WO2011058776A1 - Copolymère séquencé, corps composite copolymère séquencé - complexe métallique, et support de structure creuse utilisant ceux-ci - Google Patents

Copolymère séquencé, corps composite copolymère séquencé - complexe métallique, et support de structure creuse utilisant ceux-ci Download PDF

Info

Publication number
WO2011058776A1
WO2011058776A1 PCT/JP2010/058238 JP2010058238W WO2011058776A1 WO 2011058776 A1 WO2011058776 A1 WO 2011058776A1 JP 2010058238 W JP2010058238 W JP 2010058238W WO 2011058776 A1 WO2011058776 A1 WO 2011058776A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
integer
independently
metal complex
block copolymer
Prior art date
Application number
PCT/JP2010/058238
Other languages
English (en)
Japanese (ja)
Inventor
片岡一則
長田健介
岸村顕広
西山伸宏
カブラルオラシオ
Original Assignee
独立行政法人科学技術振興機構
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 独立行政法人科学技術振興機構 filed Critical 独立行政法人科学技術振興機構
Publication of WO2011058776A1 publication Critical patent/WO2011058776A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/40—Polyamides containing oxygen in the form of ether groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/48—Polymers modified by chemical after-treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L77/00—Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
    • C08L77/04—Polyamides derived from alpha-amino carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L87/00—Compositions of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds
    • C08L87/005—Block or graft polymers not provided for in groups C08L1/00 - C08L85/04

