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WO2015170573A1 - Agent d'imagerie de nœud lymphatique - Google Patents

Agent d'imagerie de nœud lymphatique Download PDF

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Publication number
WO2015170573A1
WO2015170573A1 PCT/JP2015/061943 JP2015061943W WO2015170573A1 WO 2015170573 A1 WO2015170573 A1 WO 2015170573A1 JP 2015061943 W JP2015061943 W JP 2015061943W WO 2015170573 A1 WO2015170573 A1 WO 2015170573A1
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WO
WIPO (PCT)
Prior art keywords
branched polymer
anionic
lymph node
group
present
Prior art date
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Ceased
Application number
PCT/JP2015/061943
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English (en)
Japanese (ja)
Inventor
千恵 児島
悠一郎 仁木
泰寛 間賀田
美香子 小川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Osaka Metropolitan University
Hamamatsu University School of Medicine NUC
Original Assignee
Osaka Prefecture University PUC
Hamamatsu University School of Medicine NUC
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Application filed by Osaka Prefecture University PUC, Hamamatsu University School of Medicine NUC filed Critical Osaka Prefecture University PUC
Priority to JP2016517855A priority Critical patent/JPWO2015170573A1/ja
Publication of WO2015170573A1 publication Critical patent/WO2015170573A1/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
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
    • G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
    • G01T1/16—Measuring radiation intensity
    • G01T1/161—Applications in the field of nuclear medicine, e.g. in vivo counting

