WO2006090924A1 - Copolymere bloc ayant un ligand peptidique - Google Patents

Copolymere bloc ayant un ligand peptidique Download PDF

Info

Publication number
WO2006090924A1
WO2006090924A1 PCT/JP2006/304202 JP2006304202W WO2006090924A1 WO 2006090924 A1 WO2006090924 A1 WO 2006090924A1 JP 2006304202 W JP2006304202 W JP 2006304202W WO 2006090924 A1 WO2006090924 A1 WO 2006090924A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
block copolymer
integer
peptide
independently
Prior art date
Application number
PCT/JP2006/304202
Other languages
English (en)
Japanese (ja)
Inventor
Kazunori Kataoka
Keiji Itaka
Nobuhiro Nishiyama
Makoto Oba
Shigeto Fukushima
Naoki Kanayama
Original Assignee
The University Of Tokyo
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 The University Of Tokyo filed Critical The University Of Tokyo
Publication of WO2006090924A1 publication Critical patent/WO2006090924A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • A61K47/6455—Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates

Definitions

  • the present invention relates to a peptide block copolymer usefully used as a carrier of a drug delivery system for the purpose of therapy or diagnosis, particularly a gene delivery system for the purpose of gene therapy, and more specifically, targeting to a carrier.
  • the present invention relates to a block copolymer having a peptide ligand that imparts properties and a method for producing the same. Background technology
  • imparting target directivity to a target site or cell is important in various aspects such as enhancing therapeutic effects, reducing side effects, and improving diagnostic accuracy.
  • the safety of gene delivery systems for gene therapy has been feared due to the successive accidents of viral vectors that have been used as gene vectors in recent years, and the creation of non-viral vectors with safety features is expected. Has been.
  • non-viral gene delivery systems have problems such as low gene transfer efficiency, and further performance improvements are necessary to reach the clinically required gene expression level.
  • approaches from various angles have been made.
  • One of them is the introduction of molecules having specific affinity with the target cells, such as antibodies and ligands, into the vector, and the gene expression by the cells. Studies have been made to increase the amount of uptake.
  • PEG polyethylene glycol
  • Reion complex (hereinafter also referred to as PIC) has been reported to form micelles and be useful as a gene carrier (K. Kakizawa, K. Kataoka, Block copolymer micelles lor delivery of gene and related compounds,
  • a target molecule such as a ligand may be bound to the end of PEGG.
  • PEGG polyethylene glycol monopoly (dimethylaminoethyl methacrylate)
  • £ 0—? ⁇ Tomii polyethylene glycol monopoly (dimethylaminoethyl methacrylate)
  • reaction a method is used in which the acetal at the end of PEG is converted to an aldehyde by acid treatment, mixed with a lactose derivative having an amino group at the end to form a Schiff base, and then reduced.
  • this is a reaction that can be performed because the side chain of PAMA is a tertiary amine, and in a system having a primary amine such as polylysine, it cannot be applied because it reacts with an aldehyde.
  • polylysine is inevitably used, the ligand is first bound in a state where the amino group is protected. However, if acid or alkali is used after deprotection, the peptide ligand is inactivated.
  • the problem to be solved by the present invention is to provide a drug carrier imparted with a target directivity, particularly a gene carrier, introduce a peptide ligand by a simple operation, and cause side reactions and inactivation as much as possible. There is no way to provide a way.
  • the present inventors succeeded in introducing a ligand having a target function for recognizing a specific cell to the end of the block copolymer by a simple operation, Furthermore, in gene transfer experiments into cells having a receptor for the ligand, it was found that gene expression was greatly improved, and the present invention was completed.
  • the present inventors firstly made a polyamino acid-derived segment as a carrier by deprotection or derivatization while retaining the acetal group at the end of the uncharged segment of the block copolymer.
  • the block copolymer and the peptide having a cysteine end are mixed in an acidic solution, and the conversion of the acetyl group to the aldehyde group and the binding of the ligand are carried out simultaneously.
  • side reactions such as aldol condensation can be suppressed, and under acidic conditions, even if primary amines are present in the polyamino acid-derived segment, they are protonated and do not react with aldehydes.
  • the cysteine reaction is irreversible, and we found that a stable bond can be obtained without performing reduction or other operations.
  • the present invention has been completed.
  • a block copolymer having an uncharged segment and a polyamino acid-derived segment, wherein the terminal end of the uncharged segment is an acetal group. Is done.
  • the uncharged segment is preferably polyethylene dalycol or a derivative thereof.
  • the polyamino acid-derived segment is preferably a polycation, and includes one or more selected from the group consisting of polylysine, polylysine derivatives, polyaspartic acid derivatives, polyglutamic acid derivatives, and salts thereof, or
  • the polyamino acid-derived segment is selected from the group consisting of polylysine, polylysine derivatives, and salts thereof, and the group consisting of polyaspartic acid derivatives, polyglutamic acid derivatives, and salts thereof It is more preferable that one or more of these be included.
  • the block copolymer is preferably represented by the following formula (1).
  • R ia and R ib are each independently the same or different, and may be a C i to C 10 alkyl group which may have a substituent, L represents a linking group, Y Represents a segment derived from polyamino acid, R 2 represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group, 1 is an integer of 1 to 5, and m is 5 to 20 or 0 0 0 Is an integer.
  • R la and R lb are preferably independent of each other and the same or different and each is a methyl group or an ethyl group.
  • one L and one are one (CH 2 ) a- NH-[where a is :! It is an integer of ⁇ 5. It is preferable that it is what is shown by these.
  • R 2 is preferably a hydrogen atom or an acetyl group.
  • 1 is preferably 2.
  • one Y— may be represented by the following formula (Y 1) or a salt thereof.
  • R3 independently of each other, is a hydrogen atom or a protecting group, provided that at least one is a hydrogen atom, wherein the protecting group is an acidic group within the protecting group of the amino group.
  • ⁇ is an integer from 2 to 5,000.
  • 1 ⁇ - may be represented by the following formula ( ⁇ 2) or a salt thereof.
  • R4 independently of each other, is a methylene group or an ethylene group
  • R 5 s independently of each other, are a hydroxyl group, a benzyloxy group, or an amine compound residue, wherein at least one of R 5 is an amine compound residue, and n is 2 to 5,000.
  • X is an integer between 0 and 5, 000, but not greater than n.
  • one Y— may be represented by the following formula (Y 3) or a salt thereof.
  • each R 3 independently of one another is a hydrogen atom or a protecting group, wherein the protecting group is a protecting group of an amino group that can be deprotected without acidic conditions, R 4 is each independently a methylene group or ethylene group, and R 5 is each independently a hydroxyl group, a benzyloxy group, or an amine compound residue, provided that at least R 3 One is a hydrogen atom, at least one of R 5 is an amine compound residue, or both, n is an integer from 2 to 5, 00, and X is 0 to 4 , 9 9 is an integer of 9 and y is :!