Definitions

  • the present invention relates to a hollow structure carrier capable of enclosing a water-soluble substance, and a block copolymer and a block copolymer-metal complex composite constituting the carrier.
  • Non-Patent Document 1 M. Yokoyama, T. Okano, Y. Sakurai, S. Suwa and K. Kataoka, Introduction of cisplatin intoleric micule 19
  • Non-Patent Document 2 N. Nishiyama, M. Yokoyama, T. Aoyagi, T. Okano, Y. Sakurai, K.
  • Patent Document 3 N. Nishiyama, K. Kataoka, Preparation and charac- terization of size-controlled polymeric contining cis-dichlorodiammine platinum II) in the core, J. Control.Rel., 74 (2001) 83.
  • Non-patent document 4 Y. Mizumura, Y. Matsumura, T. Hamaguchi, N. Nishiyama, K.
  • Non-Patent Document 6 N.A. Nishiyama, S .; Okazaki, H .; Cabral, M.M. Miyamoto, Y. et al. Kato.
  • Non-Patent Document 7 H .; Uchino, Y. et al.
  • Cisplatin-incorporating polymeric micelles can reduce nephrotoxicity and neurogenicity of citplatin in rats, 78.
  • Non-Patent Document 8 H .; Cabral, N.M.
  • Non-Patent Document 9 H .; Cabral, N.M. Nishiyama, K .; Kataoka, Optimization (1,2-diaminocyclohexane) platinum (II) -loaded polymeric miracles directed to improved tumor targeting and enhanced anti-Jumper. Control Rel. 121 (2007) 146. ).
  • This anticancer drug-encapsulating polymer micelle has a tumor tissue accumulation property based on long-term blood retention and is known to exhibit an excellent antitumor effect.
  • the polymer micelle needs to give the inner core cohesion by some mechanism, it is difficult to encapsulate a water-soluble substance that does not interact with the carrier.
  • a hollow structure such as a liposome
  • a delivery system containing a water-soluble substance can be obtained, but a delivery system containing a high-molecular weight water-soluble substance such as protein and nucleic acid can be obtained. Have difficulty.
  • the release of the delivery substance is due to the collapse of the liposome structure, it cannot be sustained.
  • the present invention has been made in view of the above situation, and includes the following block copolymer, block copolymer-metal complex complex, hollow structure carrier, cancer therapeutic pharmaceutical composition, cancer diagnostic pharmaceutical composition, tumor A tissue detection composition, a tumor tissue detection method, a tumor tissue imaging composition, and a tumor tissue imaging method are provided.
  • a block copolymer comprising, as constituent components, a polymer chain (A) having a carboxyl group in at least a part of side chains and an uncharged hydrophilic polymer chain (B), wherein one of the polymer chains (A) A plurality of polymer chains (B) bonded to the terminal side of the copolymer.
  • the block copolymer of the present invention include those in which a hydrophobic group is bonded to the other terminal side of the polymer chain (A).
  • examples of the hydrophobic group include a group derived from at least one selected from the group consisting of an aliphatic compound, an aromatic compound, and an alicyclic compound, and among them, a group derived from cholesterol is preferable.
  • the polymer chain (A) is at least one polymer chain selected from the group consisting of polyamino acid, poly (acrylic acid), poly (methacrylic acid) and poly (malic acid), for example. Things.
  • examples of the polyamino acid include poly (glutamic acid) and / or poly (aspartic acid).
  • the polymer chain (B) has, for example, polyethylene glycol, poly (2-methyl-2-oxazoline), poly (2-ethyl-2-oxazoline), poly (2-isopropyl-2-oxazoline).
  • the block copolymer of the present invention includes, for example, the following general formula (1): [In formula (1), each R 1 independently represents a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group, L 1 represents a linking group, and R 2 represents a hydrophobic group. R 3 represents a methylene group or an ethylene group, and R 4 each independently represents a hydrogen atom or an alkali metal ion.
  • n is an integer from 2 to 20,000
  • p is an integer from 2 to 5.
  • the value of p is represented by the following formula (a) bonded to L 1 : Represents the number of polymer chains represented by ] The thing shown by is mentioned.
  • the block copolymer of the present invention has, for example, the following general formula (1 ′): [In Formula (1 ′), R 3 each independently represents a methylene group or an ethylene group, R 4 each independently represents a hydrogen atom or an alkali metal ion, and R 5 represents Formula (b): Represents a group derived from cholesterol or a hydrogen atom.
  • m is an integer of 2 to 1,000
  • n is independently It is an integer from 2 to 20,000.
  • the thing shown by is mentioned.
  • a block copolymer-metal complex composite comprising the copolymer according to (1) above and a metal complex.
  • the complex of the present invention include those obtained by bonding a plurality of molecules of the copolymer to one molecule of the metal complex.
  • the complex include those in which a carboxyl group in the copolymer is bonded to the metal complex.
  • the composite of the present invention include those in which the metal complex is, for example, a metal complex having antitumor activity, and specifically, those in which the central metal of the metal complex is platinum. Cisplatin and / or dahaplatin may be mentioned.
  • the block copolymer-metal complex composite of the present invention includes, for example, the following general formula (2): [In Formula (2), each R 1 independently represents a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group, L 1 represents a linking group, and R 2 represents Independently represents a hydrophobic group or a hydrogen atom, R 3 independently represents a methylene group or an ethylene group, R 4 independently represents a hydrogen atom or an alkali metal ion, and R 6 represents the following formula (c Or (d): (In formulas (b) and (c), M represents a metal atom of platinum, copper, gold or iron.) The metal complex shown by is represented.
  • n is each independently an integer of 2 to 20,000
  • p is each independently an integer of 2 to 5.
  • the value of p is represented by the following formula (a) bonded to L 1 : Represents the number of polymer chains represented by ] The thing shown by is mentioned.
  • the block copolymer-metal complex composite of the present invention has, for example, the following general formula (2 ′): [In the formula (2 ′), each R 3 independently represents a methylene group or an ethylene group, each R 4 independently represents a hydrogen atom or an alkali metal ion, and each R 5 independently represents the following formula (b ): Represents a group derived from cholesterol or a hydrogen atom, and R 7 represents the following formula (c ′) or (d ′): The metal complex shown by is represented.
  • n is each independently an integer of 2 to 20,000.
  • a hollow structure carrier in which the complex according to (2) is associated examples include those in which a single hydrophobic compound is contained in a structure in which the complex is associated. Examples of the carrier of the present invention include those in which the associated complex forms a membrane structure, and specifically, those in the shape of an endoplasmic reticulum.
  • Examples of the carrier of the present invention include those capable of encapsulating a water-soluble substance, particularly a high-molecular-weight water-soluble substance, and specifically those capable of encapsulating a water-soluble protein.
  • Examples of the carrier of the present invention include those having sustained release properties.
  • Examples of the carrier of the present invention include those having an average particle diameter of 50 to 1,000 nm.
  • Examples of the carrier of the present invention include those having tumor tissue selectivity.
  • a composition for imaging a tumor tissue comprising the carrier according to (3) above.
  • Examples of the imaging composition of the present invention include those that can be used for in vivo imaging.
  • a tumor tissue imaging method using the carrier according to (3) above. Examples of the imaging method of the present invention include those that can be used for in vivo imaging.
  • FIG. 1A shows a schematic diagram of an example of Pt-some formation regarding the preparation and physical property evaluation of Pt-some corresponding to the hollow structure carrier of the present invention.
  • FIG. 1A shows a poly (magnetic acid).
  • ) Is a diagram showing the formation of aggregates by complex formation between a carboxylic acid unit and a metal atom (here, Pt).
  • FIG. 1B is a diagram showing the particle size distribution of Pt-some obtained by dynamic light scattering measurement regarding the preparation and physical property evaluation of Pt-some corresponding to the hollow structure carrier of the present invention.
