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Polymer/metal complex composite having mri contrast ability and mri contrasting and/or antitumor composition using the same

Foreign code F110003680
File No. AF12-02WO
Posted date Jul 1, 2011
Country EPO
Application number 09770271
Gazette No. 2308916
Gazette No. 2308916
Date of filing Jun 26, 2009
Gazette Date Apr 13, 2011
Gazette Date Nov 9, 2016
International application number JP2009061772
International publication number WO2009157561
Date of international filing Jun 26, 2009
Date of international publication Dec 30, 2009
Priority data
  • 2009JP061772 (Jun 26, 2009) WO
  • P2008-167823 (Jun 26, 2008) JP
Title Polymer/metal complex composite having mri contrast ability and mri contrasting and/or antitumor composition using the same
Abstract The present invention provides a polymer-metal complex composite, which comprises a block copolymer capable of serving as a constituent member of a polymeric micelle and a metal complex having MRI contrast ability, accumulates in a tumor-specific manner, achieves high image contrast even in a small amount, and has reduced side effects and a long retention time in blood.
The polymer-metal complex composite of the present invention comprises a block copolymer (A) represented by general formula (a) and a metal complex (B) having MRI contrast ability, wherein the composite comprises a structure in which a carboxyl anion of poly(carbo) in the copolymer (A) is attached to the metal complex (B) via a metal atom (M).
Scope of claims [claim1]
1. A polymer-metal complex composite, which comprises a block copolymer (A) represented by the following general formula (a) and a metal complex (B) having MRI contrast ability:

poly(hph)-block-poly(carbo) (a)