  • the method includes a deprotection reaction in which part or all of R 3 ′ is eliminated from the block copolymer represented by the following formula (3):
  • R la and R ib are each independently the same or different, and may be a C i to C 10 alkyl group which may have a substituent, L represents a linking group, R 2 is water Represents an elementary atom, a protecting group, a hydrophobic group or a polymerizable group, R 3 ′ is a protecting group that can be deprotected without being subjected to acidic conditions, 1 is an integer of 1 to 5, and m is 5 to 20 , 00 0 and n is an integer from 2 to 5,000. ]
  • Ria, Rib, L, R2, 1, m, n have the above-mentioned meanings.
  • R3 is their respective independently of one another, are the same protecting group with a hydrogen atom or R 3 ', provided that one at least of the R 3 is a hydrogen atom.
  • the second embodiment of the present invention includes a conversion reaction that converts a part or all of the side chain benzyl ester of the block copolymer represented by the following formula (5) by aminolysis.
  • Rla and Rib are each independently the same or different, and may be a Ci to Ci 0 alkyl group which may have a substituent, L represents a linking group, and R 2 represents Each represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group; R 4 independently represents a methylene group or an ethylene group; 1 is an integer of 1 to 5; m is 5 to 20 , 000, and
  • n is an integer from 2 to 5,000.
  • a method for producing a block copolymer represented by the following formula (4) or a salt thereof is provided.
  • R la , R lb , L, R 2, R 4, 1, m and n have the above-mentioned meanings.
  • R 5 is each independently a hydroxyl group, a benzyloxy group, or an amine compound residue, provided that at least one of R 5 is an amine compound residue, and X is an integer of 0 to 5,000 , But not greater than n. ]
  • R la and R lb are each independently the same or different and each may be a Ci to C io alkyl group which may have a substituent
  • L represents a linking group
  • R 2 Represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group
  • R 3 ′ is a protecting group that can be deprotected without being subjected to acidic conditions
  • R 4 s are each independently a methylene group Or an ethylene group
  • 1 is an integer of 1 to 5
  • m is an integer of 5 to 20 and 0 0
  • n is an integer of 2 to 5 and 0 0
  • y is 1 to 4
  • 9 9 An integer of 9 9 and smaller than n.
  • R 3 is each independently a hydrogen atom or the same protecting group as R 3 '
  • R 5 is each independently a hydroxyl group, a benzyloxy group,' or an amine compound residue.
  • at least one of R 3 is a hydrogen atom, or at least one of R 5 is It is an amine compound residue or both
  • X is an integer from 0 to 4,999, provided that x + y is not greater than n.
  • R 3 is preferably a trifluoroacetyl group.
  • R 4 is preferably a methylene group.
  • R la and R ib are each independently the same or different and are preferably a methyl group or an ethyl group.
  • 1 L 1 is 1 (CH 2 ) a- NH-[wherein, a is an integer of 1 to 5. It is preferable that it is what is shown by these.
  • R 2 is preferably a hydrogen atom or a acetyl group. Further, 1 is preferably 2.
  • the uncharged segment is preferably polyethylene dalycol or a derivative thereof.
  • the polyamino acid-derived segment contains one or more selected from the group consisting of polylysine, polylysine derivatives, polyaspartic acid derivatives, polyglutamic acid derivatives, and salts thereof, or Amino acid-derived segments consist of polylysine, polylysine derivatives, and their salts. And at least one selected from the group consisting of polyaspartic acid derivatives, polyglutamic acid derivatives, and salts thereof.
  • the peptide block copolymer is preferably represented by the following formula (8).
  • A represents a peptide ligand
  • L represents a linking group
  • Y represents a segment derived from polyamino acid
  • R 2 represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group.
  • 1 is an integer from 1 to 5
  • m is an integer from 5 to 20,000.
  • A is preferably a peptide having 1 to 200 amino acid residues
  • A is a peptide capable of specifically binding to integrin. More preferably, A is cyclo (L-ArgG1y-L-AspDPheLLys) -Z [wherein Z represents an amino acid residue. It is more preferable that it is what is shown by these.
  • 1 L— is 1 (CH 2 ) a-NH 2 [wherein a is an integer of 1 to 5. It is preferable that it is what is shown by these.
  • R 2 is preferably a hydrogen atom or a acetyl group.
  • 1 is preferably 2.
  • —Y— may be represented by the following formula (Y 1).
  • R3 independently of each other, are a hydrogen atom or a protecting group, and at least one is a hydrogen atom, wherein the protecting group is an acidic condition among the protecting groups of the amino group.
  • N is an integer from 2 to 5,000.
  • one Y— may be represented by the following formula (Y2).
  • R 4 s are each independently a methylene group or an ethylene group, and R 5 s are each independently a hydroxyl group, a benzyloxy group, or an amine compound residue, provided that At least one of R 5 is an amine compound residue, n is an integer from 2 to 5,000, and X is an integer from 0 to 5,000, but not greater than n. ]
  • 1′Y— may be represented by the following formula (Y3).
  • Y3 One y — ( Y3)
  • each R 3 independently of one another represents a hydrogen atom or a protecting group, wherein the protecting group is a protecting group of an amino group that can be deprotected without acidic conditions, and R 4 is each independently a methylene group or ethylene group, and R 5 is each independently a hydroxyl group, benzyloxy group, or amine compound residue, provided that at least one of R 3 One is a hydrogen atom, at least one of R 5 is an amine compound residue, or both, n is an integer from 2 to 5, 0 0 0, and X is 0 to 4, 9 9 is an integer of 9 and y :! It is an integer of ⁇ 4, 9 99, where y is smaller than n and x + y is not larger than n.
  • R 4 is preferably a methylene group.
  • a polymer having an acetal end and a peptide having a cysteine end are mixed in an acidic solution without previously converting the acetal into aldehyde.
  • a method for introducing a peptide ligand into a molecule is provided.
  • the polymer having an acetal end may be polyethylene glycol or a derivative thereof, the high molecule having an acetal end may be a polycation, and further has an acetal end.
  • the polymer may be a block copolymer or graft copolymer of polyethylene dallicol and polycation, and the polymer having an acetal end may be polyethylene.
  • the copolymer may be a block copolymer or a graft copolymer of polyglycol with a polyamino acid or a derivative thereof, or a salt thereof.
  • A represents a ligand peptide
  • L represents a linking group
  • R 2 represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group
  • m is an integer from 5 to 20,000.
  • Ria and Rib are each a Ci Cw alkyl group which is independent of each other and is the same or different and may have a substituent. ]
  • A is preferably a peptide having 1 to 200 amino acid residues, and A is more preferably a peptide capable of specifically binding to integrin.
  • A is cyclo (L-Arg_G1yL-AspDPheLLys) -Z [wherein Z represents an amino acid residue. It is more preferable that it is what is shown by these.
  • —L— is 1 (CH 2 ) a-NH 1 [wherein, a is an integer of 1 to 5. It is preferable that it is what is shown by these.
  • R 2 is preferably a hydrogen atom or a acetyl group.
  • 1 is preferably 2 ′.
  • —Y— may be represented by the following formula (Y 1) or a salt thereof.