  • FIG. 1A shows a schematic diagram of an example of Pt-some formation regarding the preparation and physical property evaluation of Pt-some corresponding to the hollow structure carrier of the present invention.
  • FIG. 1A shows a poly (magnetic acid).
  • Is Is a diagram showing the formation of aggregates by complex formation between a carboxylic acid unit and a metal atom (here, Pt).
  • Pt metal atom
  • FIG. 1C is a diagram showing an image obtained by staining Pt-some with uranyl acetate and observing it with a transmission electron microscope, regarding preparation and physical property evaluation of Pt-some corresponding to the hollow structure carrier of the present invention.
  • the scale bar in the figure is 100 nm.
  • FIG. 1D is a diagram in which Pt-some containing FITC-dextran and FITC-dextran alone were detected by gel permeation chromatography with respect to the preparation and physical property evaluation of Pt-some corresponding to the hollow structure carrier of the present invention.
  • FIG. 1E is a diagram showing a TEM image of an aggregate formed from different block copolymers and DACHPt with respect to the preparation and physical property evaluation of Pt-some corresponding to the hollow structure carrier of the present invention.
  • a is a TEM image by uranyl acetate staining of an association of DACHPt and PEG-b-P (Glu) -Chol, and polymer micelles were observed as white spots.
  • FIG. 2A is a schematic view showing that the Pt-some membrane permeability is improved by the sustained release of the Pt complex, and the Pt-some inclusion substance is released with respect to the physicochemical characteristics of Pt-some.
  • FIG. 2B is a diagram showing a sustained release profile of a Pt complex from Pt-some with respect to the physicochemical properties of Pt-some.
  • FIG. 2C is a diagram showing a sustained release profile of FITC-dextran from FIt-dextran-encapsulated Pt-some regarding the physicochemical properties of Pt-some.
  • FIG. 2D is a diagram showing a change in the size of Pt-some in a physiological environment (150 mM NaCl concentration, 10 mM PBS buffer) obtained by dynamic light scattering measurement with respect to the physicochemical characteristics of Pt-some.
  • FIG. 2E is a diagram showing a frozen phase-contrast electron microscope image of Pt-some regarding the physicochemical properties of Pt-some. 0 hours (left) and 48 hours (right) under physiological conditions.
  • FIG. 3A is a graph showing the disappearance profile of Pt from plasma after intravenous administration of oxaliplatin ( ⁇ ) and Pt-some ( ⁇ ) regarding the pharmacokinetics of Pt-some.
  • FIG. 3B shows the pharmacokinetics of Pt-some, FITC-dextran alone ( ⁇ ), FITC-dextran alone and Pt-some co-administration ( ⁇ ), and FITC-dextran-encapsulated Pt-some ( ⁇ ) intravenously It is a figure which shows the disappearance profile from the later plasma.
  • FIG. 3A is a graph showing the disappearance profile of Pt from plasma after intravenous administration of oxaliplatin ( ⁇ ) and Pt-some ( ⁇ ) regarding the pharmacokinetics of Pt-some.
  • FIG. 3B shows the pharmacokinetics of Pt-some, FITC-dextran alone ( ⁇ ), FITC-dextran alone and Pt-some co-administration ( ⁇ ), and FITC-dextran
  • FIG. 3C is a diagram showing a tumor accumulation profile of Pt after intravenous administration of oxaliplatin ( ⁇ ) and Pt-some ( ⁇ ) regarding the pharmacokinetics of Pt-some.
  • FIG. 3D shows the pharmacokinetics of Pt-some, FITC-dextran carrier ( ⁇ ), FITC-dextran alone and Pt-some co-administration ( ⁇ ), and FITC-dextran-encapsulated Pt-some ( ⁇ ) intravenous administration It is a figure which shows the tumor accumulation profile of latter FITC.
  • FIG. 4A is a graph showing the relative tumor volume regarding the anticancer activity of Pt-some.
  • FIG. 4B is a graph showing changes in relative body weight with respect to the anticancer activity of Pt-some.
  • Control x
  • *: Toxicity death 6/6 mice, ⁇ S. E. M.M. n 6
  • nanostructured materials When nanostructured materials are applied as medical nanodevices such as treatment, bioimaging, and medical diagnosis, biocompatibility, structural stability in a biological environment, size, and shape are important factors.
  • polymersomes that are hollow nanostructures have excellent properties as multifunctional bio-nano devices (Ahmed, F. et al., Mol. Pharmaceuticals, 2006, vol. 3, p. 340-). 350; Ranquin, A. et al., Nano Lett., 2005, vol.5, p.2220-2224; Ben-Haim, N. et al., Nano Lett., 2008, vol.8, p.1368- 1373; Koide, A. et al., J.
  • polymersomes can provide tumor accumulation based on blood retention and EPR (enhanced permeability and retention) effects by molecular design, for anticancer agents, diagnostic agents, and combination therapies with low therapeutic indices.
  • EPR enhanced permeability and retention
  • the hollow structure carrier of the present invention can be easily encapsulated with a high-molecular-weight water-soluble substance such as protein, and the encapsulated substance or the like can be contained in a desired target tissue (particularly tumor tissue).
  • the hollow structure carrier of the present invention capable of loading and delivering multiple drugs can also be used for new therapeutic strategies such as combination therapy by simultaneous delivery of various anticancer agents and diagnosis of treatment effect in real time by simultaneously carrying imaging agents Is what The creation of an integrated nano-therapeutic system that combines disease diagnosis and drug delivery enables medical treatment that applies an appropriate therapeutic policy while monitoring therapeutic effects, and thus tailor-made medical treatment tailored to the individual.
  • the hollow structure carrier of the present invention is easy to prepare and has excellent characteristics in vivo and in vitro, and thus can be the basis of a nanomedical device that enables diagnosis and treatment at the same time. is there.
  • the hollow structure carrier of the present invention can simultaneously deliver a low molecule, a polymer, or a nanoparticle, the complexity of administering a plurality of drugs can be eliminated. Furthermore, the hollow structure carrier of the present invention can be multi-functionalized by chemically modifying the block copolymer constituting the carrier, and further development of medicine using a drug delivery system is possible. It is. 2. Hollow structure carrier The hollow structure carrier of the present invention is obtained by associating a block copolymer-metal complex complex comprising a specific block copolymer and a metal complex. Below, each structural component, preparation method, use, etc. of the hollow structure carrier of this invention are demonstrated.
  • Block copolymer-metal complex composite (A) Block copolymer
  • the block copolymer of the present invention is a block copolymer comprising at least a polymer chain (A) having a carboxyl group in a side chain and an uncharged hydrophilic polymer chain (B) as constituent components, A) is characterized in that a hydrophobic group or a hydrogen atom is bonded to one terminal side, and a plurality of polymer chains (B) are bonded to the other terminal side.
  • the polymer chain (A) having a carboxyl group in at least a part of the side chains is not limited, and examples thereof include polyamino acids, poly (acrylic acid), poly (methacrylic acid), and poly ( Preferred are those derived from anionic polymers such as malic acid), more preferred are those derived from polyamino acids, and even more preferred are those derived from poly (glutamic acid) and poly (aspartic acid).
  • the uncharged hydrophilic polymer chain (B) is not limited, and examples thereof include polyethylene glycol (PEG), poly (2-methyl-2-oxazoline), poly (2-ethyl- 2-oxazoline), poly (2-isopropyl-2-oxazoline), polyacrylamide, polymethacrylamide, polyvinyl alcohol, polyethyl acrylate and poly (hydroxyethyl methacrylate) are preferred. Among them, those derived from polyethylene glycol are more preferable.
  • the group derived from an aliphatic compound, an aromatic compound, and an alicyclic compound is mentioned preferably.
  • the group derived from the aliphatic compound include, but are not limited to, for example, an unsubstituted or substituted linear or branched C 1-12 Preferred examples include alkyl groups, specifically, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n- A hexyl group, a decyl group, an undecyl group, etc.
  • the group derived from the aromatic compound is not limited, and examples thereof include a phenyl compound, a naphthalene compound, an anthracene compound, a pyrene compound, a perylene compound, and a triphenylene compound.
  • the group derived from the alicyclic compound is not limited, and examples thereof include groups derived from cholesterol, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like.
