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WO2007088952A1 - Preparation de liposome comprenant une substance ayant une action anticancereuse - Google Patents

Preparation de liposome comprenant une substance ayant une action anticancereuse Download PDF

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Publication number
WO2007088952A1
WO2007088952A1 PCT/JP2007/051741 JP2007051741W WO2007088952A1 WO 2007088952 A1 WO2007088952 A1 WO 2007088952A1 JP 2007051741 W JP2007051741 W JP 2007051741W WO 2007088952 A1 WO2007088952 A1 WO 2007088952A1
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Prior art keywords
peptide
sequence
ribosome
tumor tissue
peptide containing
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Ceased
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English (en)
Japanese (ja)
Inventor
Naoto Oku
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Taiho Pharmaceutical Co Ltd
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Taiho Pharmaceutical Co Ltd
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Priority to JP2007556922A priority Critical patent/JP4881327B2/ja
Publication of WO2007088952A1 publication Critical patent/WO2007088952A1/fr
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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a liposome preparation including a medically useful antitumor active substance.
  • Liposomes are closed vesicles mainly composed of phospholipids derived from biological components, and are characterized by low toxicity and antigenicity when administered to living bodies. It has also been shown that encapsulating a drug in a ribosome can improve the reach to the target tissue by changing the blood qualitative and biodistribution of the drug (for example, Non-patent Document 1, Patent Document 1). ) In addition, the blood vessel walls of new blood vessels that are abundant in cancer tissues are more permeable than those of existing blood vessels, and vesicles such as ribosomes are known to accumulate easily in cancer tissues (for example, non- Patent Document 2). Therefore, the antitumor active substance is enclosed in the ribosome.
  • the added formulation is one of the DDS that is expected to enhance main effects and reduce side effects.
  • the normal liposome composition has insufficient selective reachability to the cancer tissue, and thus has an antitumor effect. In many cases, it is not fully demonstrated.
  • the occurrence of side effects due to the large amount of ribosomes distributed in organs other than the target is also a problem.
  • the ribosomal lipid membrane is physically or chemically modified with a peptide (hereinafter referred to as a tumor tissue affinity peptide), protein, or antibody that selectively collects in cancer tissue, and then transferred to cancer tissue. Attempts have been made to increase sex.
  • a tumor tissue affinity peptide As a tumor tissue affinity peptide, it is rare in normal tissues, and is expressed specifically in white blood vessels in tumors. Integrins, vasculargrowthfactors, matrime talloproteases ⁇ high—molecular—weightproteoglycan, etc. Those that migrate and join are well known.
  • a typical example is a peptide containing an RGD sequence, which has been reported to selectively bind to integrin ⁇ - ⁇ ⁇ -3 and ⁇ — V; 3-5 in tumor neovasculature (for example, non-patent Reference 3).
  • Peptides containing PRP sequences have been confirmed to accumulate specifically in new blood vessels, and are one of the vascular endothelial growth factor (VEGF) receptors fms— 1 iketyrosinekinase— 1 (f 1 t- 1) It has been suggested that it has an affinity (for example, Non-Patent Document 4, Patent Document 2). In addition, it has been confirmed that a peptad containing a PLPL sequence has an affinity for membranetype-1 matrix meloproteases (MT1-MMP) (for example, Non-Patent Document 5).
  • VEGF vascular endothelial growth factor
  • Non-Patent Document 6 WO 9 5/24 2 0 1
  • Patent Document 2 Republished WO 0 0/2 34 7 6
  • Non-Patent Document 1 J ournalof L ipos ome Reserch) 4, 667 (1994)
  • Non-Patent Document 2 Dru g D e l i v e r y Sy s te m, 14, 4 ⁇ ⁇ (1999)
  • Non-Patent Document 3 B i o te c hno o g y, 12, 265 (1 995)
  • Non-Patent Document 4 On c o g e ne e, 21, 2662 (2002)
  • Non-Patent Document 5 I NTERNAT I ONAL J OURNAL OF CA NCER, 108 301 (2004)
  • An object of the present invention is to provide a ribosome preparation that includes a substance having an anti-malignant tumor activity, has a high cancer tissue reachability, and has an enhanced anti-serum activity. Disclosure of the invention
  • the present invention relates to the following inventions.