Definitions

  • the present invention relates to a lymph node imaging agent.
  • the sentinel lymph node (primary lymph node) is the lymph node that first passes when cancer cells metastasize, and detection of the lymph node is very important in detecting and diagnosing metastatic cancer. Is done.
  • Non-Patent Document 1 discloses a method for detecting a lymph node using radiolabeled liposomes.
  • Such liposomes are anionic liposomes having a molecular size of about 100 nm, and are known to be phagocytosed by macrophages present in the lymph nodes when they are administered subcutaneously, and as a result, accumulate in the lymph nodes.
  • Non-Patent Document 2 discloses that poly L-lysine dendrimers having a benzyl sulfate group on the surface and a molecular diameter of about 2.8 nm accumulate in lymph nodes by subcutaneous administration and tail vein administration. .
  • Non-Patent Document 3 discloses a method for detecting a lymph node by administering 20 to 40 nm quantum dots into the tail vein.
  • Non-Patent Document 4 discloses a lymph node imaging method using a radiolabeled polyamidoamine amine dendrimer, and discloses that G4 to G8 dendrimers are suitable for imaging. As an administration method, a method of directly administering such a dendrimer to the mammary gland is disclosed.
  • Patent Document 1 discloses a complex of a dendrimer prepared using polyamidoimine and polyamidoamine and alginic acid or gamma polyglutamic acid having a molecular diameter of about 24 nm and a zeta potential of about ⁇ 49 mV.
  • a method of imaging a sentinel lymph node by administering Foot pad is disclosed.
  • an object of the present invention is to provide a lymph node imaging agent capable of imaging a lymph node with a small amount and a simple administration method.
  • imaging of lymph nodes can be performed with a small dose by using an anionic branched polymer having a specific molecular diameter. It was.
  • the present invention has been completed based on such knowledge, and includes the inventions of the following broad aspects.
  • Item 1 An anionic branched polymer having at least one labeling substance and having a molecular diameter of 5 to 20 nm, which is used as a lymph node imaging agent.
  • Item 2 The anionic branched polymer according to Item 1, wherein the zeta potential is ⁇ 10 mV or less.
  • Item 3 The anionic branched polymer according to Item 1 or 2, which has at least one kind of anionic group.
  • Item 4 The anionic branched polymer according to Item 3, wherein the anionic group is at least one selected from the group consisting of a carboxyl group, a sulfone group, and a phenol group.
  • Item 5 The anionic branched polymer according to Item 3, wherein the anionic group is a carboxyl group.
  • Item 6 In any one of Items 1 to 5, wherein the labeling substance is at least one selected from the group consisting of a radioisotope, a low molecular organic dye, a fluorescent dye, and a gadolinium coordination chelating agent.
  • the labeling substance is at least one selected from the group consisting of a radioisotope, a low molecular organic dye, a fluorescent dye, and a gadolinium coordination chelating agent.
  • Item 7 The anionic branched polymer according to any one of Items 1 to 6, which is used as a lymph node imaging agent for intradermal administration.
  • Item 8 The anionic branched polymer according to any one of Items 1 to 7, wherein the anionic branched polymer is a graft polymer, a star polymer, a hyperbranched polymer, a dendron, a dendrimer, a dendron polymer, or a dendrigraft polymer. .
  • Item 9 A lymph node imaging agent comprising the anionic branched polymer according to any one of Items 1 to 8.
  • Item 10 A method for imaging a lymph node, comprising a step of administering the anionic branched polymer according to any one of Items 1 to 9.
  • the anionic branched polymer according to the present invention can be suitably used as an imaging agent for lymph nodes.
  • the anionic branched polymer according to the present invention as an imaging agent for lymph nodes, it is possible to image the lymph nodes by a small amount and a simple administration method, for example, intradermal administration.
  • NMR spectra and partial structures of various dendrimers prepared in this example NMR spectra of various dendrimers prepared in this example. NMR spectra of various dendrimers prepared in this example. NMR spectra of various dendrimers prepared in this example.
  • the figure (sentinel lymph node) which shows distribution after administering the various dendrimers produced in the present Example.
  • the figure (liver) which shows distribution after administering various dendrimers produced in a present Example.
  • the figure (spleen) which shows distribution after administering various dendrimers produced in the present Example.
  • the figure which shows distribution after administering the various dendrimers produced in a present Example kidney).
  • part) which shows distribution after administering the various dendrimers produced in the present Example.
  • the figure (blood) which shows distribution after administering the various dendrimers produced in the present Example.
  • the figure (lung) which shows distribution after administering various dendrimers produced in a present Example.
  • the figure (heart) which shows distribution after administering various dendrimers produced in the present Example.
  • the figure (muscle) which shows distribution after administering the various dendrimers produced in the present Example.
  • SPECT / CT images taken after administration of various dendrimers prepared in this example.
  • the anionic branched polymer according to the present invention is used as a lymph node imaging agent.
  • the anionic branched polymer according to the present invention has at least one labeling substance and has a molecular diameter of 5 to 20 nm.
  • the branched polymer according to the present invention is 5 nm or more, it exhibits the effect of being easily accumulated in the lymph node without diffusing from the administration site. Moreover, since it is 20 nm or less, the effect which is hard to be recognized by macrophages etc. is exhibited.