  • the hydrophobic group is more preferably a group derived from an alicyclic compound, and more specifically a group derived from cholesterol and its derivatives.
  • R 1 Each independently represents a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12
  • An alkyl group (an alkyl group having 1 to 12 carbon atoms) is represented.
  • Examples of the linear or branched alkyl group having 1 to 12 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, Examples thereof include an n-pentyl group, an n-hexyl group, a decyl group, and an undecyl group.
  • Examples of the substituent of the alkyl group include an acetalized formyl group, a cyano group, a formyl group, a carboxyl group, an amino group, an alkoxycarbonyl group having 1 to 6 carbon atoms, an acylamide group having 2 to 7 carbon atoms, a siloxy group, Examples thereof include a silylamino group and a trialkylsiloxy group (each alkylsiloxy group independently has 1 to 6 carbon atoms).
  • the substituent is an acetalized formyl group, it can be converted into another substituent, a formyl group (aldehyde group; —CHO), by hydrolysis under acidic mild conditions.
  • L 1 Represents a linker portion (linking group) between the polymer chain (A) and the polymer chain (B).
  • L 1 Specifically, there is no limitation, and any linking group can be selected.
  • the group shown by] is preferable.
  • R 2 represents a hydrophobic group or a hydrogen atom, and the hydrophobic group is the same as described above.
  • R 3 Each independently represents a methylene group (—CH 2 -) Or ethylene group (-CH 2 -CH 2 -).
  • R 4 Each independently represents a hydrogen atom or a salt of a carboxylic acid. Although it does not limit as a salt of carboxylic acid, For example, lithium ion, sodium ion, potassium ion, ammonium ion etc. are mentioned.
  • the value of m represents the average degree of polymerization of the polymer chain portion corresponding to the polymer chain (A), specifically 2 to 1,000 (preferably 5 to 500, more preferably It is an integer of 10 to 100).
  • n represents the average degree of polymerization of the PEG-derived polymer chain portion corresponding to the polymer chain (B). Specifically, it is independently 2 to 20,000 (preferably 40 to 4,000, more preferably). Is an integer of 100 to 1,000).
  • the value of p is L which is a linking group. 1
  • the number of PEG-derived polymer chains bonded to the polymer chain, that is, the polymer chain represented by the following formula (a) is L 1 Represents an integer of 2 to 5 (preferably 2 to 3).
  • the average molecular weight (Mw) of the block copolymer represented by the formula (1) is not limited, but is preferably 400 to 1,000,000, more preferably 2,500 to 250,000.
  • the average molecular weight (Mw) of the PEG-derived polymer chain part corresponding to the polymer chain (B) is not limited, but is 100 to 880,000 per polymer chain. It is preferably 1,800 to 180,000, more preferably 44,000 to 440,000, and the average molecular weight (Mw) of the polymer chain portion corresponding to the polymer chain (A) is not limited. Is preferably 750 to 75,000, more preferably 1,500 to 15,000.
  • the production method of the block polymer represented by the above formula (1) is not limited, but can be summarized as, for example, (a) R 1 And a segment containing a polymer chain portion derived from PEG (PEG segment; L as a linking group) 1 (B1)
  • PEG segment PEG segment; L as a linking group
  • One end of this PEG segment R 1 Or the other side of the PEG segment and the side chain containing a carboxyl group, if necessary, or by substitution or conversion so that the side chain contains a carboxyl group.
  • R 1 a segment containing a polymer chain portion derived from PEG
  • L as a linking group
  • the method and conditions of various reaction can be suitably selected or set in consideration of a conventional method.
  • the production method reference can be made to the synthesis schemes described in Examples described later.
  • the said PEG segment can be prepared using the manufacturing method of the PEG segment part of the block copolymer as described in WO96 / 32434, WO96 / 33233, or WO97 / 06202, for example.
  • specific examples of the block copolymer represented by the above formula (1) include a copolymer represented by the following general formula (1 ′). In the above formula (1 ′), R 3 And R 4 Is the same as in the case of formula (1).
  • R 5 Represents a group derived from cholesterol represented by the following formula (b) or a hydrogen atom.
  • the values and explanation of m, m1, m2 and n are the same as in the case of the formula (1).
  • (B) Block copolymer-metal complex composite The block copolymer-metal complex complex of the present invention is a complex comprising the block copolymer of the present invention and a metal complex, and is a direct component of the hollow structure carrier of the present invention described later. .
  • the composite of the present invention is preferably one in which the carboxyl group in the block copolymer of the present invention (carboxyl group derived from the side chain of the polymer (A) chain) and a metal complex are bonded. It is preferable that a plurality of molecules of the block copolymer are bonded to the molecule. Although it does not limit as a metal complex, For example, it is preferable to use the metal complex which has antitumor activity. Moreover, as a metal complex, what a central metal is a metal atom of platinum, copper, nickel, vanadium, zinc, gold
  • the block copolymer-metal complex complex of the present invention include a complex represented by the following general formula (2).
  • R 1 , L 1 , R 2 , R 3 And R 4 Are the same as in the case of Formula (1).
  • R 6 Is a portion derived from a metal complex that connects the block copolymers of the present invention, and has a structure represented by the following formula (c) or (d).
  • M represents a metal atom of platinum, copper, gold or iron, and platinum is particularly preferable.
  • the values and description of m, m1, m2, n, and p are the same as in the case of the above formula (1).
  • R derived from the block copolymer and the metal complex 6 As for the binding mode, the mode shown by the above formula (2) is an example, and is not limited thereto.
  • R can be combined in any manner capable of bonding. 6 A bond can be formed.
  • the bonding mode is as follows: (i) a two-molecule block copolymer represented by the formula (2) is R 6 It is also possible to have an embodiment in which the molecules are bonded to each other via (ii), or (ii) groups surrounded by a dotted line in one molecule of the block copolymer are R 6 (Iii) One group surrounded by a dotted line instead of the intermolecular bond or the intramolecular bond is one molecule R 6 Or (iv) an embodiment in which these (i) to (iii) are arbitrarily mixed, and is not particularly limited, but in the complex of the present invention, at least the above It is preferable that the coupling
  • block copolymer-metal complex complex represented by the above formula (2) include a complex represented by the following general formula (2 ′).
  • R 3 And R 4 Is the same as in the case of the formula (1), and R 5 Is the same as in the above formula (1 ′).
  • R 7 Is R in the formula (2).
  • the carrier is preferably one in which the above complex is formed into a membrane structure, and as a whole, the carrier is preferably a carrier having a hollow vesicular shape. .
  • a desired substance can be easily included by having a hollow area
  • the hollow structure carrier of the present invention has an uncharged hydrophilic polymer chain (B) (eg, a polymer chain derived from PEG) on the surface of the membrane structure, that is, on both the outer and inner surfaces, and the membrane structure Inside, the film structure is stabilized by the bond between the polymer chain (A) and the metal complex, and at least a part of the hydrophobic group exists, so that the structure of the entire film and thus the structure of the entire carrier are very stable. Excellent in properties.
  • B uncharged hydrophilic polymer chain
  • A polymer chain derived from PEG
  • the carrier of the present invention has a feature that even a water-soluble substance, particularly a high-molecular weight water-soluble substance (specifically, a water-soluble protein), which has been difficult with conventional carriers, can be included.
  • the hollow structure carrier of the present invention can be prepared by dissolving and stirring the block copolymer of the present invention and the metal complex, respectively. That is, the hollow structure carrier of the present invention is a structure having a form in which the complex of the block copolymer of the present invention and the metal complex is associated, but the complex is prepared in advance.