  • R 3 s are each independently a hydrogen atom or a protecting group, provided that at least one is a hydrogen atom, wherein the protecting group is an acidic condition among the protecting groups of the amino group.
  • N is an integer of 2 to 5, 0 0 0. ]
  • one Y— may be represented by the following formula (Y 2) or a salt thereof.
  • R 4 s are each independently a methylene group or an ethylene group, and R 5 s are each independently a hydroxyl group, a benzyloxy group, or an amine compound residue, provided that At least one of R 5 is an amine compound residue, n is an integer from 2 to 5, 0 0 0, and X is an integer from 0 to 5, 0 0 0, but not greater than n Shall. ]
  • one Y— may be represented by the following formula (Y 3) or a salt thereof.
  • each R 3 independently of one another is a hydrogen atom or a protecting group, wherein the protecting group is a protecting group of an amino group that can be deprotected without acidic conditions, R 4 is each independently a methylene group or ethylene group, and R 5 is each independently a hydroxyl group, a benzyloxy group, or an amine compound residue, provided that at least R 3 One is a hydrogen atom, or at least one of R 5 is a force containing an amine compound residue, or both, n is an integer from 2 to 5, 00, and X is from 0 to It is an integer of 4, 9 9 9, and y is an integer of 1 to 4, 9 9 9, where y is smaller than n and x + y is not larger than n. ]
  • R 4 is preferably a methylene group.
  • a peptide block copolymer according to the third aspect of the present invention, or a peptide block copolymer obtained by the method according to the fifth aspect of the present invention, and a nucleic acid or a chargeable property A polyion complex characterized by comprising a protein is provided.
  • the nucleic acid is selected from the group consisting of a gene used for gene therapy, a gene encoding a protein, a DNA fragment, an RNA fragment, an antisense DNA, and a double-stranded oligonucleic acid. It is preferable.
  • the polyion complex of the present invention has a form of a polymer micelle having a core part and a shell part, and the core part is a nucleic acid or a charged substance.
  • a polyion complex characterized in that a poly (ethylene glycol) segment in a peptide block copolymer is mainly present in the shell part, and a peptide ligand is present in the vicinity of the surface layer of the polymer micelle. Preferably there is.
  • a peptide block copolymer according to the third aspect of the present invention or a peptide block copolymer obtained by the method according to the fifth aspect of the present invention, and a drug or fine particles.
  • a composite is provided, characterized in that it comprises.
  • the composite has a form of a polymer micelle having a core part and a seal part, and the core part encloses a drug or fine particles, and the shell part contains a peptide. It is preferably a complex characterized in that the polyethylene glycol segment in the block copolymer is mainly present and a peptide ligand is present in the vicinity of the surface layer of the polymer micelle.
  • a pharmaceutical composition comprising the polyion complex according to the sixth aspect of the present invention or the complex according to the seventh aspect of the present invention.
  • FIG. 1 is a diagram showing 1 H-NMR data of acetal-PEG-PLL (TFA).
  • FIG. 2 is a diagram showing ⁇ -NMR data of Acetal-PEG-PLL.
  • FIG. 3 is a diagram showing -NMR data of a mouth opening (RGDffO-PEG-PLL).
  • FIG. 4 shows luciferase gene expression using a cyclo (RGDfK) -PEG-PLL / pDNA complex.
  • FIG. 5 is a graph showing the evaluation results of the number of receptors on the surface of HeLa cells.
  • the uncharged segment may be, for example, a polyalkylene glycol such as polyethylene glycol or polypropylene glycol, a polyalkylene oxide, a polysaccharide, a polyacrylamide, or a polysubstituted acrylamide.
  • a polyalkylene glycol such as polyethylene glycol or polypropylene glycol
  • a polyalkylene oxide such as polyethylene glycol or polypropylene glycol
  • a polyalkylene oxide such as polyethylene glycol or polypropylene glycol
  • a polyalkylene oxide such as polyethylene glycol or polypropylene glycol
  • a polyalkylene oxide such as polyethylene glycol or polypropylene glycol
  • a polyalkylene oxide such as polyethylene glycol or polypropylene glycol
  • a polyalkylene oxide such as polyethylene glycol or polypropylene glycol
  • a polyalkylene oxide such as polyethylene glycol or polypropylene glycol
  • a polyalkylene oxide
  • the weight average molecular weight of the uncharged segment is preferably from 1, 0 00 to 2 0 0, 0 0 0, and from 5, 0 0 0 to 2 0, 0 0 0 More preferably it is.
  • polyethylene glycol or a derivative thereof is preferably used as the non-chargeable segment from the viewpoint of imparting biocompatibility to the carrier.
  • the polyamino acid-derived segment is preferably poly-force thione, and examples thereof include polylysine, polylysine derivatives, polyaspartic acid derivatives, polyglutamic acid derivatives, or salts thereof. be able to.
  • the polyamino acid-derived segment can easily synthesize polycations of various structures, can control the molecular weight and molecular weight distribution, and can also have a plurality of functions.
  • the acetal groups Rla and Rib at the end of the uncharged segment are not particularly limited, but the acetal does not change when neutral and is converted to aldehyde when acidic. It is preferable to have the following stability.
  • R la and R ib are, for example, C i to C io (C i-io) alkyl groups which are independent of each other and are the same or different and may have a substituent.
  • the “r C wo alkyl group” may be cyclic or acyclic, and may be linear or branched.
  • d-ioalkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • a substituent such as halogen may be introduced.
  • jetyl acetal or dimethyl acetal is often used as the acetal group at the end of the uncharged segment.
  • the block copolymer is preferably one represented by the following formula (1).
  • Rla and Rib are each independently the same or different, and are Ci to Ci 0 alkyl groups which may have a substituent.
  • R la and R lb are preferably a methyl group or an ethyl group.
  • L represents a linking group
  • 1 L 1 is a structure derived from the terminal structure of the PEG derivative or the like used, but 1 (CH 2 ) a-NH— [wherein a is an integer of 1 to 5 It is. And a is more preferably 2 or 3.
  • R 2 represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group.
  • the “protecting group” include Cl-6 alkylcarbonyl group, preferably a acetyl group.
  • examples of the “hydrophobic group” include derivatives such as benzene, naphthalene, anthracene and pyrene.
  • Examples of the “polymerizable group” include a methacryloyl group and an atalyloyl group. Such polymerizable groups When the block copolymer represented by the formula (1) has, these copolymers can be used as a so-called macromer. For example, after forming a polyion complex micelle described later, another comonomer is used as necessary. It can also be bridged via these polymerizable groups.
  • Examples of methods for introducing these protecting groups, hydrophobic groups, and polymerizable groups into the end of the copolymer include conventional methods such as methods using acid halides, methods using acid anhydrides, and methods using active esters. The method used in is mentioned.
  • R 2 is preferably a hydrogen atom or a acetyl group.
  • 1 is an integer of 1-5, and it is preferable that it is 2.
  • m is an integer of 5 to 20 and 0 0 0, preferably 2 0 to 5 and 0 0 0, and more preferably 1 0 0 to 5 0 0 .