  • the branched polymer according to the present invention is preferably about 5 to 15 nm. Since it is 15 nm or less, it exerts an effect that it is more difficult to be recognized by macrophages.
  • the average molecular diameter is a molecular diameter measured based on the dynamic light scattering method (DLS) method, as shown in the following examples, and the measured value obtained based on the principle of DLS is expressed in a polydisperse system. It is the average particle size of the smallest distribution in the volume-based particle size distribution obtained by analysis by a certain Marquardt method.
  • the measuring instrument used for the dynamic light scattering method is ELSZ-DN2 (Otsuka Electronics) or its equivalent.
  • a branched polymer is a polymer having a branched structure.
  • a branched polymer in which a molecular chain extending from a branch point existing in the main chain or the central point is a single chain, such as a graft polymer and a star polymer.
  • a molecular chain extending from a branch point existing in the main chain or the central point such as a hyperbranched polymer, a dendron, a dendritic polymer (dendrimer), a dendron polymer, etc.
  • a dendrigraft polymer in which a branch polymer is further connected in a graft polymer form to the branch polymer of the graft polymer is also included in the branched polymer according to the present invention.
  • Dendrimers have regular branches in the molecular chain extending from the center, can be synthesized step by step (also called generations), are perfectly aligned in shape and size, are regular and symmetrical It is a branched polymer rich in properties.
  • hyperbranched polymers and dendron polymers are branched polymers that do not have regularity, symmetry, and the like as in dendrimers.
  • the dendron polymer is a branched polymer in which a dendron that is a partial structure of a dendrimer is bonded to a side chain of a main chain polymer.
  • the branched polymer according to the present invention has a plurality of branched chains as described above, it is common in that it can have a plurality of anionic groups. Therefore, any of the branched polymers can exhibit the effects of the present invention.
  • the branched polymer according to the present invention is not particularly limited as long as it is the above-described branched polymer.
  • it is preferably a dendrimer.
  • the branched polymer according to the present invention has an anionic property, and due to the anionic property, when such a polymer is administered to a living body, it exhibits an effect of being accumulated in a lymph node.
  • the fact that the branched polymer according to the present invention is anionic can be determined based on the zeta potential of the branched polymer measured using sodium chloride as a solvent.
  • the specific zeta potential of the branched polymer according to the present invention is not particularly limited.
  • the zeta potential is usually about ⁇ 10 mV or less, preferably about ⁇ 20 mV or less.
  • Such an anionic property of the branched polymer according to the present invention can be imparted depending on the anionic group of the branched polymer, and it is preferable that the branched polymer has an anionic group on the surface group. More preferably, it has an anionic group at the terminal of the branched polymer. Such an anionic group is preferably covalently bonded to the branched polymer.
  • the ratio of the anionic group when the branched polymer according to the present invention has an anionic property on the surface group is usually 100% or less and about 50% or more with respect to the entire surface group of the branched polymer.
  • anionic groups are not particularly limited, and examples thereof include a carboxyl group, a sulfone group, and a phenol group. These branched polymers according to the present invention may contain only one type of anionic group or two or more types. Among the anionic groups described above, a carboxyl group is particularly preferable.
  • the anionic branched polymer according to the present invention has at least one labeling substance.
  • labeling substances are not particularly limited.
  • radioisotopes such as 11 C, 13 N, 15 O, and 18 F compounds (for PET), radioisotopes such as 111 In compounds (for SPECT), indigo Low molecular organic dyes such as carmine or patent blue V; fluorescent dyes such as indocyanine green, fluorescein, rhodamine, Alexa Fluor dye; and contrast agents for nuclear magnetic resonance imaging such as gadolinium chelating agents.
  • the anionic branched polymer according to the present invention can be produced by a known method.
  • an anionic group may be bound to the branched polymer using a known method.
  • Such a bonding mode is not particularly limited, and for example, covalent bonding is preferable.
  • the labeling substance to be bound to the branched polymer can also be imparted using a known method, and the labeling substance can be bound to the branched polymer through another compound such as a chelating agent.
  • a binding mode is not particularly limited, and can be appropriately determined in view of, for example, the physical properties of the branched polymer and the physical properties of the labeling substance.
  • the anionic branched polymer according to the present invention is used as a lymph node imaging agent.
  • the specific method of use can be the same as described in ⁇ Lymph node imaging agent according to the present invention> described later.
  • the lymph node imaging agent according to the present invention includes the above-described anionic branched polymer according to the present invention.
  • the content of the anionic branched polymer is not particularly limited. The specific content is usually about 0.001 to 100 parts by weight with respect to 100 parts by weight of the lymph node imaging agent, for example. That is, the anionic branched polymer according to the present invention itself can be used as the lymph node imaging agent according to the present invention.