  • a ribosome preparation that contains an anti-S heavy tumor active substance and has two or more tumor tissue affinity peptides bound to the liposome surface.
  • Two peptides selected from the group consisting of peptides containing an RGD sequence, peptides containing a PRP sequence, peptides containing a PLPL sequence, and peptides containing an NGR sequence as S-hepatic tissue affinity peptides A ribosome preparation comprising at least.
  • a ribosome preparation comprising at least a peptide containing an RGD sequence and a peptide containing a PRP sequence as a tumor tissue affinity peptide.
  • the tumor tissue affinity peptide comprises two or more peptides selected from the group consisting of a peptide containing an RGD sequence, a peptide containing a PRP sequence, a peptide containing a PLPL sequence and a peptide containing an NGR sequence.
  • a liposome preparation in which the tumor tissue affinity peptide is a peptide containing RGD sequence and a peptide containing PRP sequence.
  • a liposome preparation in which the tumor or tissue affinity peptide is a peptide containing an RGD sequence, a peptide containing a PRP sequence or a peptide containing an NGR sequence.
  • a method for treating a tumor wherein an effective amount of an antitumor active substance contained in the ribosome preparation is administered to a mammal.
  • the present inventors have synergized the ability to migrate to tumor tissue and affinity by using a combination of multiple types of tumor tissue affinity peptides.
  • these peptides have synergistic effects on heavy tumor tissue affinity.
  • Antitumor activity when administered intravascularly is significantly increased compared to ribosomes that are not peptide-modified and ribosomes that are modified with a single tumor tissue affinity peptide, and increased toxicity was found not to accompany, and the present invention was completed.
  • the liposome used in the liposome preparation of the present invention is a closed vesicle having an inner aqueous phase part surrounded by a lipid bilayer formed by dispersing phospholipids constituting a cell membrane in water as described above.
  • Multi-phase ribosome Mo 1 ti 1 ame 1 1 ar Ve sicle: MLV
  • large unilamellar ribosome Large Unilamellar ribosome
  • Small unilamellar ribosome Small unilamellar ribosome
  • Sma 1 1 Un i 1 ame 1 1 ar vesicle: SUV Any type of liposome can be used in the present invention.
  • the liposome of the present invention forms a stable ribosome structure before and after in vivo administration.
  • a phospholipid having a phase transition temperature of 37 ° C or higher examples include hydrogenated purified egg yolk phosphatidylcholine (phase transition temperature 50-60 ° C, hereinafter referred to as HEPC), hydrogenated refined soybean phosphatidylcholine (phase transition temperature approximately 55 ° C, hereinafter referred to as HSPC) Dipalmitoylphosphatidylcholine (phase transition temperature about 41 ° C, hereinafter referred to as DPPC) and distearoylphosphatidylcholine (phase transition temperature about 58 ° C, hereinafter referred to as DSPC), more preferably DS PC And DP PC.
  • HEPC hydrogenated purified egg yolk phosphatidylcholine
  • HSPC hydrogenated refined soybean phosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • DSPC distearoylphosphatidylcholine
  • DSPC distearoylphosphatidyl
  • the liposomes used in the present invention are preferably used in admixture with stabilizers such as cholesterol derivatives that have been reported to improve the stability of ribosomes.
  • the molar ratio of cholesterol derivative to phospholipid is preferably 1: 0.3 to 3, more preferably 1: 1 to 2.5.
  • an isotonic agent for example, glycerin, glucose, sodium chloride and the like can be added.
  • preservatives such as parabens, chlorobutanol, benzyl alcohol, propylene glycol may be added.
  • the tumor tissue affinity peptide used in the present invention is not particularly limited as long as it is a peptide that exhibits directivity to the tumor tissue when bound to the surface of a liposome, but a peptide containing an RGD sequence, a PRP sequence And peptides containing PLPL sequences, peptides containing NPL sequences, and peptides containing PLPL sequences. In addition, peptides other than the above may be bound. Furthermore, the tumor tissue affinity peptide used in the present invention includes a peptide containing two or more sequences selected from the group consisting of RGD sequence, PRP sequence, PL PL sequence and NGR sequence in one peptide. A peptide can be illustrated.
  • the peptide containing the RGD sequence used in the present invention may be any peptide containing the amino acid sequence of arginine monoglycine-spartamate, and can be prepared by a known method in the field of peptide synthesis.
