、少なくとも 2つの OH基を有する低 分子の親水性ィ匕合物であることを特徴とする、又はトリス (ヒドロキシアルキル)アミノア ルカンであることを特徴とする請求項 1に記載の糖鎖修飾リボソーム。 [9] The hydrophilic compound is a low molecular weight hydrophilic compound, preferably a low molecular weight hydrophilic compound having at least one OH group, and more preferably a low molecular weight hydrophilic compound having at least two OH groups. 2. The sugar chain-modified ribosome according to claim 1, wherein the sugar chain-modified ribosome is a compound, or is a tris (hydroxyalkyl) aminoalkane. [10] 請求項 1〜9のいずれか 1項に記載の糖鎖修飾リボソーム及び薬剤を含有することを 特徴とする薬剤送達組成物。 [10] A drug delivery composition comprising the sugar chain-modified ribosome according to any one of claims 1 to 9 and a drug. [11] 前記薬剤が、医薬、研究試薬、化粧品および機能性食品から選択される物質である ことを特徴とする請求項 10に記載の薬剤送達組成物。 11. The drug delivery composition according to claim 10, wherein the drug is a substance selected from pharmaceuticals, research reagents, cosmetics, and functional foods. [12] 前記薬剤が、抗癌剤、抗炎症剤、バイオ医薬品又はビタミン剤であることを特徴と する請求項 10又は 11に記載の薬剤送達組成物。 12. The drug delivery composition according to claim 10 or 11, wherein the drug is an anticancer drug, an anti-inflammatory drug, a biopharmaceutical or a vitamin drug. [13] 前記薬剤送達組成物が経口投与されるものであることを特徴とする請求項 10〜 12 の!、ずれかに記載の薬剤送達組成物。 13. The drug delivery composition according to any one of claims 10 to 12, wherein the drug delivery composition is orally administered. [14] 前記薬剤送達組成物が静脈から投与されるものであることを特徴とする請求項 10〜14. The drug delivery composition is administered intravenously, [10] 12の 、ずれかに記載の薬剤送達組成物。 12. The drug delivery composition according to any one of the above.
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