  • the block copolymer used for the preparation of the hollow structure carrier of the present invention is not limited, as long as it contains at least part of the polymer chain (A) having a hydrophobic group bonded thereto.
  • the number of molecules of the block copolymer having a hydrophobic group bonded to the polymer chain (A) is preferably 1 to 99%, more preferably 3 to the total number of molecules of the block copolymer used. 60%.
  • a hydrophobic compound may be added alone to the reaction system of the block copolymer and the metal complex in advance or with the progress of the reaction.
  • the single hydrophobic compound include compounds derived from the groups exemplified as the hydrophobic group that can be bonded to the polymer chain (A), specifically, aliphatic compounds, aromatic compounds, alicyclic compounds, and derivatives thereof. Among them, alicyclic compounds are preferable, and cholesterol or a derivative thereof is particularly preferable.
  • the amount of the hydrophobic compound added to the reaction system is not limited, and can be appropriately set in consideration of the stable formation of the hollow structure.
  • Isolation and purification of the hollow structure carrier of the present invention can be recovered from an aqueous medium by a conventional method. Typical methods include ultrafiltration, diafiltration, dialysis, and the like.
  • the hollow structure carrier of the present invention has sustained release properties. Specifically, when the formed carrier of the present invention is placed in the presence of a chloride ion such as NaCl, for example, the bond between the block copolymer of the present invention and the metal complex is gradually released, and the inclusion substance is gradually released. Released.
  • the level of sustained release of the carrier of the present invention is not limited, but can be sustainedly released in a period of 1 minute to 1 month, for example.
  • the average particle size of the hollow structure carrier of the present invention is not limited, but is 50 to 1,000 nm.
  • the particle size by dynamic light scattering measurement (DLS) is preferably 50 to 200 nm. 3.
  • Pharmaceutical composition for cancer treatment, pharmaceutical composition for cancer diagnosis In this invention, the pharmaceutical composition for cancer treatment and / or cancer diagnosis characterized by including the hollow structure carrier of the said this invention is provided.
  • the pharmaceutical composition of the present invention comprises a substance (such as a protein having antitumor activity) encapsulated in a hollow structure carrier, a metal complex (for example, cisplatin or dahaplatin) present in a film constituting the carrier, and the characteristics of the carrier itself.
  • a substance such as a protein having antitumor activity
  • a metal complex for example, cisplatin or dahaplatin
  • tumor tissue selectivity tumor tissue accumulation property
  • it can be used as a cancer (malignant tumor) treatment means and / or a cancer (malignant tumor) diagnosis / detection means.
  • a sensitive substance that is a target of radiation is used as the carrier inclusion substance, it can also be used as a means of radiotherapy.
  • the type of tumor is not limited, and various known cancer types can be mentioned.
  • the content ratio of the hollow structure carrier is not limited and can be appropriately set in consideration of the type of substance to be encapsulated and the antitumor effect.
  • the pharmaceutical composition of the present invention can be applied to various animals such as humans, mice, rats, rabbits, pigs, dogs and cats, and is not limited.
  • parenteral methods such as intravenous drip infusion are usually adopted, and each condition such as dose, number of times of administration, and administration period depends on the type and condition of the test animal and the purpose of use of the composition. Can be set as appropriate.
  • the dose for intravenous administration to humans is determined by conducting a small experiment with laboratory animals or volunteers, considering the results, and further considering the patient's condition. However, it is preferable that it be determined by a specialist, and although it is not limited, it is generally 1.0 to 1,000 mg / m once a day. 2 (Body surface area of the patient) and 10 to 200 mg / m 2 (Patient body surface area) is administered once a day for several consecutive days, and the drug is withdrawn for a certain period, or 50 to 500 mg / m 2
  • An appropriate dose can be selected according to the administration schedule, such as administration of (patient body surface area) once a day, followed by several days off.
  • the pharmaceutical composition of the present invention takes into account uses such as antitumor use, and is generally used in the manufacture of pharmaceuticals, such as excipients, fillers, extenders, binders, wetting agents, disintegrants, lubricants, surfactants, dispersions
  • An agent, a buffering agent, a preservative, a solubilizing agent, a preservative, a flavoring agent, a soothing agent, a stabilizer, a tonicity agent and the like can be appropriately selected and used, and can be prepared by a conventional method.
  • the form of a pharmaceutical composition normally employs an intravenous injection (including infusion), and is provided, for example, in the state of a unit dose ampoule or a multi-dose container.
  • the hollow structure carrier of the present invention and / or the pharmaceutical composition for cancer treatment and / or cancer diagnosis is administered to a patient or a non-human mammal, and And / or use of the hollow structure carrier of the present invention and / or a pharmaceutical composition for cancer treatment and / or cancer diagnosis for the treatment and / or diagnosis of cancer, and / or cancer treatment and / or Use of the hollow structure carrier of the present invention for producing a diagnostic drug, as well as an invention relating to a cancer treatment and / or diagnostic kit containing the hollow structure carrier of the present invention are also provided. can do. 4).
  • Tumor tissue detection composition, tumor tissue imaging composition The present invention provides a composition for tumor tissue detection and / or tumor tissue imaging, comprising the hollow structure carrier of the present invention.
  • the composition of the present invention selects a substance effective for detection and imaging of a tumor tissue as a substance included in the hollow structure carrier, and utilizes the tumor tissue selectivity (tumor tissue accumulation property) which is a characteristic of the carrier itself. Thus, it can be used as a tumor tissue detection or imaging means.
  • the substance effective for detection and imaging of tumor tissue is not limited, but various proteins used in fluorescence detection and fluorescence imaging techniques such as various fluorescent proteins can be used, preferably GFP (green fluorescent protein) or luciferase Alternatively, derivatives or mutants thereof can be used.
  • the type of tumor to be detected or imaged is not limited, and various known cancer types can be mentioned.
  • the composition of this invention can be used suitably also for the detection and imaging of the tumor tissue in vivo.
  • the content of the hollow structure carrier is not limited, and can be appropriately set in consideration of the type of substance to be included.
  • the composition of the present invention can be applied to the detection and imaging of tumor tissues in various animals such as humans, mice, rats, rabbits, pigs, dogs, cats and the like, but is not limited thereto. When such detection and imaging are performed, administration to a test animal is required. However, parenteral methods such as intravenous infusion are usually adopted as the administration method, and various conditions such as dosage, number of administrations, and administration period are adopted. Can be appropriately set according to the purpose and use of the composition in addition to the type and condition of the test animal.
  • the composition of the present invention is intended for use in detection and imaging of antitumor tissue, and is generally used for drug production, such as an excipient, a filler, an extender, a binder, a wetting agent, a disintegrant, a lubricant, and an interface.
  • Activators, dispersants, buffers, preservatives, solubilizers, preservatives, flavoring agents, soothing agents, stabilizers, tonicity agents, etc. are appropriately selected and used and prepared by conventional methods. You can also.
  • the form of the composition of the present invention usually employs an intravenous injection (including infusion), and is provided, for example, in the state of a unit dose ampoule or a multi-dose container.