  • the peptide may be linear or cyclic.
  • GRGDS, GRGDL, GRGDR, GR GD F can be exemplified.
  • the peptide containing the PRP sequence used in the present invention may be any peptide containing the amino acid sequence of proline-arginine-proline, and can be prepared by a known method in the field of peptide synthesis.
  • APRPG, GPRPL, GP RPR can be exemplified.
  • the peptide containing the PLP L sequence used in the present invention may be a peptide containing the amino acid sequence of proline-synthetic-synaptic-synthetic-sin, and can be prepared by a known method in the peptide synthesis field.
  • GPLPLR, HP LPLS, PVPLPL, PLP LVR can be exemplified as follows:
  • the peptide containing the NGR sequence used in the present invention may be any peptide containing the amino acid sequence of asparagine, glycine and arginine, and can be prepared by a known method in the field of peptide synthesis.
  • CNGRC and CNGRG can be exemplified.
  • the ribosome preparation of the present invention it is more preferable to introduce 2 to 4 kinds of tumor tissue affinity peptides.
  • the combination of two kinds of tumor tissue affinity peptides in the liposome preparation of the present invention includes a peptide containing RGD sequence and a peptide containing PRP sequence; a peptide containing RGD sequence and a peptide containing PLPL sequence.
  • a peptide containing an RGD sequence and an NGR sequence Peptides containing PRP sequences and peptides containing PLPL sequences; Peptides containing PRP sequences and peptides containing NGR sequences; Peptides containing PLPL sequences and peptides containing NGR sequences it can.
  • the molar ratio of the two tumor tissue affinity peptides in the liposome preparation of the present invention can be arbitrarily set depending on the drug to be encapsulated and the cancer to be treated, but for example, a peptide containing an RGD sequence and a peptide containing a PRP sequence.
  • the combination of the three tumor tissue affinity peptides in the liposome preparation of the present invention includes a peptide containing an RGD sequence, a peptide containing a PRP sequence, and a peptide containing a PLPL sequence; a peptide containing an RGD sequence, Peptide containing PRP sequence and peptide containing NGR sequence; Peptide containing RGD sequence, Peptide containing PLPL sequence and Peptide containing NGR sequence; Peptide containing PRP sequence, P LP L sequence included Peptides containing peptides and NGR sequences can be exemplified. Preference is given to peptides comprising an RGD sequence, peptides comprising a PRP sequence and peptides comprising an NGR sequence.
  • the molar ratio of the three tumor tissue-affinity peptides in the liposome preparation of the present invention can be arbitrarily set depending on the drug to be encapsulated and the cancer to be treated.
  • a peptide containing an RGD sequence a peptide containing a PRP sequence
  • peptides containing NGR sequences 1: 0. 1 to: 1 0: 0.:!
  • To 10 is preferable, 1: 0.3 to 3: 3: 0.3 to 3 is more preferable, and 1: 1 to 1 is more preferable.
  • the combination of the four types of tumor tissue affinity peptides in the liposome preparation of the invention includes peptides containing RGD sequences, peptides containing PRP sequences, peptides containing PL PL sequences and peptides containing NGR sequences. It can be illustrated.
  • the molar ratio of the four tumor tissue affinity peptides in the liposome preparation of the present invention can be arbitrarily set depending on the drug to be encapsulated and the cancer to be treated.
  • a peptide containing an RGD sequence For example, a peptide containing an RGD sequence, a peptide containing a PRP sequence, P
  • peptides containing LP L sequences and peptides containing NGR sequences peptides containing LP L sequences and peptides containing NGR sequences
  • the number of constituent amino acids of the tumor tissue affinity peptide used in the present invention is preferably 3 to 15 because of its low antigenicity, ease of modification to ribosomes and low production costs. 12 is more preferable, and 5 to 10 is particularly preferable.
  • Specific examples of amino acids constituting the tumor tissue affinity peptide used in the present invention include arginine, glycine, aspartic acid, proline, leucine, phenenolealanine, serine, histidine, asparagine, cysteine and the like. it can.
  • the molar ratio between the phospholipid used in the present invention and the total amount of each peptide having affinity for tumor tissue is preferably from 1: 0.01 to 0.3, more preferably from 1: 0.05 to 0.2 force S, 1 : 0.1 is particularly preferred.