  • Y represents a segment derived from a polyamino acid.
  • 1 Y— may be represented by the following formula (Y 1) or a salt thereof.
  • R 3 s are each independently a hydrogen atom or a protecting group, provided that at least one is a hydrogen atom.
  • the protecting group is a protecting group of an amino group that can be deprotected without being subjected to acidic conditions, and is preferably a trifluoroacetyl group.
  • the total of R 3 is preferably 85% or more, more preferably 95% or more, still more preferably 98% or more, and particularly preferably 100% is a hydrogen atom.
  • n is an integer of 2 to 5,000, preferably 5 to 1,000, and more preferably 10 to 200.
  • One Y— may be a salt of the above formula (Y 1).
  • C ⁇ , Br-, I-, (1/2 S0 4 )-, NO3—, (I / 2 CO3) —, (1/3 PO4) — , CH 3 CO_ ⁇ -, CFsCOO-, CH 3 S0 3 - , CF 3 S_ ⁇ 3 - in a first aspect of the like can be mentioned are t present invention, the formula (1) in one Y- is represented by the following formula ( Y2) or a salt thereof may be used.
  • I-( ⁇ 2) In the above formula ( ⁇ ⁇ 2), each repeating unit is shown in the order specified for convenience of description: Each repeating unit can exist randomly.
  • R 4 s are each independently a methylene group or an ethylene group.
  • the methylene group corresponds to a polyaspartic acid derivative
  • the ethylene group corresponds to a polyglutamic acid derivative.
  • aminolysis proceeds quantitatively under mild conditions.
  • R 4 is more preferably a methylene group, that is, a polyaspartic acid derivative.
  • R 5 is each independently a hydroxyl group, a benzyloxy group, or an amine compound residue, provided that at least one of R 5 is an amine compound residue.
  • amine compound residue means a general formula —NH— (CH 2 ) b—
  • b is an integer of 1 to 5, and preferably 2 or 3.
  • examples of the substituent that can be X include the substituents shown below, but are not limited thereto.
  • X 2 represents a hydrogen atom, a d-6 alkyl group or an amino d-6 alkyl group.
  • R 7a is a hydrogen atom or a methyl group
  • R 8 a benzylidene Okishikarubo is commonly used as a protecting group for a hydrogen atom or an amino group - Le group (.
  • ⁇ group amino group - Le group
  • Boc group tert -Butoxycarbonyl group
  • a protecting group such as a til group or a trifluoroacetyl group
  • d 1 is an integer of 1 to 5, preferably 2 or 3
  • e 1 is an integer of 1 to 5, preferably 1 to 3 It is an integer.
  • R? B and R 7 c are a hydrogen atom or a methyl group
  • R 8 b is a Z group, a B oc group or a acetyl group which are usually used as a protective group for a hydrogen atom or an amino group.
  • a protecting group such as a trifluoroacetyl group
  • d 2 and d 3 are each independently an integer of 1 to 5
  • e 2 and e 3 are each independently an integer of 1 to 5.
  • 85% or more of the total of R 5 is preferably an amin compound residue, more preferably 95% or more, still more preferably 98% or more, and particularly preferably 100% is an amine compound residue. It is a group.
  • n is an integer of 2 to 5,000, preferably 5 to 1,000, and more preferably 10 to 200.
  • X is an integer of 0 to 5,000, but not greater than n.
  • One Y— may be a salt of the above formula (Y2).
  • the salt forming salt is C l-, B r-, I-, (l / 2 SO + 4 )-, N0 3- , (1 2 CO 3 )-, (1/3 P0 4 ) —, CH 3 COO—, CF 3 COO—, CH 3 S 0 3 ⁇ CF 3 SO 3 — and the like.
  • one Y— may be represented by the following formula (Y3) or a salt thereof.
  • each repeating unit in the above formula (Y3) is shown in the order specified for convenience of description, each repeating unit can be present at random. .
  • R 3 s are each independently a hydrogen atom or a protecting group, where the protecting group can be deprotected without being subjected to acidic conditions in the protecting group of the amino group. And is preferably a trifluoroacetyl group.
  • R 4 s are each independently a methylene group or an ethylene group.
  • R 5 s are each independently a hydroxyl group, a benzyloxy group, or an amine compound residue.
  • At least one of R 3 is a hydrogen atom, at least one of R 5 is an amine compound residue, or both.
  • 85% or more of the total of R 3 is preferably a hydrogen atom, more preferably 95% or more, still more preferably 98% or more, and particularly preferably 100% is a hydrogen atom.
  • preferably 85% or more of the total of R 5 is an amine compound residue, more preferably 95% or more, still more preferably 98% or more, and particularly preferably 100% is the amine compound residue. It is a group.
  • n is an integer of 2 to 5,000, preferably 5 to 1,000, and more preferably 10 to 200.
  • X is an integer from 0 to 4,999 and y is :! It is an integer of ⁇ 4,999, where y is smaller than n and x + y is not larger than n: 1 Y— may be a salt of the above formula (Y3).
  • one aspect of the second embodiment of the present invention includes a deprotection reaction in which a part or all of R 3 ′ is eliminated from the block copolymer represented by the following formula (3).
  • a method for producing a block copolymer represented by the formula (2) or a salt thereof is provided.
  • R 1, Rlb, R 2 , L 1 , i, m and n are the same as those in the first embodiment of the present invention. It is the same as described in the case of 1).
  • R 3 ′ is a protecting group that can be deprotected without using acidic conditions, and is preferably a trifluoroacetyl group.
  • each R 3 independently of one another is a hydrogen atom or the same protecting group as R 3 ′, provided that at least one of R 3 is a hydrogen atom.
  • preferably 85% or more of the total of R 3 is a hydrogen atom, more preferably 95% or more, still more preferably 98% or more, and particularly preferably 100%.
  • the produced block copolymer may form a salt thereof.
  • the counter ions forming the salt include C 1, Br 1, I 1, (1/2 S0 4) 1, NO 3 ⁇ (1/2 C0 3 )-, (1/3 P 0 4 ) CH 3 COO, C F3COO—, CH3SO3 ”, CF3SO3— and the like.
  • an alkali solution is added to a solution of the block copolymer represented by the above formula (3) to form a block represented by the following formula (3). Part or all of R 3 'is eliminated from the copolymer.
  • the method for producing the block copolymer represented by the above formula (3) is not particularly limited, but as one method, for example, an acetal group at one terminal is used. PEG derivative having an amino group at the other end and blocking by polymerizing lysine N-carboxylic acid anhydride (NCA) protected with R 3 , using the amino terminus as an initiator A method for synthesizing a copolymer can be mentioned. '
  • examples of the alkaline solution to be used include sodium hydroxide solution, hydroxylated lithium solution, ammonia solution, hydrazine solution, Examples include triethylamine solution, sodium carbonate solution, and carbonated lithium solution.
  • the amount of the alkaline solution used is preferably an excess amount relative to the protecting group in the block copolymer represented by the above formula (3).
  • the reaction is preferably carried out in a temperature range of 0 ° C to 100 ° C, more preferably a temperature range of 20 ° C to 80 ° C, especially Preferably it is performed at 30 ° C to 70 ° C.
  • the pressure may be, for example, normal pressure.
  • the reaction time is not particularly limited as long as the reaction proceeds sufficiently, but it is usually 2 hours to 2 days.
  • the solvent is preferably a solvent capable of dissolving both the block copolymer represented by the above formula (3) and the alkyl group used.
  • a solvent an aliphatic or aromatic organic solvent, water, or a mixed solvent thereof is used, and a lower alcohol solvent such as methanol, acetonitrile, dioxane, or a mixed solvent thereof with water can be preferably used.