  • the apparatus used for detection and imaging of tumor tissue after administration of the composition of the present invention is not particularly limited, and an apparatus commonly used in conventional fluorescence imaging techniques such as a fluorescence microscope and FACS may be used in appropriate combination. Can do.
  • a tumor tissue (in vivo) detection and / or imaging method characterized by using the hollow structure carrier of the present invention (specifically, administered to a test animal),
  • the invention relating to a cancer treatment and / or diagnostic kit containing the hollow structure carrier of the present invention can be provided in the same manner.
  • the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.
  • PEGasus-b-poly ( ⁇ -benzyl L-glutamate) (PEGasus-b-PBLG; Compound 3) is a ring-opening of NCA using PEGasus-NH 2 (Mw 20k; Compound 1) with aminated terminal as an initiator. Obtained by polymerization.
  • the molecular weight distribution of PEGasus-b-PBLG (compound 3) was determined by GPC measurement.
  • the molecular weight of PBLG (poly ( ⁇ -benzyl L-glutamate)) was calculated from the ratio of the hydrogen of the methylene unit of PEG and the hydrogen of the phenyl group of PBLG from 1 H-NMR, and was estimated to be a 20-mer.
  • PEGasus-b-PBLG The amino terminal of PEGasus-b-PBLG (Compound 3) was reacted with cholesterol chloroform (Compound 4) at room temperature to obtain PEGasus-b-PBLG-Chol (Compound 5). Cholesterol content was determined from 1 H-NMR.
  • the PBLG segment was deprotected by reacting PEGasus-b-PBLG-Chol (Compound 5) with 0.5N NaOH at room temperature to obtain PEGasus-b-P (Glu) -Chol (Compound 6). It was confirmed that the deprotection reaction proceeded completely from 1 H-NMR.
  • PEGasus-b-P (Glu) -Chol (Compound 6) corresponding to the block copolymer of the present invention was obtained.
  • the obtained PEGasus-b-P (Glu) -Chol had an average molecular weight (Mw) of PEG chain of 20,000 and an average degree of polymerization of polyglutamic acid of 20.
  • Mw average molecular weight
  • Pt-some Pt-some corresponding to the hollow structure carrier of the present invention was prepared and its physical properties were confirmed.
  • mice were sacrificed 1, 4, and 24 hours after administration, and tumor, liver, kidney, and spleen tissues were removed.
  • Plasma was obtained by collecting blood from the inferior vena cava, heparinizing, and centrifuging.
  • the tissue was dissolved in nitric acid, dried and then redissolved in hydrochloric acid, and the Pt concentration was measured by ICP-MS.
  • the amount of FITC-dextran accumulated was measured from the fluorescence intensity of each homogenized tissue. As fluorescence background, the fluorescence intensity of each organ of untreated mice was measured.
  • Pt-some corresponding to the hollow structure carrier of the present invention includes Pt of dahaplatin (DACHPt), which is an active substance of the anticancer drug oxaliplatin, and double-stranded PEG-polyglutamic acid-cholesterol group (Y-shaped poly (ethylene).
  • DACHPt dahaplatin
  • Y-shaped poly (ethylene) double-stranded PEG-polyglutamic acid-cholesterol group
  • Pt-some has a vesicle structure which is a hollow structure.
  • Pt-some which is a hollow structure, is a combination of PEGasus-b-P (Glu) without cholesterol (Chol) group and DACHPt, or a combination of block copolymer consisting of single-chain PEG (Mw 12k) ( Since it was not formed with PEG-P (Glu) -Chol / DACHPt) (FIG. 1E), it was considered that at least two PEG chains and a hydrophobic group were required for vesicle structure formation.
  • Pt-some was prepared from PEGasus-b-P (Glu) -Chol and DACHPt in the presence of FITC-labeled dextran (FITC-dextran 10,000 Da).
  • FITC-dextran that was not encapsulated in Pt-some was removed by ultrafiltration.
  • the confirmation of the inclusion of FITC-dextran in the vesicle was examined using a UV absorption detector and a fluorescence detector using GPC.
  • FITC-dextran (free) alone had a slow elution time (35 minutes), the fluorescence of FITC-dextran contained in vesicles was observed at the same fast elution time (13 minutes) as Pt-some (Fig. 1D).
  • FITC-dextran is encapsulated in Pt-some, which supports the hollow structure of Pt-some and also shows high potential of Pt-some as a carrier of hydrophilic substance.
  • the amount of inclusion of DACHPt and FITC-dextran in Pt-some was examined using ICP-MS and a fluorescence spectrophotometer.
  • the amount of DACHPt inclusion in the Pt-some film was estimated to be 10 wt% of the polymer. This means that approximately 50% of the carboxylic acid of P (Glu) is complexed with Pt.
  • 10% of DACHPt added at the time of preparation of Pt-some is taken into Pt-some.
  • the amount of FITC-dextran included in Pt-some is estimated to be 20 wt% of the polymer, which means that 24% of FITC-dextran added during the preparation of Pt-some was actually included.
  • Pt-some does not release DACHPt and dextran in the water, but in the presence of chloride ion, it releases DACHPt by the ligand exchange reaction between carboxylic acid and chloride ion, and subsequently releases the inclusion substance.
  • DACHPt the ligand exchange reaction between carboxylic acid and chloride ion
  • the initial induction time is due to the dissociation reaction between Pt and P (Glu), and the membrane permeability is improved by the release of DACHPt from the P (Glu) -Chol / DACHPt layer. It was considered.
  • This induction time was thought to be a very useful property in terms of tumor selective delivery, since the sustained release of the encapsulated material began after accumulation of the carrier into the tumor.
  • the sustained release profile over several days of FITC-dextran showed that the Pt-some structure was maintained even after Pt was considerably lost. This was supported by the fact that Pt-some maintained a particle size of 80 to 90 nm over a long period under physiological conditions (FIG. 2D).
  • the film structure of Pt-some was observed even after 48 hours under physiological conditions, and it was confirmed that the vesicle structure was retained (FIG. 2E).
  • the contrast of the P (Glu) -Chol / DACHPt layer was different when placed under physiological conditions for 0 hour and 48 hours. This is because the contrast in the TEM image greatly depends on the Pt concentration, and it was considered that the contrast of the P (Glu) -Chol / DACHPt layer was lowered by the sustained release of DACHPt by contact with NaCl for 48 hours. From the sustained release profile, it was estimated that 40% of the initial inclusion amount was released after 48 hours (FIG. 2B).
  • Pt-some showed cytotoxicity by sustained release of DACHPt, as shown in in vitro experiments (see Table 2). Therefore, it was considered that Pt-some can be expected to have anticancer activity together with tumor imaging.
  • C-26 tumor-bearing mice (CDF1) were administered free oxaliplatin (Pt conversion 8, 10 mg / kg) and Pt-some (Pt conversion 6 mg / kg) 3 times every 2 days via the tail vein. The cancer activity was examined. Free oxaliplatin did not inhibit tumor growth at either dose (FIG. 4A), and at a dose of 10 mg / kg, due to toxicity, it died after the third dose (day 8) (FIG. 4B). ).
  • Pt-some (6 mg / kg) showed a clear tumor growth inhibitory effect (FIG. 4A), and no significant weight loss based on systemic toxicity was observed (FIG. 4B). This was considered to be due to high tumor selectivity (tumor accumulation) based on the EPR effect of Pt-some.
  • Pt-some which can be loaded and delivered with multiple drugs, enables new treatment strategies such as combination therapy by simultaneous delivery of various anticancer drugs and real-time diagnosis of treatment effects by simultaneously carrying imaging agents. It was thought to be held.
  • a pharmaceutical composition for cancer treatment for example, a pharmaceutical composition for cancer treatment, a pharmaceutical composition for cancer diagnosis, a composition for detecting tumor tissue, a method for detecting tumor tissue, a composition for imaging tumor tissue, and a method for imaging tumor tissue And a block copolymer and a block copolymer-metal complex composite as a constituent component of the carrier can be provided.
  • the hollow structure carrier of the present invention can encapsulate not only an anticancer agent but also a high molecular weight water-soluble substance, and selectively deliver the encapsulated substance or the like to a desired target tissue (particularly a tumor tissue). It is extremely useful as a carrier that can be released and has sustained release properties.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Polyamides (AREA)
  • Polyethers (AREA)
  • Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)