  • a tumor tissue affinity peptide such as a stearoyl group, a acyl group (for example, Japanese Patent No. 2620729), a cholesteryl group (for example, Japanese Patent No. 2579730), a phospholipid (for example, Japanese Patent Laid-Open No. 04-099795), etc.
  • the hydrophobic side chain is attached to the lipid membrane part of the liposome. It is possible to produce peptide-modified liposomes that are coordinated and have a tumor tissue affinity peptide introduced on the surface of the liposome membrane. Even when multiple types of tumor tissue affinity peptides are introduced into the ribosomal membrane, as long as these peptides do not show adverse physicochemical interactions, It can be prepared by the method described above in the same manner as in the case of the affinity peptide.
  • the binding direction of the hydrophobic side chain is arbitrary.
  • the hydrophobic side chain may be bound to either the R side or the D side, but preferably R On the side.
  • the ribosome preparation of the present invention is prepared by a known method.
  • Known preparation methods for ribosomes include, for example, the reverse phase evaporation method [Proceeding of the Nashonanore Academy 'Ob'Sciences'US'A (Proc. N at 1. USA, 75, 41 94 (1978), WO 97/48398], Freezing and thawing method [Arche's Biochemistry-And No Physics (Ar c h. B ioch em.
  • the pH gradient method is useful for encapsulating drugs with greatly different solubility depending on pH in the liposome at a high inclusion rate.
  • a method for preparing the liposomal preparation of the present invention by the pH gradient method for example, a tumor tissue affinity peptide to which a lipid component and a hydrophobic side chain are bound is dissolved in a solvent such as chloroform, ether, ethanol, etc. Put in a mold flask and evaporate the solvent under reduced pressure to form a lipid film. Next, a weakly acidic buffer solution is added to the thin film and freeze-thawed to prepare large multiphase ribosomes (MLV) whose inner aqueous phase is weakly acidic.
  • MLV multiphase ribosomes
  • Ribosome particle size has been reported to have a significant effect on the biodistribution of contained drugs and its delivery to tumor tissue.
  • a ligand such as a polyethylene glycol derivative
  • the interaction with plasma proteins after administration of liposomes into the blood vessels is reduced, and reticules such as liver Kupffer cells.
  • Incorporation into endothelial cells can be suppressed, and the transferability of liposomes to tumor tissue and the like can be further improved.
  • the ribosome preparation of the present invention is prepared, and if necessary, the ultracentrifugation treatment, the gel filtration treatment, the ultrafiltration treatment and the dialysis treatment can be carried out alone or in combination to appropriately encapsulate in the ribosome. Drugs that have not been done can be removed.
  • the ribosome preparation of the present invention obtained by the above method can be used as it is.
  • excipients such as mannitol, trehalose, lactose, glycine and freeze-dry.
  • the type of drug encapsulated in the ribosome preparation of the present invention is not particularly limited, but the liposomal preparation of the present invention has an excellent affinity for tumor tissue, so long as it has activity in the tumor tissue, antitumor activity Substances are preferred.
  • Specific antitumor active substances are not particularly limited. For example, alkylic drugs, various antimetabolites, antitumor antibiotics, other antitumor agents, antitumor plant components, BRM (biological response) Sex control substances), angiogenesis inhibitors, cell adhesion inhibitors, matrix / metalloprotease inhibitors or hormones.
  • alkyl alkylating agents include, for example, nitrogen mustard, nitrogen mustard N-oxide, ifosfamide, menolephalan, chlorophosphamide, chloroethylamine alkylating agents such as kulamumbucil,
  • aziridin-based alkylating agents such as carbocone and thiotepa
  • epoxide-based alkylating agents such as dib mouth momannitol and dipromodalcitol
  • chlorozotocin ranimustine and other nitrosolean-type anorequinolei chiral lj
  • busu ⁇ / fan tosinoreic acid improsulfan, pisnolevane and other sulfonic acid estenoles
  • dacarbazine azine
  • Examples of various antagonists include, for example, 6-mercaptopurine, azathioprine, 6-thioguanine, thioinosin and other purine antimetabolites; fluorouracil, tegafur, tegafur uracil, tegafur, gimeracil oteracyl potassium combined lj, canolemofur, And pyrimidine antimetabolite such as doxyfluridine, proxuridine, cytarabine, and enocytabine; antifolate antimetabolite such as methotrexate, trimetrexate, etc., and salts or complexes thereof.
  • Antitumor antibiotics include, for example, anthracyclines such as daunorubicin, aclarubicin, doxorubicin, pirarubicin, and epilubicin; actinomycins such as actinomycin D; chromomycins such as chromomycin A 3; Tomycins; bleomycins such as bleomycin and peplomycin; and their salts or complexes.
  • Other anti-tumor agents include, for example, cisplatin, carboplatin, oxalibratin, TAS-1103, tamoxifen, L-parasinease, asperaton, schizophyllan, picibanil, ubenimex, krestin, and the like. A salt or a complex may be mentioned.
  • antitumor plant component examples include plant driversoids such as camptothecin, vindesine, vintalistin, and vinblastine; epipodophyllotoxins such as etoposide and teniposide; and salts or complexes thereof.
  • plant driversoids such as camptothecin, vindesine, vintalistin, and vinblastine
  • epipodophyllotoxins such as etoposide and teniposide
  • salts or complexes thereof examples include piperoproman, neocalcinostatin, and hydroxyurea.
  • BRM examples include tumor lobe death factor, indomethacin, and salts or complexes thereof.
  • angiogenesis inhibitor examples include fumagillol derivatives, and salts or complexes thereof.
  • Examples of the cell adhesion inhibitor include substances having an RGD sequence, and salts or complexes thereof.
  • matrix 'meta-oral protease inhibitors examples include marimastat, batimastat and the like, and salts or complexes thereof.
  • Hormones include, for example, hydroconorethone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oximetron, nandrolone, methenolone, phosfestrone, ethininorestradiol, chlormadinone, salt, Or a composite is mentioned.
  • Examples of the form of the drug include low molecular weight compounds, peptides, proteins, antibodies, siRNA V, and genes.
  • the ribosome preparation of the present invention is generally used as an injection (intravenous, intramuscular, subcutaneous administration) by suspending or diluting with a physiologically acceptable aqueous solution at the time of use. It can also be used as nasal drops, inhalants, suppositories, transdermal absorbents, transmucosal absorbents, and the like. Final preparations include malignant tumors (lung cancers of mammals such as humans, extirpator cancers (esophageal cancer, stomach cancer, rectal cancer, colon cancer, etc.), breast cancer, head and neck cancer, liver cancer, gallbladder.
  • an antitumor active substance may be contained as an intravenously administered ribosome preparation in an amount of 0 ⁇ 01 to 100 mg. Ribosome preparation of the present invention
  • the dosage of the active ingredient contained in is preferably from 0.01 to 1 000 mg / day.
  • FIG. 1 is a graph showing the antitumor effect of Test Example 3.
  • FIG. 2 is a graph showing the change in body weight of the mouse of Test Example 3.
  • FIG. 3 is a draaf showing the antitumor effect of Test Example 4.
  • FIG. 4 is a graph showing changes in body weight of the mice of Test Example 4. BEST MODE FOR CARRYING OUT THE INVENTION
  • Test Example 1 (TAS — 1 0 3 encapsulation rate in ribosome)
  • Test Example 2 (TAS—10 3 liposome stability in serum)
  • the liposome solution prepared in Example 1 and Comparative Examples 1 to 3 was incubated with 50% non-immobilized serum serum PBS (—) at 37 ° C. for 3 hours, and then released. After removing 3 with a centrifuge, the amount of TAS-10 3 in the liposome was determined by the method of Test Example 1. As a result, it was confirmed that the encapsulation rate of 99% or more was maintained compared to that before incubation, and that it was stable in serum.
  • Test Example 3 Anti-tumor effect and toxicity evaluation of TAS-103 liposome
  • High lung metastatic tumor cell line used for evaluation of anti-tumor effect Lewys Lung C arcinoma 5. Cultivation was carried out in 37 ° C 10% FBS (Fetal Bovine Serum, Fetal Bovine Serum) and DMEM (Dulbecco's Modified Eagle's Medium) in the presence of 0 ° C 0 2 and subcultured.