  • the second embodiment of the present invention comprises a conversion reaction that converts a part or all of the side chain benzyl ester of the block copolymer represented by the following formula (5) by aminolysis.
  • a method for producing a block copolymer represented by the following formula (4) or a salt thereof is provided. Conversion reaction
  • Ria, Rib, R 2 , R R5, L, 1, m, n and x are not particularly limited in the first embodiment of the present invention. This is the same as explained when Y — is the above formula (Y2).
  • preferably 85% or more of the total R 5 is an amine compound residue, more preferably 95% or more, still more preferably 98% or more, and particularly preferably 100%. Is an amine compound residue.
  • the produced block copolymer may form a salt thereof.
  • an amine compound (NH 2 — (CH 2 ) bX) is added to the block copolymer solution represented by the above formula (5) and stirred. Then, a part or all of the side chain benzyl ester of the block copolymer represented by the following formula (5) is converted by aminolysis d
  • the method for producing the block copolymer represented by the above formula (5) is not particularly limited, but one method is, for example, that an acetal group is present at one end.
  • N-force rubonic acid anhydride of polyaspartic acid and / or polyglutamic acid protected with benzyloxy group using the amino terminus as an initiator ) Is synthesized to synthesize a block copolymer.
  • the amount of the amine compound may be an excess amount with respect to the benzyl ester of the block copolymer represented by the above formula (5) unless otherwise specified.
  • 10 to 50 equivalents are usually used.
  • the reaction is preferably performed in a temperature range of 0 ° C to 80 ° C, more preferably in a temperature range of 30 ° C to 50 ° C. Is called.
  • the pressure may be normal pressure, for example.
  • the reaction time is not particularly limited as long as the reaction proceeds sufficiently, but it is usually 2 hours to 2 days.
  • the solvent is preferably a solvent that can dissolve both the block copolymer represented by the above formula (5) and the amine compound.
  • the solvent an aliphatic or aromatic organic solvent is used, and N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dichloromethane, and black mouth form are preferably used. Further, it is preferable that the solvent used contains as little water as possible.
  • a pH region for example, 6 to 6
  • a modification in which a part or all of the side chain benzyl ester of the block copolymer represented by the following formula (7) is converted by aminolysis is converted by aminolysis.
  • R la , R lb , L, R 2 , R 4 , R 5, 1, m, n, x, y are the same as those in the first aspect of the present invention.
  • one Y— is the same as described above in the case of the formula (Y 3).
  • R 3 and R 3 ′ are the same as those described in the one aspect of the second embodiment of the present invention.
  • a total of R 3 preferably 85% or more is a hydrogen atom, more preferably 95% or more, still more preferably 98% or more, particularly preferably 1 0 0% is a hydrogen atom.
  • the total of R 5 preferably 85% or more is an amine compound residue, more preferably 95% or more, more preferably 98% or more, particularly preferably 100% is an amine compound residue.
  • the produced block copolymer may form a salt thereof.
  • C is the counter ion that forms the salt, ⁇ ⁇ , (1Z2 S0 4 )-, N0 3- , (l / 2 C0 3 ) "(1/3 P0 4 )-, CH 3 CO O, CF 3 COO, CH 3 S0 3 —, CF 3 S 0 3 "and the like.
  • the block copolymer represented by the above formula (7) is first subjected to a conversion reaction by aminolysis, and then to a deprotection reaction.
  • the method for producing the block copolymer represented by the above formula (7) is not particularly limited, but as one method, for example, an acetal group is formed at one end.
  • NCA N-force rubonic acid anhydride
  • preferable conditions for the deprotection reaction are the same as those described above in the one aspect of the second embodiment of the present invention.
  • a pH region in which the acetal is not changed after the conversion reaction and deprotection reaction by aminolysis for example, It is preferable that all or a part of the amino group is made into a proton by dialysis in 6-8).
  • a peptide block copolymer having an uncharged segment and a segment derived from a polyamino acid, the terminal of the uncharged segment is a peptide having a weight average molecular weight of 50 to 20,000.
  • a peptide block copolymer, a ligand is provided.
  • the description of the uncharged segment and the segment derived from the polyamino acid is the same as that described in the first aspect of the present invention.
  • the peptide block copolymer is preferably represented by the following formula (8).
  • L, Y, R 2 , 1 and m are the same as those described in the first embodiment of the present invention.
  • A represents a peptide ligand.
  • the peptide ligand has a weight average molecular weight of 50 to 20 and 0 0, preferably 1 0 to 1 0 and 0 0 0, more preferably 1 5 0 to 3 and 0 0 0 preferable.
  • A is preferably a peptide having 1 to 200 amino acid residues, and preferably a peptide having 1 to 100 amino acid residues. More preferably, the peptide has 1 to 30 amino acid residues.
  • A specifically binds to an integrin involved in angiogenesis, intimal thickening, and malignant tumor growth from the point of view of specifically recognizing a diseased cell.
  • A is a peptide (L 1 A rg -G 1 y -LA sp—D—Pe—L—L ys) -Z [wherein Z is an arbitrary Represents an amino acid residue. It is more preferable that it is what is shown by these.
  • an arbitrary amino acid residue a natural amino acid and an unnatural amino acid can be mentioned.
  • a polymer having an acetal terminal and a peptide having a cysteine terminal are mixed in an acidic solution without previously converting the acetal into aldehyde.
  • a method for introducing a peptide ligand into a peptide is provided.
  • the polymer having an acetal end may be polyethylene glycol or a derivative thereof, and the high molecule having an acetal end may be a polycation, or has an acetal end.
  • the polymer may be a block copolymer or a graft copolymer of polyethylene dallicol and polycation, and the polymer having an acetal end is polyethylene glycol, polyamino acid or a derivative thereof, or their It may be a block copolymer or a graft copolymer with a salt.
  • An example of the method for introducing a peptide ligand according to the fourth aspect of the present invention is a method for producing a peptide block copolymer according to the fifth aspect of the present invention. That is, in the fifth aspect of the present invention, a method for producing a peptide block copolymer represented by the following formula (8), which comprises a block copolymer represented by the following formula (1) and the following formula (9): A method for producing a peptide block copolymer is provided, which comprises reacting the peptide with : CH (CH 2 ),
  • R la , R lb , L, Y, R 2 , 1 and m are the same as those described in the first embodiment of the present invention.
  • a solution of the peptide represented by the above formula (9) is added to the block copolymer represented by the above formula (1) and reacted.
  • the amount of the peptide represented by the above formula (9) used is preferably 1 to 30 times equivalent to the block copolymer represented by the above formula (1), It is more preferably 3 to 20 times equivalent, and even more preferably 7 to 10 times equivalent.
  • the reaction is preferably performed in a temperature range of 10 ° C to 50 ° C, more preferably 15 ° (: to a temperature range of 35 ° C, particularly preferably room temperature.