Abstract

La présente invention a pour objet un support de structure creuse qui possède des propriétés de libération prolongée et qui administre sélectivement non seulement un agent carcinostatique mais aussi une substance hydrosoluble ayant un poids moléculaire élevé à un tissu cible souhaité (spécialement à un tissu tumoral). Le support de structure creuse est caractérisé en ce qu'il est obtenu par association de corps composites copolymère séquencé - complexe métallique dont chacun contient un copolymère séquencé spécifique et un complexe métallique.
PCT/JP2010/058238 2009-11-12 2010-05-10 Copolymère séquencé, corps composite copolymère séquencé - complexe métallique, et support de structure creuse utilisant ceux-ci WO2011058776A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009259305A JP2011105792A (ja) 2009-11-12 2009-11-12 ブロックコポリマー、ブロックコポリマー−金属錯体複合体、及びそれを用いた中空構造体キャリア
JP2009-259305 2009-11-12

Publications (1)

Publication Number Publication Date
WO2011058776A1 true WO2011058776A1 (fr) 2011-05-19

Family

ID=43991440

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/058238 WO2011058776A1 (fr) 2009-11-12 2010-05-10 Copolymère séquencé, corps composite copolymère séquencé - complexe métallique, et support de structure creuse utilisant ceux-ci

Country Status (2)

Country Link
JP (1) JP2011105792A (fr)
WO (1) WO2011058776A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012255697A (ja) * 2011-06-08 2012-12-27 Jeol Ltd 電子顕微鏡観察用染色剤および電子顕微鏡観察用試料の染色方法
CN102863627A (zh) * 2012-10-10 2013-01-09 中国科学院长春应用化学研究所 顺铂配合物及其制备方法
CN105997878A (zh) * 2012-11-22 2016-10-12 原创生医股份有限公司 降低自由基伤害的复合微胞载体医药组成物
WO2019034429A1 (fr) * 2017-08-14 2019-02-21 Universität Konstanz Copolymères à blocs multifonction pour dissoudre les plaques d'athérome
US10596191B2 (en) 2015-09-14 2020-03-24 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of hexa-coordinated platinum complex
US10946028B2 (en) 2015-12-22 2021-03-16 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of sulfoxide derivative-coordinated platinum(II) complex
US10988496B2 (en) 2015-06-24 2021-04-27 Nippon Kayaku Kabushiki Kaisha Platinum (IV) complex

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI568453B (zh) * 2011-11-22 2017-02-01 原創生醫股份有限公司 具有螯合型複合微胞之藥物載體及其應用
US8785569B2 (en) * 2011-11-22 2014-07-22 Original Biomedicals Co., Ltd. Drug carrier with chelating complex micelles and the application thereof
JP6083738B2 (ja) * 2013-03-06 2017-02-22 公立大学法人大阪市立大学 ホウ素中性子捕捉療法用組成物およびその製造方法
KR101770705B1 (ko) 2013-08-06 2017-08-23 고쿠리츠켄큐카이하츠호진 카가쿠기쥬츠신코키코 핵산 내포 고분자 미셀 복합체 및 그 제조 방법
JP7289155B2 (ja) * 2019-04-10 2023-06-09 国立大学法人 東京大学 妊婦又は妊娠可能性のある女性に対して投与するための医薬組成物
JP7281140B2 (ja) * 2019-04-15 2023-05-25 日油株式会社 生体関連物質とブロックポリマーとの結合体、および前記結合体を得るためのブロックポリマー誘導体
WO2020251061A1 (fr) * 2019-06-10 2020-12-17 Kawasaki Institute Of Industrial Promotion Glucocorticoïde destiné à être utilisé dans l'amélioration de l'effet d'un médicament anticancéreux, et son utilisation
CN110862536B (zh) * 2019-11-29 2022-06-14 辽宁师范大学 一种pH敏感脂质材料及其制备方法和用途

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026241A1 (fr) * 2000-09-26 2002-04-04 Center For Advanced Science And Technology Incubation, Ltd. Micelle polymere renfermant du cisplatine et utilisation
JP2003012505A (ja) * 2001-07-06 2003-01-15 Nano Career Kk 薬物含有高分子ミセルの凍結乾燥
WO2005056641A1 (fr) * 2003-12-10 2005-06-23 Toudai Tlo, Ltd. Complexe de coordination de diaminocyclohexaneplatine (ii) et d'un copolymere contenant un segment d'acide poly(carboxylique), et agent antitumoral comprenant ce complexe
JP2005520006A (ja) * 2002-03-13 2005-07-07 北京鍵▲凱▼科技有限公司 Ｙ型分鎖親水性ポリマー誘導体、それらの調製方法、前記誘導体および薬剤分子の結合生成物、ならびに前記結合生成物を含む医薬組成物
WO2006057429A1 (fr) * 2004-11-24 2006-06-01 Nanocarrier Co., Ltd. Procédé de changement de morphologie d’un copolymère séquencé
WO2006098496A1 (fr) * 2005-03-18 2006-09-21 The University Of Tokyo Compose de coordination compose du diaminocyclohexane platine (ii) et d’un copolymere sequence et agent anticancereux le comprenant
WO2009096245A1 (fr) * 2008-01-28 2009-08-06 Nanocarrier Co., Ltd. Composition pharmaceutique et agent associé
WO2009157279A1 (fr) * 2008-06-24 2009-12-30 ナノキャリア株式会社 Composition liquide comprenant un composé de coordination de la cisplatine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026241A1 (fr) * 2000-09-26 2002-04-04 Center For Advanced Science And Technology Incubation, Ltd. Micelle polymere renfermant du cisplatine et utilisation
JP2003012505A (ja) * 2001-07-06 2003-01-15 Nano Career Kk 薬物含有高分子ミセルの凍結乾燥
JP2005520006A (ja) * 2002-03-13 2005-07-07 北京鍵▲凱▼科技有限公司 Ｙ型分鎖親水性ポリマー誘導体、それらの調製方法、前記誘導体および薬剤分子の結合生成物、ならびに前記結合生成物を含む医薬組成物
WO2005056641A1 (fr) * 2003-12-10 2005-06-23 Toudai Tlo, Ltd. Complexe de coordination de diaminocyclohexaneplatine (ii) et d'un copolymere contenant un segment d'acide poly(carboxylique), et agent antitumoral comprenant ce complexe
WO2006057429A1 (fr) * 2004-11-24 2006-06-01 Nanocarrier Co., Ltd. Procédé de changement de morphologie d’un copolymère séquencé
WO2006098496A1 (fr) * 2005-03-18 2006-09-21 The University Of Tokyo Compose de coordination compose du diaminocyclohexane platine (ii) et d’un copolymere sequence et agent anticancereux le comprenant
WO2009096245A1 (fr) * 2008-01-28 2009-08-06 Nanocarrier Co., Ltd. Composition pharmaceutique et agent associé
WO2009157279A1 (fr) * 2008-06-24 2009-12-30 ナノキャリア株式会社 Composition liquide comprenant un composé de coordination de la cisplatine

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012255697A (ja) * 2011-06-08 2012-12-27 Jeol Ltd 電子顕微鏡観察用染色剤および電子顕微鏡観察用試料の染色方法
CN102863627A (zh) * 2012-10-10 2013-01-09 中国科学院长春应用化学研究所 顺铂配合物及其制备方法
CN105997878A (zh) * 2012-11-22 2016-10-12 原创生医股份有限公司 降低自由基伤害的复合微胞载体医药组成物
US10988496B2 (en) 2015-06-24 2021-04-27 Nippon Kayaku Kabushiki Kaisha Platinum (IV) complex
US10596191B2 (en) 2015-09-14 2020-03-24 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of hexa-coordinated platinum complex
US11033577B2 (en) 2015-09-14 2021-06-15 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of hexa-coordinated platinum complex
US10946028B2 (en) 2015-12-22 2021-03-16 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of sulfoxide derivative-coordinated platinum(II) complex
WO2019034429A1 (fr) * 2017-08-14 2019-02-21 Universität Konstanz Copolymères à blocs multifonction pour dissoudre les plaques d'athérome

Also Published As

Publication number Publication date
JP2011105792A (ja) 2011-06-02

Similar Documents

Publication Publication Date Title
WO2011058776A1 (fr) Copolymère séquencé, corps composite copolymère séquencé - complexe métallique, et support de structure creuse utilisant ceux-ci
US20180036417A1 (en) Porphyrin modified telodendrimers
JP4758346B2 (ja) 高分子ミセル型ｍｒｉ造影剤
JP6356614B2 (ja) 薬剤のミトコンドリア輸送のためのナノ粒子
Melnyk et al. Therapeutic potential of polypeptide-based conjugates: rational design and analytical tools that can boost clinical translation
Zhang et al. Redox-and light-responsive alginate nanoparticles as effective drug carriers for combinational anticancer therapy
US20130071482A1 (en) Block copolymer cross-linked nanoassemblies as modular delivery vehicles
TWI572369B (zh) 酸鹼應答型奈米微粒的製備並應用於製備促進抗癌藥物於腫瘤的傳輸與深層滲透之藥物的用途
KR101580251B1 (ko) Tpp-pcl-tpp 고분자 및 상기 고분자를 이용한 미토콘드리아 표적 나노약물전달용 조성물
US20190151454A1 (en) Molecular assembly using amphipathic block polymer, and substance-conveyance carrier using same
EP2359860B1 (fr) Composition de micelles polymères pour le traitement de cellules cancéreuses résistantes
US20140296173A1 (en) Stable nanocomposition comprising epirubicin, process for the preparation thereof, its use and pharmaceutical compositions containing it
JP4892378B2 (ja) 高分子ミセル型ｍｒｉ造影剤
US8961949B2 (en) Polymer-metal complex composite having MRI contrast ability and MRI contrasting and/or antitumor composition using the same
US20220001024A1 (en) Guanylurea functionalized peptides and proteins for therapeutics
Wrobel et al. Glucose-modified carbosilane dendrimers: Interaction with model membranes and human serum albumin
US9557332B2 (en) Glucose-sensitive nanoparticle for cancer diagnosis and therapy
Beygi et al. Recent progress in functionalized and targeted polymersomes and chimeric polymeric nanotheranostic platforms for cancer therapy
KR101466511B1 (ko) 저산소증 관련 질환의 진단 및 치료용 저산소 감응형 나노입자
Xu et al. pH-sensitive deoxycholic acid dimer for improving doxorubicin delivery and antitumor activity in vivso
US20220323432A1 (en) Nanoparticles for delivering drug, whose surface is modified with peptide for targeting brain cancer, preparation method thereof and use thereof
JP7320448B2 (ja) 脳への薬剤送達用のキャリアおよびこれを含んでなる組成物
US10869941B2 (en) Gas-generating polymer micells and manufacturing method of the same
Yuan et al. In vivo metabolizable branched poly (ester amide) based on inositol and amino acids as a drug nanocarrier for cancer therapy
KR101562369B1 (ko) 폴리히스티딘과 인지질의 결합체를 함유한 pH 감응형 지질펩타이드 및 그의 제조방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10829736

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10829736

Country of ref document: EP

Kind code of ref document: A1