  • FBS Fetal Bovine Serum, Fetal Bovine Serum
  • DMEM Dulbecco's Modified Eagle's Medium
  • a high lung metastatic tumor cell line Lewis Lung Carcinoma, prepared to 5 X 10 6 ce 11 sZmL, was administered 0.2 mL subcutaneously to the left ventral region of 6-week-old male C57 B LZ6 mice. Cancer-bearing mice were created. L ew is Lung Carcinoma transplantation 7, 11 1 and 15 days in total, 3 times in total, phosphate buffer [PBS (—)] as control and TAS prepared in Example 1 and Comparative Examples 1-3 — 103-encapsulated ribosome solution (20 mg / kg as TAS-103) was administered 0.2 mL Zbo dyZday into the tail vein of mice. The antitumor effect of the TAS-103-encapsulated liposome solution was examined by measuring the tumor volume 3 days after cancer transplantation. Tumor volume was calculated using the following formula.
  • 103 treatment group consists of A RPG— l i p o. TAS-103 treatment group, GRGD S—
  • TAS-103 treatment group and cn t— 1 i p o. TAS—103 treatment group showed significant tumor growth inhibitory effect.
  • OX OX
  • a doxorubicin-containing liposome preparation (APRPG-1 ipo. DOX) modified with an APRPG peptide was prepared according to the method of Example 2 below. The average particle size of the ribosome was 0.2 ⁇ .
  • Test Example 4 Anti-tumor effect and toxicity evaluation of doxorubicin ribosome
  • Cololon 2 6 NL 1 7 used for evaluation of antitumor effect was cultured in 3 7 ° C 10% FBS—DMEMZH am F 1 2 in the presence of 5% C0 2 and passaged did.
  • Cololon 2 6 NL 17 prepared at 5 X 10 6 ce 11 s / mL was administered 0.2 mL subcutaneously to the left ventral region of 6-week-old male B a 1 b / c mice. Created a kangan mouse.
  • APRPG 'GRGDS— 1 ip o. DOX treatment group is divided into APRPG— 1 ip o. DOX treatment group, GRGDS— 1 ip o. DOX treatment group and c 0 nt— 1 ip. o.
  • the tumor growth was significantly suppressed.
  • the antitumor effect of cn t-1 i p o.D0X is higher than that of the non-ribosomal doxorubicin hydrochloride solution.
  • * indicates that the result of the significant difference test is p ⁇ 0.05.
  • anti-tumor active substance-encapsulated ribosome preparations modified with multiple tumor tissue affinity peptides are compared to non-ribosomal solutions, normal ribosome preparations, and liposomes modified with a single peptide.
  • the reason for the enhancement of anticancer activity is that the reachability and affinity of the antitumor active substance to the tumor tissue have been significantly improved by the synergistic contribution of multiple peptides with affinity for different tumor molecules. Conceivable.
  • the liposomal preparation of the present invention has an effect of enhancing the effect of a substance having an antineoplastic activity contained therein and reducing its toxicity, which is clearly superior to conventional ribosome preparations. Therefore, in the actual treatment of malignant tumors, it is highly expected to suppress the progression of cancer while reducing side effects.

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Abstract

La présente invention concerne une préparation de liposome qui comporte une substance ayant une action anticancéreuse, au moins deux peptides ayant chacun une affinité avec un tissu tumoral étant liés à la surface du liposome.
PCT/JP2007/051741 2006-01-31 2007-01-26 Preparation de liposome comprenant une substance ayant une action anticancereuse Ceased WO2007088952A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009125858A1 (fr) * 2008-04-07 2009-10-15 大鵬薬品工業株式会社 Préparation de dispersion de lipides comprenant un dérivé de 2-indolinone
WO2011083845A1 (fr) * 2010-01-08 2011-07-14 富士フイルム株式会社 Agent de ciblage pour site tumoral
ITMI20102043A1 (it) * 2010-11-03 2012-05-04 Alberto Gramaglia Kit per l attivazione localizzata di elevate concentrazioni di un farmaco e suo procedimento
JP2014062084A (ja) * 2012-09-19 2014-04-10 Georgetown Univ 標的化されたリポソーム
WO2019168177A1 (fr) * 2018-03-01 2019-09-06 静岡県公立大学法人 Agent prophylactique ou thérapeutique anticancéreux
US11951167B2 (en) 2012-09-19 2024-04-09 Georgetown University Targeted liposomes

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