  • the pressure is preferably normal pressure, for example.
  • the reaction time is preferably 3 hours to 10 days, more preferably 3 days to 7 days, and particularly preferably about 6 days.
  • an acidic buffer solution is preferred as the solvent used as the solution of the peptide represented by the formula (9).
  • Solvent is pH 3.0-p
  • An acetate buffer solution of H 6.0 is used, and an acetate buffer solution of pH 4.0 is preferable.
  • a peptide block copolymer according to the third aspect of the present invention, or a peptide block copolymer obtained by the method according to the fifth aspect of the present invention, and a nucleic acid or a charged protein A polyion complex comprising:
  • the nucleic acid is selected from the group consisting of a gene used for gene therapy, a gene encoding a protein, a DNA fragment, an RNA fragment, an antisense DNA, and a double-stranded oligonucleic acid. It is preferable that
  • the polyion complex has a form of a polymer micelle having a core portion and a shell portion, and the core portion encloses a nucleic acid or a charged protein, and the shell portion includes
  • the polyion complex is preferably characterized in that the polyethylene glycol segment in the peptide block copolymer is mainly present, and the peptide ligand is present in the vicinity of the surface layer of the polymer micelle.
  • the mixing ratio of the nucleic acid and the peptide block copolymer is represented by the ratio (N / P ratio) between the phosphate group in the nucleic acid molecule and the cation in the peptide block copolymer. be able to.
  • the N / P ratio is an amount defined by the following formula. Unless otherwise noted, the N / P ratio refers to this amount.
  • N / P ratio [total number of cations in peptide block copolymer in solution]
  • the N / P ratio is not limited as long as a polyion complex can be formed, and varies depending on the properties of the non-charged segment or the polyamino acid-derived segment contained in the block copolymer.
  • N / P ratio in the sixth embodiment of the present invention can be appropriately selected by those skilled in the art.
  • a peptide block copolymer according to the third aspect of the present invention or a peptide block copolymer obtained by the method according to the fifth aspect of the present invention, and a drug or fine particles.
  • a composite is provided, characterized in that it comprises.
  • examples of the drug include adriamycin, daunomycin, cisplatin, carpoplatin, methotrexate, mitomycin 0, taxol, camptothecin, retinoic acid and other anticancer agents, antiviral agents, and anti-inflammatory agents. Can be mentioned.
  • examples of the fine particles include inorganic fine particles such as silica, metal fine particles such as gold colloid and iron colloid, and organic and polymer fine particles such as dendrimer and gel.
  • the composite has a form of a polymer micelle having a core part and a shell part, and the core part encloses a drug or fine particles, and a peptide is contained in the shell part. It is preferably a complex characterized in that the polyethylene glycol segment in the block copolymer is mainly present and a peptide ligand is present in the vicinity of the surface layer of the polymer micelle.
  • the polyion complex or complex is obtained by mixing a peptide block copolymer and a nucleic acid, a charged protein, a drug, or a fine particle in an appropriate solution. can get. Furthermore, operations such as dialysis, agitation, dilution, concentration, sonication, temperature control, pH control, ionic strength control, and addition of organic solvent can be added as appropriate. In addition, nucleic acids used, charged proteins If the quality, drug, or microparticles, and the polyion complex or complex containing them are stable under acidic conditions, a block copolymer at the end of the acetal is used to form a polyion complex or complex. It is also possible to conduct a ligand introduction reaction after the reaction.
  • a pharmaceutical composition comprising the polyion complex according to the sixth aspect of the present invention or the complex according to the seventh aspect of the present invention.
  • the pharmaceutical composition according to the eighth aspect of the present invention contains the polyion complex complex complex obtained as described above, it can be used as a pharmaceutical composition for treatment and diagnosis.
  • a person skilled in the art can appropriately set the amounts of the nucleic acid, the charged tank, the drug, and the fine particles contained in the pharmaceutical composition according to the eighth aspect of the present invention.
  • the dosage form include injection, and in addition to systemic administration such as normal intravenous and intraarterial administration, it can be locally administered into muscles, joints, subcutaneous, intracutaneous and the like. It is also possible to adopt a dosage form using a catheter. In this case, it may be a powder which is usually provided in the form of a unit dose ampoule or a multi-dose container and redissolved in a suitable carrier, for example, pyrogen-free sterilized water. In addition, these dosage forms may contain additives generally used in pharmaceutical preparations.
  • the dosage, dosage form, and administration schedule can be arbitrarily set according to the purpose.
  • the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the examples.
  • NMR spectrum was measured using JEOL EX300. Measurement conditions are as follows. 'Acetal-PEG-PLL (TFA): Solvent DMSO_d6, 80 ° C Acetal-PEG-PLL Solvent D 2 0, 80 ° C
  • Acetanore-PEG-PLL (TFA) 500 mg was dissolved in 40 mL of methanol, 4 mL of 1N sodium hydroxide solution was added, and the mixture was reacted at 40 ° C. for 1 day. Place the reaction solution in a dialysis tube with a molecular weight cut off of 12,000, dialyz with 150 mM NaCl-pH 7.4 phosphate buffer solution as the external solution, collect the dialysis membrane solution, freeze-dry it, and acetal-PEG-PLL 498 mg was obtained as a white solid. iH-NMR data are shown in FIG.
  • the complex of the mouthpiece (RGDfK)-PEG-PLL and the plasmid DNA (pDNA) encoding the luciferase gene is the same as the N / P ratio of cyclo (RGDfK)-PEG-PLL solution and pDNA solution the day before transfection.
  • the mixture was mixed and left at rest for a while.
  • a PEG-PLL and pDNA complex was prepared in the same manner.
  • the N / P ratio here is defined by the following equation.
  • N / P ratio [total number of cations in the block copolymer in solution]
  • the HeLa cells can be squeezed at any time.
  • FITC-labeled antibody v A FITC-labeled antibody (hereinafter referred to as “FITC-labeled antibody v” 33J, respectively) in which antibodies against each of the vj33 integrin, avi35 integrin and mouse IgG were labeled with FITC in advance (manufactured by Cosmo Bio Inc.) “FITC labeled ⁇ 5” and “FITC labeled IgG”) were prepared.
  • HeLa cells were detached by trypsinization and washed twice with PBS solution.
  • HeLa 106 cells after washing the 2 g of FITC Hyoshikyi ⁇ alpha v] 33, were suspended in DMEM medium Loo / ⁇ L, and allowed to stand for one hour on ice in the dark. The cells were then washed 3 times with chilled DMEM medium and collected, and the number of receptor 3 integrins distributed on the cell surface was measured and evaluated using a flow cytometer.
  • the peptide block copolymer of the present invention since a carrier function for recognizing a specific cell is mounted on the carrier, the retention time at the target site of the carrier is extended, and the uptake of the specific cell is promoted. Is possible.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)