  • the dosage form of the lymph node imaging agent according to the present invention is not particularly limited.
  • a desired dosage form can be obtained together with various conventionally known pharmaceutically acceptable carriers.
  • Specific dosage forms include injections such as liquids, implantable injections, and sustained injections; dialysis agents such as peritoneal dialysis agents and hemodialysis agents.
  • These dosage forms can be manufactured based on known documents such as the 16th revised Japanese Pharmacopoeia Manual.
  • the lymph node imaging agent includes a pH adjuster; a preservative; an isotonic agent; an antiseptic; a solvent such as water for injection, sesame oil, soybean oil, corn oil, olive oil; Stabilizers such as inert gases (nitrogen, carbon dioxide, etc.), chelating agents (EDTA, thioglycolic acid, etc.), reducing substances (sodium bisulfite, L-ascorbic acid, etc.); paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol Preservatives such as phenol, benzalkonium chloride; binding solubilizers (sodium iodide, sodium benzoate, sodium nicotinate, etc.), solvent-soluble solubilizers (alcohol, propylene glycol, liquid macrogol, etc.), etc.
  • Stabilizers such as inert gases (nitrogen, carbon dioxide, etc.), chelating agents (EDTA, thioglycolic acid, etc
  • Solubilizing agents such as procaine hydrochloride and benzyl alcohol; glucose, sorbi Such as citric acid, acetic acid, sodium phosphate, and those for injection; carmellose sodium, PVP, aluminum monostearate, these for injection, etc.
  • a suspending agent or the like can be contained.
  • the dosage of the lymph node imaging agent according to the present invention is not particularly limited.
  • Such a dose is usually about 50 to 300 ⁇ L in terms of volume.
  • the administration method of the lymph node imaging agent of the present invention is not particularly limited, and examples thereof include intravenous administration, subcutaneous administration, and intradermal administration. Of these, intradermal administration is preferred.
  • the apparatus capable of performing imaging using the lymph node imaging agent according to the present invention can be appropriately selected according to the type of labeling substance contained in the above-mentioned anionic branched polymer, and is not particularly limited.
  • Examples of such an apparatus usually include a nuclear medicine examination apparatus, an MRI apparatus, a fluorescence detection apparatus, and the like.
  • a specific imaging method can be performed by appropriately changing the conditions in accordance with the manual of the above apparatus.
  • the method for imaging a lymph node according to the present invention includes a step of administering the above-mentioned anionic branched polymer.
  • the anionic branched polymer, the dose, the administration method, the equipment used for imaging, and the like should be as described in the above ⁇ Anionic branched polymer according to the present invention> or ⁇ Lymph node imaging agent according to the present invention>. it can.
  • PAMAM dendrimers used was obtained from ALDRICH, PAMAM dendrimer, ethylenediamine core, generation 2.0 solution (412406;.
  • G2-NH 2 PAMAM dendrimer , ethylenediamine core, generation 4 0.0 solution (41449; hereinafter referred to as G4-NH 2 in this example)
  • PAMAM dendrimer, ethylenediamine c re, generation 8.0 solution 536741; .
  • G8-NH 2 p-SCN-Bn-DTPA was obtained from MACROCYCLICS (B-305).
  • the amount of p-SCN-Bn-DTPA binding was estimated from a calibration curve of p-SCN-Bn-DTPA by measuring a UV spectrum.
  • Production Example 2 Preparation of acetylated / carboxylated PAMAM dendrimer
  • the chelated PAMAM dendrimer having various sizes described above was further subjected to acetylation or carboxylation.
  • reaction rate was identified using a fluorescamine color reaction.
  • reaction was confirmed using 1 H NMR measurement (FIGS. 1 to 4). It was revealed that an acetylation peak was present at 1.95 ppm.
  • G2-Ac G4-Ac
  • G6-Ac G8-Ac
  • reaction rate was identified using a fluorescamine color reaction.
  • reaction was confirmed using 1 H NMR measurement (FIGS. 1 to 4). It was revealed that a carboxyl group peak was present at 2.4 ppm.
  • the zeta potential was measured using PBS as a solvent, and as a result, a result that the zeta potential was on the negative side as a whole was obtained.
  • the zeta potential measured for unchelated G4-NH 2 PAMAM dendrimer with 10 mM NaCl was +2.82 mV, whereas the zeta potential measured with PBS was -15.63 mV.
  • Modification number indicates the number of modifications by p-SCN-Bn-DTPA per molecule of various dendrimers.
  • reaction product was purified using a PD-10 column (solvent: PBS). Then, it refine
  • Rats were euthanized at 1, 6 and 24 hours after administration, respectively, and the administration site and various organs (popliteal lymph nodes, blood, spleen, kidney, liver, heart, lung, and muscle) were taken out, their weight and radio Activity was measured. The results are shown in FIGS.
  • G2 and G4 are excreted from the kidney because they are small molecules.
  • SPECT imaging was performed using FX Pre-clinical platform (Gamma Medica Ideas Inc) (60 sec / projection; 64 projection).
  • the captured images are shown in FIGS.
  • the site surrounded by a circle in the figure is an administration site, the region surrounded by a square is the primary lymph node, and the region surrounded by a triangle is the secondary lymph node.
  • G8-COOH and G6-COOH were able to image not only the sentinel lymph node (primary lymph node) but also the secondary lymph node.
  • the sentinel lymph node could be imaged, but with G2-COOH, it was found that the molecular weight was too small to diffuse.
  • G6-NH 2 stays considerably at the administration site and that G6-Ac diffuses from the administration site.
  • G6-COOH or G8-COOH is suitable for imaging of sentinel lymph nodes.

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Abstract

La présente invention vise à fournir un agent d'imagerie de nœud lymphatique qui permet l'imagerie d'un nœud lymphatique, même lorsqu'il est utilisé en petite quantité, et qui peut être administré de façon simple pour l'imagerie. Un polymère ramifié anionique, qui peut être utilisé comme agent d'imagerie de nœud lymphatique, a au moins une substance de marquage liée à ce dernier et a un diamètre de molécule de 5 à 20 nm.
PCT/JP2015/061943 2014-05-08 2015-04-20 Agent d'imagerie de nœud lymphatique Ceased WO2015170573A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005507933A (ja) * 2001-10-29 2005-03-24 ザ　ダウ　ケミカル　カンパニー 抗新生物性の樹枝状ポリマー薬物送達システム
WO2011105520A1 (fr) * 2010-02-26 2011-09-01 国立大学法人 長崎大学 Corps composite pour libération d'antigènes ou de médicaments
JP2013518841A (ja) * 2010-02-03 2013-05-23 ミフェニオン ゲゼルシャフト ミット ベシュレンクテル ハフツング 増殖及びタンパク質合成の細胞内ターゲッティングのためのポリアニオン性多価高分子

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005507933A (ja) * 2001-10-29 2005-03-24 ザ　ダウ　ケミカル　カンパニー 抗新生物性の樹枝状ポリマー薬物送達システム
JP2013518841A (ja) * 2010-02-03 2013-05-23 ミフェニオン ゲゼルシャフト ミット ベシュレンクテル ハフツング 増殖及びタンパク質合成の細胞内ターゲッティングのためのポリアニオン性多価高分子
WO2011105520A1 (fr) * 2010-02-26 2011-09-01 国立大学法人 長崎大学 Corps composite pour libération d'antigènes ou de médicaments

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
N. MALIK ET AL.: "Dendrimers: Relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo", JOURNAL OF CONTROLLED RELEASE, vol. 65, no. 1-2, 2000, pages 133 - 148, XP004190318, ISSN: 0168-3659 *
VLADIMIR S. TALANOV ET AL.: "Dendrimer-Based Nanoprobe for Dual Modality Magnetic Resonance and Fluorescence Imaging", NANO LETTERS, vol. 6, no. 7, 2006, pages 1459 - 1463, XP007901388, ISSN: 1530-6984 *

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