[wherein poly(hph) represents an uncharged hydrophilic polymer chain segment, and poly(carbo) represents a polymer chain segment having carboxyl groups in its side chain] wherein the composite comprises a structure in which a carboxyl anion of poly(carbo) in the copolymer (A) is attached to the metal complex (B) via a metal atom (M).
[claim2]
2. The composite according to claim 1, which comprises a structure in which a metal atom (M) is attached to a carboxyl anion of poly(carbo) in the copolymer (A), and the metal complex (B) is attached to the metal atom (M).
[claim3]
3. The composite according to claim 1 or 2, wherein: i) poly(hph) is derived from a hydrophilic polymer selected from the group consisting of polyethylene glycol, poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), poly(2-isopropyl-2-oxazoline), polyacrylamide, polymethacrylamide, polyvinyl alcohol, poly(hydroxyethyl acrylate) and poly(hydroxyethyl methacrylate); and/or ii) poly(carbo) is derived from an anionic polymer selected from the group consisting of poly(glutamic acid), poly(aspartic acid), poly(acrylic acid), poly(methacrylic acid) and poly(malic acid); and/or iii) the metal atom (M) is a central metal atom in a metal complex, typically wherein the metal complex is a metal complex (C) having antitumor activity, and typically wherein the metal complex (C) is immobilized to the block copolymer (A).
[claim4]
4. The composite according to claim 1, which is represented by the following general formula: i) general formula (1) or (2) (see diagramm) [wherein R **1 represents a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group, L **1 and L **2 each represent a linker group, R **2 independently represents a methylene group or an ethylene group, R **3 independently represents a hydrogen atom, a protecting group for an amino group, a hydrophobic group or a polymerizable group, R **4 represents a hydroxyl group or an initiator residue, R **5 independently represents a hydrogen atom, an alkali metal ion, or a group represented by the following general formula (3) or (4): (see diagramm) (wherein R **6 represents a metal atom or a group derived from a metal complex, and R **7 represents a group derived from a metal complex having MRI contrast ability) (provided that R **5 comprises, at least in part, the group represented by general formula (3)), m represents an integer of 5 to 20,000, n represents an integer of 2 to 5,000, and x represents an integer of 0 to 5,000 (provided that x<=n)]; or ii) general formula (1-a) or (2-a) (see diagramm) [wherein R **1 represents a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group, L **1 and L **2 each represent a linker group, R **2 independently represents a methylene group or an ethylene group, R **3 independently represents a hydrogen atom, a protecting group for an amino group, a hydrophobic group or a polymerizable group, R **4 represents a hydroxyl group or an initiator residue, R **5 independently represents a hydrogen atom, an alkali metal ion, or a group represented by the following general formula (3) or (4): (see diagramm) (wherein R **6 represents a metal atom or a group derived from a metal complex, and R **7 represents a group derived from a metal complex having MRI contrast ability) (provided that R **5 comprises, at least in part, the group represented by general formula (3)), m represents an integer of 5 to 20,000, and n represents an integer of 2 to 5,000].
[claim5]
5. The composite according to claim 4, wherein R **6 is independently: i) a metal atom selected from platinum, copper, gold or iron; ii) a group derived from a metal complex having platinum, copper, gold or iron as a central metal atom, typically wherein R **6 is independently a group represented by the following general formula (5) or (6) (see diagramm) [wherein M represents a metal atom selected from platinum, copper, gold or iron]; or iii) a group derived from a metal complex having antitumor activity, typically represented by the following formula (5-a) or (6-a) (see diagramm)
[claim6]
6. The composite according to any one of claims 4 or 5, wherein R **7 is independently a group derived from a metal complex having gadolinium, europium, manganese, iron or copper as a central metal atom,
typically wherein the metal complex is a metal complex with a multidentate ligand,
preferably wherein the multidentate ligand is an aminocarboxylic acid or phosphoric acid compound, a porphyrin compound, or deferrioxamine B,
preferably wherein the aminocarboxylic acid or phosphoric acid compound is ethylene diamine tetraacetic acid, diethylene triamine pentaacetic acid, diethylene triamine pentaacetic acid bismethylamide, triethylene tetramine hexaacetic acid, benzyloxypropionic pentaacetic acid, ethylene glycol tetramine tetraacetic acid, tetraazacyclododecane tetraacetic acid, tetraazacyclododecane triacetic acid, dihydroxyhydroxymethylpropyltetraazacyclododecane triacetic acid, hydroxypropyltetraazacyclododecane triacetic acid, or tetraazacyclododecane tetraphosphoric acid.
[claim7]
7. The composite according to claim 6, wherein R **7 is independently a group represented by the following: i) general formula (7), (8), (9) or (10) (see diagramm)(see diagramm)(see diagramm)(see diagramm) [wherein M **1 represents a metal atom selected from gadolinium, europium, manganese, iron or copper] ii) formula (7-a), (8-a), (9-a) or (10-a) (see diagramm)(see diagramm)(see diagramm)(see diagramm)
[claim8]
8. The composite according to claim 4, wherein the group represented by general formula (3) is independently: i) a group represented by the following general formula (11), (12), (13), (14), (15), (16), (17) or (18) (see diagramm)(see diagramm)(see diagramm)(see diagramm)(see diagramm)(see diagramm)(see diagramm)(see diagramm) [wherein M represents a metal atom selected from platinum, copper, gold or iron, or M **1 represents a metal atom selected from gadolinium, europium, manganese, iron or copper] ii) a group represented by the following formula (11-a), (12-a), (13-a), (14-a), (15-a), (16-a), (17-a) or (18-a).(see diagramm)(see diagramm)(see diagramm)(see diagramm)(see diagramm)(see diagramm)(see diagramm)(see diagramm)
[claim9]
9. The composite according to any one of claims 1 to 8, which encapsulates the metal complex having MRI contrast ability within micellar particles whose shell and core are formed by the poly(hph) and poly(carbo) segments, respectively.
[claim10]
10. The composite according to claim 9, which further encapsulates a metal complex having antitumor activity.
[claim11]
11. The composite according to claim 9 or 10, which has an average dispersed particle size of 10 nm to 1 micron m in an aqueous medium, as measured by dynamic light scattering.
[claim12]
12. A composition which comprises a composite as defined in any one of claims 1 to 11 for use in a method of treating a tumour.
[claim13]
13. Use in a MRI contrasting method for tumour detection of a composition which comprises a composite as defined in any one of claims 1 to 11.
[claim14]
14. An MRI contrasting method for tumor detection, which comprises administering the composite according to any one of claims 1 to 11 to the body of an animal subject.
[claim15]
15. An MRI contrasting and/or antitumor kit, which comprises the composite according to any one of claims 1 to 11.
  • Applicant
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
  • Inventor
  • KATAOKA KAZUNORI
  • KAIDA SACHIKO
  • CABRAL HORACIO
  • KUMAGAI MICHIAKI
  • SEKINO MASAKI
IPC(International Patent Classification)
Reference ( R and D project ) CREST Establishment of Innovative Manufacturing Technology Based on Nanoscience AREA
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