Abstract

L'invention présente un véhicule médicamenteux ayant une propriété d'orientation ciblée, précisément un véhicule génique. Elle concerne un copolymère bloc peptidique ayant un segment non chargé et un segment dérivé d'un acide polyaminé, le segment non chargé ayant une extrémité comprenant un ligand peptidique ayant un poids moléculaire moyen de 50 à 20 000.
PCT/JP2006/304202 2005-02-28 2006-02-28 Copolymere bloc ayant un ligand peptidique WO2006090924A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005-054260 2005-02-28
JP2005054260 2005-02-28

Publications (1)

Publication Number Publication Date
WO2006090924A1 true WO2006090924A1 (fr) 2006-08-31

Family

ID=36927542

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2006/304202 WO2006090924A1 (fr) 2005-02-28 2006-02-28 Copolymere bloc ayant un ligand peptidique

Country Status (1)

Country Link
WO (1) WO2006090924A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007043486A1 (fr) * 2005-10-05 2007-04-19 Tokyo Cro, Inc. Copolymère séquencé biocompatible, son utilisation et son procédé de fabrication
WO2007133807A2 (fr) * 2006-05-15 2007-11-22 Massachusetts Institute Of Technology Polymères pour particules fonctionnelles
WO2008075968A1 (fr) * 2006-12-20 2008-06-26 Ge Healthcare As Agents de contraste
WO2009133968A1 (fr) * 2008-04-30 2009-11-05 国立大学法人東京大学 Polyplex ternaire à conversion de charge
WO2010110455A1 (fr) 2009-03-27 2010-09-30 国立大学法人 鹿児島大学 Complexe polyionique comprenant un acide polyaminé hydrophobisé et son utilisation
EP2272897A1 (fr) * 2008-03-10 2011-01-12 The University of Tokyo Copolymère comprenant un bloc hydrophile non chargé et un bloc poly(acide aminé) cationique ayant une chaîne latérale dans laquelle un radical hydrophobe est partiellement introduit, et utilisation de copolymère
WO2013062982A1 (fr) * 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Homopolymères poly(lysine) pour l'administration d'oligonucléotides
US8562998B2 (en) 2008-10-12 2013-10-22 President And Fellows Of Harvard College Targeting of antigen presenting cells with immunonanotherapeutics
US8637028B2 (en) 2008-10-12 2014-01-28 President And Fellows Of Harvard College Adjuvant incorporation in immunonanotherapeutics
US8906381B2 (en) 2008-10-12 2014-12-09 Massachusetts Institute Of Technology Immunonanotherapeutics that provide IGG humoral response without T-cell antigen
US8932595B2 (en) 2008-10-12 2015-01-13 Massachusetts Institute Of Technology Nicotine immunonanotherapeutics
US9217129B2 (en) 2007-02-09 2015-12-22 Massachusetts Institute Of Technology Oscillating cell culture bioreactor
US9267937B2 (en) 2005-12-15 2016-02-23 Massachusetts Institute Of Technology System for screening particles
US9333179B2 (en) 2007-04-04 2016-05-10 Massachusetts Institute Of Technology Amphiphilic compound assisted nanoparticles for targeted delivery
US9381477B2 (en) 2006-06-23 2016-07-05 Massachusetts Institute Of Technology Microfluidic synthesis of organic nanoparticles
US9474717B2 (en) 2007-10-12 2016-10-25 Massachusetts Institute Of Technology Vaccine nanotechnology
US9492400B2 (en) 2004-11-04 2016-11-15 Massachusetts Institute Of Technology Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals
WO2018038166A1 (fr) * 2016-08-23 2018-03-01 公益財団法人川崎市産業振興財団 Polymère, procédé de production de polymère, et complexe médicamenteux
WO2019163942A1 (fr) * 2018-02-22 2019-08-29 公益財団法人川崎市産業振興財団 Polymère, procédé de production d'un polymère, complexe médicamenteux, et micelle

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08188541A (ja) * 1995-01-10 1996-07-23 Res Dev Corp Of Japan 静電結合型高分子ミセル薬物担体とその薬剤
WO2002026241A1 (fr) * 2000-09-26 2002-04-04 Center For Advanced Science And Technology Incubation, Ltd. Micelle polymere renfermant du cisplatine et utilisation
WO2002096977A1 (fr) * 2001-05-30 2002-12-05 Nanocarrier Co., Ltd. Procede de liaison d'une substance a incorporer a une terminaison polymere

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08188541A (ja) * 1995-01-10 1996-07-23 Res Dev Corp Of Japan 静電結合型高分子ミセル薬物担体とその薬剤
WO2002026241A1 (fr) * 2000-09-26 2002-04-04 Center For Advanced Science And Technology Incubation, Ltd. Micelle polymere renfermant du cisplatine et utilisation
WO2002096977A1 (fr) * 2001-05-30 2002-12-05 Nanocarrier Co., Ltd. Procede de liaison d'une substance a incorporer a une terminaison polymere

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9492400B2 (en) 2004-11-04 2016-11-15 Massachusetts Institute Of Technology Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals
WO2007043486A1 (fr) * 2005-10-05 2007-04-19 Tokyo Cro, Inc. Copolymère séquencé biocompatible, son utilisation et son procédé de fabrication
US9267937B2 (en) 2005-12-15 2016-02-23 Massachusetts Institute Of Technology System for screening particles
WO2007133807A2 (fr) * 2006-05-15 2007-11-22 Massachusetts Institute Of Technology Polymères pour particules fonctionnelles
WO2007133807A3 (fr) * 2006-05-15 2008-12-04 Massachusetts Inst Technology Polymères pour particules fonctionnelles
US9080014B2 (en) 2006-05-15 2015-07-14 Massachusetts Institute Of Technology Polymers for functional particles
US9688812B2 (en) 2006-05-15 2017-06-27 Massachusetts Institute Of Technology Polymers for functional particles
US8367113B2 (en) 2006-05-15 2013-02-05 Massachusetts Institute Of Technology Polymers for functional particles
US9381477B2 (en) 2006-06-23 2016-07-05 Massachusetts Institute Of Technology Microfluidic synthesis of organic nanoparticles
WO2008075968A1 (fr) * 2006-12-20 2008-06-26 Ge Healthcare As Agents de contraste
US9217129B2 (en) 2007-02-09 2015-12-22 Massachusetts Institute Of Technology Oscillating cell culture bioreactor
US9333179B2 (en) 2007-04-04 2016-05-10 Massachusetts Institute Of Technology Amphiphilic compound assisted nanoparticles for targeted delivery
US9474717B2 (en) 2007-10-12 2016-10-25 Massachusetts Institute Of Technology Vaccine nanotechnology
US9526702B2 (en) 2007-10-12 2016-12-27 Massachusetts Institute Of Technology Vaccine nanotechnology
US9539210B2 (en) 2007-10-12 2017-01-10 Massachusetts Institute Of Technology Vaccine nanotechnology
US10736848B2 (en) 2007-10-12 2020-08-11 Massachusetts Institute Of Technology Vaccine nanotechnology
US11547667B2 (en) 2007-10-12 2023-01-10 Massachusetts Institute Of Technology Vaccine nanotechnology
AU2009224286B2 (en) * 2008-03-10 2014-06-12 The University Of Tokyo Copolymer including uncharged hydrophilic block and cationic polyamino acid block having hydrophobic group in part of side chains, and use thereof
US8431545B2 (en) 2008-03-10 2013-04-30 The University Of Tokyo Copolymer including uncharged hydrophilic block and cationic polyamino acid block having hydrophobic group in part of side chains, and use thereof
EP2272897A4 (fr) * 2008-03-10 2012-01-25 Univ Tokyo Copolymère comprenant un bloc hydrophile non chargé et un bloc poly(acide aminé) cationique ayant une chaîne latérale dans laquelle un radical hydrophobe est partiellement introduit, et utilisation de copolymère
EP2272897A1 (fr) * 2008-03-10 2011-01-12 The University of Tokyo Copolymère comprenant un bloc hydrophile non chargé et un bloc poly(acide aminé) cationique ayant une chaîne latérale dans laquelle un radical hydrophobe est partiellement introduit, et utilisation de copolymère
US20150141575A1 (en) * 2008-04-30 2015-05-21 The University Of Tokyo Charge conversional ternary polyplex
JP5645186B2 (ja) * 2008-04-30 2014-12-24 国立大学法人 東京大学 電荷変換型三元系ポリプレックス
US9303122B2 (en) 2008-04-30 2016-04-05 The University Of Tokyo Charge conversional ternary polyplex
WO2009133968A1 (fr) * 2008-04-30 2009-11-05 国立大学法人東京大学 Polyplex ternaire à conversion de charge
US20110060123A1 (en) * 2008-04-30 2011-03-10 Kazunori Kataoka Charge conversional ternary polyplex
US8562998B2 (en) 2008-10-12 2013-10-22 President And Fellows Of Harvard College Targeting of antigen presenting cells with immunonanotherapeutics
US9439859B2 (en) 2008-10-12 2016-09-13 Massachusetts Institute Of Technology Adjuvant incorporation in immunoanotherapeutics
US8906381B2 (en) 2008-10-12 2014-12-09 Massachusetts Institute Of Technology Immunonanotherapeutics that provide IGG humoral response without T-cell antigen
US8637028B2 (en) 2008-10-12 2014-01-28 President And Fellows Of Harvard College Adjuvant incorporation in immunonanotherapeutics
US9233072B2 (en) 2008-10-12 2016-01-12 Massachusetts Institute Of Technology Adjuvant incorporation in immunonanotherapeutics
US8932595B2 (en) 2008-10-12 2015-01-13 Massachusetts Institute Of Technology Nicotine immunonanotherapeutics
US9308280B2 (en) 2008-10-12 2016-04-12 Massachusetts Institute Of Technology Targeting of antigen presenting cells with immunonanotherapeutics
WO2010110455A1 (fr) 2009-03-27 2010-09-30 国立大学法人 鹿児島大学 Complexe polyionique comprenant un acide polyaminé hydrophobisé et son utilisation
WO2013062982A1 (fr) * 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Homopolymères poly(lysine) pour l'administration d'oligonucléotides
WO2018038166A1 (fr) * 2016-08-23 2018-03-01 公益財団法人川崎市産業振興財団 Polymère, procédé de production de polymère, et complexe médicamenteux
WO2019163942A1 (fr) * 2018-02-22 2019-08-29 公益財団法人川崎市産業振興財団 Polymère, procédé de production d'un polymère, complexe médicamenteux, et micelle
JP2019143083A (ja) * 2018-02-22 2019-08-29 公益財団法人川崎市産業振興財団 ポリマー、ポリマーの製造方法、薬物複合体及びミセル
JP7004590B2 (ja) 2018-02-22 2022-02-04 公益財団法人川崎市産業振興財団 ポリマー、ポリマーの製造方法、薬物複合体及びミセル

Similar Documents

Publication Publication Date Title
WO2006090924A1 (fr) Copolymere bloc ayant un ligand peptidique
US8318856B2 (en) Nucleic acid delivery system comprising conjugates of PEI and hyaluronic acid
Li et al. Copolymer of poly (ethylene glycol) and poly (L-lysine) grafting polyethylenimine through a reducible disulfide linkage for siRNA delivery
EP1503802B1 (fr) Excipient de medicaments ou de biomolecules polymere dont la degradation est controlable et procede de synthese de cet excipient
US8497356B2 (en) Biomolecule polymer conjugates and methods for making the same
US20080249049A1 (en) Polycationically Charged Polymer and the Use of the Same as a Carrier for Nucleic Acid
Mavrogiorgis et al. Controlled polymerization of histidine and synthesis of well-defined stimuli responsive polymers. Elucidation of the structure–aggregation relationship of this highly multifunctional material
CN104004196A (zh) 一种可降解超支化聚酰胺胺的制备方法及其应用
CN103665384A (zh) 新型阳离子接枝共聚物及多重复合非病毒基因载体制备方法和应用
Santo et al. Poly (ethylene glycol)-block-poly (2-aminoethyl methacrylate hydrochloride)-Based Polyplexes as Serum-Tolerant Nanosystems for Enhanced Gene Delivery
CN109880021A (zh) 聚合物及其制备方法、ROS响应型siRNA纳米胶束及其应用
Yang et al. Histidylated cationic polyorganophosphazene/DNA self-assembled nanoparticles for gene delivery
Du et al. Azo-capped polysarcosine-b-polylysine as polypeptide gene vector: a new strategy to improve stability and easy optimization via host–guest interaction
Golan et al. Inhibition of gene expression and cancer cell migration by CD44v3/6-targeted polyion complexes
Zhang et al. Ionic α‐helical polypeptides toward nonviral gene delivery
Pretzer et al. Biotin‐Functionalized Block Catiomers as an Active Targeting Approach in Gene Delivery
WO2013062982A1 (fr) Homopolymères poly(lysine) pour l'administration d'oligonucléotides
Le Guen et al. Insertion of hydrophobic spacers on dodecalysines as potential transfection enhancers
US20040086481A1 (en) Cationic polymer-nucleic acid complexes and methods of making them
JPH1045630A (ja) 新規なグラフト共重合体、それを用いた薬剤、及びそれを用いて薬物を特定細胞に取り込ませる方法
WO2023149528A1 (fr) Micelles de poids moléculaire élevé comprenant un nouveau copolymère séquencé
CN110004180B (zh) 一种由功能肽a25修饰的基因载体及其制备方法和应用
KR20130024326A (ko) 핵산 전달용 ｐａｍａｍ 유도체
WO2023002012A1 (fr) Dérivés de pasp-oligoamine en étoile
Leung Novel pH-responsive hybrid peptide block copolymers for intracellular delivery applications

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06728632

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP