JP2007099930A - Triblock copolymer and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a triblock copolymer capable of fixing or releasing substances having various functions by reversible interaction and usable without deteriorating the dispersion stability in a solution system even if the change of morphology, etc., in the particle takes place by the fixing or release of the substance and provide a method for producing the triblock copolymer. <P>SOLUTION: The ternary block copolymer is composed of three kinds of blocks comprising a hydrophilic block, a block having reversible interaction with a functional substance and a hydrophobic block, wherein these three kinds of blocks have different roles. Since the hydrophilic block and the hydrophobic block controlling a dispersion stability factor are constructed independent of the block interacting with a functional substance, the self-organizing ability of the triblock copolymer is fully exhibited to easily form a nano-scale polymer micelle independent of the presence of the functional substance. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention is a triblock copolymer having a hydrophilic block, a block capable of reversible interaction with a functional substance, and a hydrophobic block, and is formed by the self-organizing function of the triblock copolymer The present invention relates to a method for producing the triblock copolymer capable of forming nanoscale polymer micelles.

  Research on immobilizing functional substances has been conducted for a long time, and metal, photosensitizers, color formers, DNA, electron acceptors, electron donors, electron mediators, etc. are mainly used for solid surfaces and polymers. In addition to a method of fixing to a chain or a side chain by a covalent bond or an ionic bond, an inclusion compound represented by cyclodextrin or a method of encapsulating in a porous material has been considered. The purpose of immobilizing the functional substance as described above was to synergistically and efficiently express the function of the substance by causing the functional substance to concentrate at a specific location.

  On the other hand, attempts to uniformly disperse functional substances have been made for a long time, and fine powders such as silica, clay, or pigment having functional groups are encapsulated with a surfactant or a surfactant-type polymer. Represented by a method of dispersing in a solution, a method of including a functional substance by hydrophobic interaction in micelles or vesicles dispersed in water, a copolymer containing acrylic acid or HEMA (hydroxyethyl methacrylate), etc. A method has been developed that includes a water-soluble monomer in a particle formed by a water-dispersible polymer.

  Furthermore, as a material that applies these properties, material development has been carried out that can carry the necessary amount of functional substances represented by DDS (drug delivery system) to the necessary place when necessary. . Materials such as water-dispersible star polymers and dendrimers (see, for example, Non-Patent Document 1) and amphiphilic diblock copolymers (see, for example, Non-Patent Document 2 and Non-Patent Document 3) have been proposed. As a method of releasing a necessary amount at a necessary place when a functional substance is freely required, a neutral hydrophobic polymer is formed by using a cross-linked hydrophobic polymer in which the functional substance is fixed in a pendant form as a core part. In core-shell particles having a shell layer (see, for example, Non-Patent Document 4), it is difficult to reversibly fix and release a functional substance. A method of disrupting the state of association is used. When releasing the functional substance, it is desirable that the polymeric micelles release only the functional substance while maintaining the morphology of the core-shell particles. Further, in order to reversibly fix and release the functional substance from the polymer micelle, a reversible immobilization method in the amphiphilic block copolymer is required. For this purpose, it is advantageous to use a method in which the functional molecular substance is immobilized by ionic bonds or coordinate bonds. For example, in a core-shell particle in which an ionic polymer is used as a shell layer in the core of a hydrophobic polymer (for example, Non-Patent Document 5), the functional substance is immobilized on the shell layer by ionic bonding or released from the particle. As a result, the surface energy of the particles is changed, and the dispersibility in the medium is deteriorated.

Angew.Chem.Int.Ed.Engl., 1990,29,138-175 ACS.polym.Mater.Sci.Eng., 1998,79,278-279 J. Am. Chem. Soc., 1999, 121, 11247-11248 Macromolecules, 1999,32,1140-1146, WO02002 / 026241 Macromolecular Rapid Communications, 2004, 25, 547-552

  The problem to be solved by the present invention is that it is possible to fix or release substances having various functionalities by reversible interaction, and even before and after the change of the morphology in the particles, It is an object of the present invention to provide a triblock copolymer capable of forming a polymer micelle that can be used without deteriorating dispersion stability in a solution system and a method for producing the same.

  As a result of intensive studies to solve the above problems, the present inventors have found that a triblock copolymer having a hydrophilic block, a block capable of reversible interaction with a functional substance, and a hydrophobic block has the above problems. The inventors have found that the present invention can be overcome, and have completed the present invention.

  That is, the present invention provides a triblock copolymer represented by the following formula (1).

（式（１）中、Ｘはエチレングリコール単位を表し、Ｙは疎水性リビングラジカル重合性モノマー単位を表し、Ｒは水素原子又アシル基を表し、ｎ_１は２又は３であり、ｍ_１は５〜１００００、ｍ_２は５〜１００００、ｍ_３は５〜１００００である。）を提供するものである。

(In the formula (1), X represents an ethylene glycol unit, Y represents a hydrophobic living radical polymerizable monomer unit, R represents a hydrogen atom or an acyl group, n ₁ is 2 or 3, and m ₁ is 5 to 10,000, m ₂ is 5 to 10,000, and m ₃ is 5 to 10,000.

  Further, the present invention provides a triblock in which a cyclic iminoether monomer (b) is subjected to living cationic polymerization to a hydrophobic polymer (a) having a halogen or sulfonic acid ester group at the terminal and then reacted with polyethylene glycol (c) at the terminal. A method for producing a copolymer and a method for producing a triblock copolymer for hydrolyzing a polyoxazoline block are also provided.

  The present invention is a triblock copolymer that can be widely used in technical fields such as medical diagnostic agents, cancer therapeutic agents, optical functional materials, catalytic functional materials, coloring materials, and metal inks. Specifically, the present invention is a triblock copolymer having a hydrophilic block, a block capable of reversible interaction with a functional substance, and a hydrophobic block, and is formed by a stable self-organizing function. Scale triblock copolymer. In such a triblock copolymer of the present invention, a medical diagnostic agent, a cancer therapeutic agent, a photofunctional substance, a catalytic functional substance, a dye, a metal ink, or the like is introduced into a block capable of reversible interaction with a functional substance. Therefore, each function can be expressed efficiently, and it is effective as a leading material in various fields.

  The triblock copolymer of the present invention is composed of three types of blocks, a hydrophilic block, a block capable of reversible interaction with a functional substance, and a hydrophobic block. Original block copolymer. Since the hydrophilic block that controls the dispersion stability factor and the hydrophobic block are constructed independently of the block that interacts with the functional substance, the self-assembly ability of the triblock copolymer can be maximized. It is a triblock copolymer that can easily form nanoscale polymer micelles with or without functional materials.

  In addition, the polymer micelle has a block capable of reversibly interacting with the functional substance of the triblock copolymer forming the medical micelle, a medical diagnostic agent, a cancer therapeutic agent, a photofunctional substance, a catalytic functional substance, a dye, and a metal ink material. Etc. can effectively express each function, and is effective as a leading material in a wide variety of fields.

  The triblock copolymer of the present invention has the following formula (1):

（式（１）中、Ｘはエチレングリコール単位を表し、Ｙは疎水性リビングラジカル重合性モノマー単位を表し、Ｒは水素原子又アシル基を表し、ｎ_１は２又は３であり、ｍ_１は５〜１００００、ｍ_２は５〜１００００、ｍ_３は５〜１００００である。）を提供するものである。
で表されるトリブロックコポリマーである。

(In the formula (1), X represents an ethylene glycol unit, Y represents a hydrophobic living radical polymerizable monomer unit, R represents a hydrogen atom or an acyl group, n ₁ is 2 or 3, and m ₁ is 5 to 10,000, m ₂ is 5 to 10,000, and m ₃ is 5 to 10,000.
It is a triblock copolymer represented by these.

  The triblock copolymer of the present invention is composed of three types of blocks. The block represented by the following formula (2) in the formula (1) is a block that plays a role as a hydrophilic block, and is a polyethylene glycol block composed of ethylene glycol units.

_{M 1} in formula (2) may be any 5 to 10,000, and more preferably 5 to 1,000.

  The block represented by the following formula (3) in the formula (1) constituting the triblock copolymer of the present invention is a block capable of reversibly interacting with a functional substance, and various functional substances can be reversed. Can be fixed or released.

When R in the formula (3) is a hydrogen atom, the block is a polyalkyleneimine, and depending on the treatment method, it may be converted into a salt with a counter ion. It is possible to act as an interactive block. Further, when R is an acyl group, it is a poly (N-acylalkyleneimine), and a polyalkyleneimine having various acyl groups can be effectively used for the block. The structure of the main chain of the block is an alkylene chain bonded by a nitrogen atom. As a general structure, n ₁ is 2 or 3, and the function can be expressed without any problem in a linear type or a branched type. Further m ₂ are polyalkyleneimines are commonly used, or may be a degree of polymerization of the (N- acylalkyleneimine). Typically _{m 2} preferably 5 to 10,000, from 5 to 1000 is more preferable.

  Preferred examples of the block include poly (alkylenimine) s such as poly (ethyleneimine) and polypropyleneimine,

  Poly (N-formylethyleneimine), poly (N-formylpropylenimine), poly (N-acetylethyleneimine), poly (N-acetylpropyleneimine), polypropionylethyleneimine, polypropionylpropyleneimine, poly (N- Butyrylethyleneimine), poly (N-butyrylpropylenimine), poly (N-isobutyrylpropylenimine), poly (N-isobutyrylpropylenimine), poly (N-pivaloylethyleneimine), poly (N-pivaloylpropylenimine), poly (N-lauroylethyleneimine), poly (N-lauroylpropylenimine), poly (N-stearoylethyleneimine), poly (N-stearoylpropylenimine), poly (N- (3- (Perfluorooctyl) propionyl) eth N'imin), poly (N-(3- (perfluorooctyl) propionyl) propylene imine) poly (alkylene imine is acylated with such aliphatic saturated carboxylic acids, etc.) such,

  Aliphatic unsaturation such as poly (N- (meth) acryloylethyleneimine), poly (N- (meth) acryloylpropylenimine), poly (N-oleoylethyleneimine), poly (N-oleoylpropylenimine), etc. Poly (alkyleneimines) acylated with carboxylic acids,

  Poly (N-benzoylethyleneimine), poly (N-benzoylpropylenimine), poly (N-toluoylethyleneimine), poly (N-toluoylpropylenimine), poly (N-naphthoylethyleneimine), poly ( N-naphthoylpropyleneimine), poly (N-cinnamoylethyleneimine), poly (alkyleneimine) s acylated with an aromatic carboxylic acid such as poly (N-cinnamoylpropylenimine), and the like.

  The block represented by the following formula (4) in the formula (1) constituting the triblock copolymer of the present invention is a block that plays a role as a hydrophobic block and has a structure that can be synthesized by living radical polymerization. I just need it.

_{M 3} in the formula (4) is preferably from 5 to 10,000, from 5 to 1000 is more preferable.

  Representative examples of structure Y satisfying both conditions are styrene units, methyl (meth) acrylate units, ethyl (meth) acrylate units, butyl (meth) acrylate units, benzyl (meth) acrylate units, 2-ethylhexyl (meth) acrylate. Examples include units.

  Preferable examples of the block include polystyrenes and poly (meth) acrylic acid esters. Specifically, polystyrenes such as polystyrene, poly 2-methylstyrene, poly 2-methyl styrene, poly 3-methyl styrene, poly 4-methyl styrene, poly α-methyl styrene, poly (meth) acrylate, Poly (meth) acrylate ethyl, poly (meth) acrylate n-butyl, poly (meth) acrylate i-butyl, poly (meth) acrylate t-butyl, poly (meth) acrylate 2-ethylhexyl, poly ( Examples thereof include poly (meth) acrylic acid esters such as cyclohexyl (meth) acrylate, benzyl poly (meth) acrylate, and dicyclopentanyl poly (meth) acrylate.

  Among them, particularly preferable examples in terms of cost and ease of handling are polystyrene, poly (meth) methyl acrylate, poly (meth) ethyl acrylate, poly (meth) acrylate n-butyl, poly (meth) acrylic acid. i-butyl, poly (meth) acrylate t-butyl, poly (meth) acrylate benzyl, poly (meth) acrylate 2-ethylhexyl and the like.

The number average degree of polymerization of each block is a value that is variously determined depending on the type of solvent to be dispersed, the type of functional substance to be immobilized, the size of the polymer micelle to be constructed, and the like. The ratio of the values of m ₁ , m ₂ and m ₃ is the application and purpose, the type of acyl group in the block represented by formula (3), the structure of the hydrophobic block represented by formula (4), and immobilization Although it is set according to the type of functional substance to be dispersed, the dispersion stability in the solvent is not particularly dependent on the change in the morphology of the polymer micelle before and after the fixation or release of the functional substance. to suitably _{retained, m 1: m 2: m} 3 = 100: 1~10000: is preferably 1 to 10,000.

  Next, the manufacturing method of the triblock copolymer of this invention is demonstrated. In the production method of the triblock copolymer of the present invention, the cyclic iminoether monomer (b) is polymerized by living cationic polymerization on the hydrophobic polymer (a) having a halogen or sulfonate group at the terminal, and then the polyethylene glycol (c ).

  The hydrophobic polymer (a) having a halogen or sulfonic acid ester group at the terminal used in the production method of the present invention is a polymer having a halogen or a sulfonic acid ester group at the terminal of the hydrophobic polymer and dispersed in water. Sometimes it becomes a polymer block represented by the above formula (4), which bears a stable associating force in the core part of the polymer micelle, and when dispersed in a hydrophobic medium, the dispersion stability is improved in the shell part of the polymer micelle. It has the property of holding a role. The terminal of the hydrophobic polymer has a halogen or sulfonic acid ester group, and preferred examples of the halogen include a chlorine atom, a bromine atom, and an iodine atom. Examples of the sulfonic acid ester group include a methanesulfonic acid ester group, a trifluoromethanesulfonic acid ester group, a trichloromethanesulfonic acid ester group, a benzenesulfonic acid ester group, a p-toluenesulfonic acid ester group, a 2-nitrobenzenesulfonic acid ester group, Examples include 2,4-dinitrobenzenesulfonic acid ester group. Of these, chlorine, bromine, and p-toluenesulfonic acid ester groups are particularly preferable because of their high ability to initiate living cationic polymerization described later.

  The terminal functional group halogen or sulfonic acid ester group of the hydrophobic polymer (a) used in the method for producing a triblock copolymer of the present invention is generally preferably one terminal. At that time, it is preferable that the other end has a structure with low reactivity. Representative examples of structures with low reactivity are methyl, ethyl, phenyl, benzyl and the like.

  The hydrophobic polymer (a) having a halogen or sulfonate group at the terminal used in the production method of the present invention is not particularly limited as long as the repeating unit has a hydrophobic structure. Examples of the general hydrophobic polymer include polyolefin having an alkyl group, polyolefin having an aromatic substituent, polyolefin having an alkyl ester group, polyolefin having an aromatic substituted ester group, and the like. Among them, preferred hydrophobic polymers are polystyrenes, poly (meth) acrylic acid esters and the like. Specific examples are polystyrene, poly (3-methylstyrene), poly (4-methylstyrene), poly (2,4,6-trimethylstyrene), poly (4-t-butylstyrene), poly (4- Phenylstyrene), polymethyl (meth) acrylate, polyethyl (meth) acrylate, polybutyl (meth) acrylate, polybenzyl (meth) acrylate, poly-2-ethylhexyl (meth) acrylate, and the like.

  The degree of polymerization of the hydrophobic polymer (a) having a halogen or sulfonic ester group at the terminal used in the production method of the present invention affects the stability of the associating force when micellized in a medium. In general, the degree of polymerization is preferably from 5 to 10,000, more preferably from 5 to 5000, in order to have both a stable associative force and good dispersion stability.

  Furthermore, the hydrophobic polymer (a) having a halogen or sulfonate group at the terminal used in the production method of the present invention was synthesized by living radical polymerization in which the growth terminal has a structure having a halogen or sulfonate group. A polymer is more preferable because the molecular weight distribution is monodispersed and the molecular weight can be easily controlled. The living radical polymerization initiator used at this time is typically a halide. Especially benzyl chloride, benzyl bromide, (1-chloroethyl) benzene, (2-chloroethyl) benzene, (1-bromoethyl) benzene, (2-bromoethyl) benzene, (1-iodoethyl) benzene, (2-iodoethyl) benzene, methyl 2-chloropropionate, methyl 2-bromopropionate, methyl 3-bromopropionate, p-toluenesulfonyl chloride, ethyl 2-bromoisobutyrate, benzhydryl chloride and the like may be mentioned as suitable examples. it can.

  When the hydrophobic polymer (a) having a halogen or sulfonic acid ester group at the terminal is synthesized by the above-mentioned living radical polymerization, copper halide is used as a catalyst. Examples of the copper halide are preferably (I) copper chloride and (I) copper bromide.

  When the hydrophobic polymer (a) having a halogen or sulfonic acid ester group at the terminal is synthesized by the above living radical polymerization, an aromatic is used as a co-catalyst. Examples of the aromatic amine are preferably 2,2-bipyridine, 4,4′-di (5-nonyl) -2,2′-bipyridine and the like.

  The monomer used when the hydrophobic polymer (a) having a halogen or sulfonic acid ester group at the terminal used in the production method of the present invention is synthesized by living radical polymerization is capable of living radical polymerization by the initiator described above, and There is no particular limitation as long as it is a hydrophobic monomer. Examples of general living radical polymerizable hydrophobic monomers include olefins having an alkyl group, olefins having an aromatic substituent, olefins having an alkyl ester group, and olefins having an aromatic substituted ester group. Among them, preferred hydrophobic polymers are styrenes, (meth) acrylic acid esters and the like. Specific examples include styrene, 3-methylstyrene, 4-methylstyrene, 2,4,6-trimethylstyrene, 4-t-butylstyrene, 4-phenylstyrene, methyl (meth) acrylate, ethyl (meth) acrylate. , Butyl (meth) acrylate, benzyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, and the like.

  When the hydrophobic polymer (a) having a halogen or sulfonic acid ester group at the terminal used in the production method of the present invention is synthesized by living radical polymerization, a known and commonly used solvent can be used. In general, an aprotic solvent is preferable, and when there is a problem in solubility of an initiator, a catalyst, a promoter, a monomer, etc., a mixed solvent can be used. The solvent to be mixed at this time may be a condition that does not affect living radical polymerization. An aprotic solvent is preferably used. It is also possible to mix two or more kinds of solvents. Examples of typical aprotic solvents include acetonitrile, cyanobenzene, phenylacetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.

  The cyclic imino ether monomer (b) used in the production method of the present invention is a monomer that can become a poly (N-acylalkyleneimine) block represented by the above formula (3) by living cationic polymerization. . As described above, the poly (N-acylalkylenimine) block can reversibly interact with a functional substance, and can play a role in reversibly immobilizing or releasing various functional substances. A functional polymer block. There is no particular limitation as long as it is a cyclic iminoether monomer that can be a poly (N-acylalkyleneimine) block having such a function. As a typical example, an oxazoline monomer or an oxazine monomer can be preferably used. Specific examples include 2-oxazoline, 2-oxazine, 2-methyl-2-methyloxazoline, 2-methyl-2-oxazine, 2-ethyl-2-oxazoline, 2-ethyl-2-oxazine, and the like.

  In the method for producing a triblock copolymer of the present invention, the cyclic iminoether monomer (b) is polymerized by living cationic polymerization on the hydrophobic polymer (a) having a halogen or sulfonate group at the terminal, and then the polyethylene glycol ( After reacting c) to produce a triblock copolymer, the polyoxazoline block of the triblock copolymer is hydrolyzed.

  In the triblock copolymer produced by hydrolyzing the polyoxazoline block of the present invention, the polyoxazoline block becomes a polyalkyleneimine block, and the functional substance is similar to the poly (N-acylalkyleneimine) block before hydrolysis. It is a polymer block capable of reversibly interacting with each other and capable of reversibly immobilizing or releasing various functional substances.

  In the production method of the triblock copolymer of the present invention, when the polyoxazoline block is hydrolyzed, the cyclic iminoether monomer (b) used for the living cationic polymerization is added to the above-mentioned hydrophilic cyclic iminoether monomer and other cyclic monomers. An iminoether monomer can be used. This is because even other cyclic imino ether monomers can be converted into polyalkyleneimine blocks by hydrolysis. Examples of the cyclic imino ether monomer that can be used at this time include 2-propyl-2-oxazoline, 2-propyl-2-oxazine, 2-isopropyl-2-propylene, in addition to the representative examples of the hydrophilic cyclic imino ether monomer described above. Oxazoline, 2-isopropyl-2-oxazine, 2- (t-butyl) -2-oxazoline, 2- (t-butyl) -2-oxazine, 2-undecyl-2-oxazoline, 2-undecyl-2-oxazine, 2-heptadecyl-2-oxazoline, 2-heptadecyl-2-oxazine, 2-vinyl-2-oxazoline, 2-vinyl-2-oxazine, 2- (2-propenyl) -2-oxazoline, 2- (2-propenyl) ) -2-oxazine, 2-allyl-2-oxazoline, 2-allyl-2-oxazine, 2-α-methyl Nyl-2-oxazoline, 2-α-methylvinyl-2-oxazine, 2- (9-heptadecenyl) -2-oxazoline, 2- (9-heptadecenyl) -2-oxazine, 2- (2-perfluorooctylethyl) ) -2-oxazoline, 2- (2-perfluorooctylethyl) -2-oxazine, 2-phenyl-2-oxazoline, 2-phenyl-2-oxazine, 2-tolyl-2-oxazoline, 2-tolyl-2 -Oxazine, 2-naphthyloxazoline, 2-naphthyloxazine, 2-styryl-2-oxazoline, 2-styryl-2-oxazine and the like.

  The living cationic polymerization method performed in the method for producing a triblock copolymer of the present invention will be described in detail. By using the hydrophobic polymer (a) having a halogen or sulfonic acid ester group at the above-mentioned terminal as an initiator, and performing a living cationic polymerization of the cyclic iminoether monomer (b), a hydrophobic polymer block and a poly (N-acylalkylene) A diblock copolymer consisting of (imine) blocks is synthesized. The method of living cationic polymerization is not particularly limited, and a known and commonly used method can be used. As the solvent that can be used, an aprotic solvent is preferable. Illustrative examples include acetonitrile, cyanobenzene, phenylacetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.

  The amount of the cyclic iminoether monomer used in the method for producing a triblock copolymer of the present invention is such that the degree of polymerization of the poly (N-acylalkylenimine) block obtained after living cationic polymerization is 5 to 10,000. It is desirable to use 5 to 5000.

  As described above, the polymer micelle formed by the triblock copolymer of the present invention is affected by the composition ratio of each block in the dispersion stability in the solution, and the composition ratio is a functional substance to be introduced and the solvent to be dispersed. It is known that it is strongly affected by the above. That is, it is preferable to determine the amount of the cyclic iminoether monomer to be added in consideration of the balance with the degree of polymerization of the hydrophobic block described later. Setting the amount of the cyclic iminoether monomer so that the polymerization degree of the poly (N-acylalkyleneimine) block synthesized by the living cationic polymerization is 1 to 10,000 when the polymerization of the hydrophobic polymer block is 100. Is preferred.

  In the living cationic polymerization reaction, the polymerization can be carried out at a polymerization reaction temperature of 40 ° C. or higher. However, considering that the polymerization time is shortened, the type of the polymerization solvent, the side reaction is not caused, etc., it is as low as acetonitrile. In the case of a boiling point solvent, the reaction is preferably performed at 60 to 80 ° C., and in the case of a high boiling point solvent having a boiling point exceeding 140 ° C., the reaction is preferably performed at 80 to 140 ° C.

  The polyethylene glycol used in the method for producing a triblock copolymer of the present invention is a hydrophilic polymer block represented by the above formula (2), which maintains dispersion stability in an aqueous medium and is stable in a hydrophobic medium. It is a polymer block having the property of associating power. The molecular weight is preferably 5 to 10,000, more preferably 5 to 5,000.

  The polyethylene glycol used in the method for producing a triblock copolymer of the present invention is a diblock obtained by subjecting a cyclic iminoether monomer (b) to living cationic polymerization to a hydrophobic polymer having a halogen or sulfonate group at the terminal. Polyethylene glycol that can be reacted with the end of the copolymer. Since the terminal of the diblock copolymer is a halogen or a sulfonate group, polyethylene glycol having a functional group capable of reacting with the terminal group at the terminal is preferable. The terminal functional group of polyethylene glycol capable of reacting with the halogen or sulfonic acid ester group at the terminal of the diblock copolymer is not particularly limited as long as it is a known and commonly used functional group. Representative examples include a hydroxyl group, a carboxyl group, and an amino group.

  Reaction when the cyclic iminoether monomer (b) is polymerized by living cationic polymerization with a hydrophobic polymer having a halogen or sulfonic acid ester at the terminal and then reacted with polyethylene glycol at the terminal in the method for producing a triblock copolymer of the present invention. The conditions vary depending on the type of the terminal functional group of polyethylene glycol, but are not particularly limited as long as they are known and conventional methods. As an example of a typical reaction, when the terminal functional group of polyethylene glycol is a hydroxyl group or an amino group, it can be synthesized at a reaction temperature of 70 to 150 ° C. in the presence of an alkali catalyst. The alkali catalyst is not particularly limited as long as it is a known and conventional one. Examples of typical alkali catalysts include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium t-butoxide, potassium t-butoxide and the like. The solvent used in the reaction is preferably a solvent capable of dissolving the diblock copolymer and polyethylene glycol at the reaction temperature. Therefore, although it depends on the kind of diblock copolymer obtained by subjecting the cyclic iminoether monomer (b) to living cationic polymerization to a hydrophobic polymer having a halogen or sulfonic acid ester at the terminal, it is a typical example that is commonly used. Examples of such solvents include acetonitrile, cyanobenzene, phenylacetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.

  The molar ratio of diblock copolymer and polyethylene glycol used in the reaction is ideally diblock copolymer: polyethylene glycol = 1: 1, but the reaction efficiency and operation such as shortening of reaction time and mild reaction temperature In consideration of the characteristics, 1: 1 to 10 is preferable, and excess polyethylene glycol can be separated by performing reprecipitation purification with a mixed solvent and changing the mixing ratio of the solvent in the treatment step after the completion of the reaction. Is possible. The mixed solvent is preferably a combination of two or more types having different polarities. If the example of a typical mixed solvent is given, two or more types can be selected from ethyl acetate, toluene, acetonitrile, acetone, methanol, ethanol, chloroform, hexane, cyclohexane, ether, and the like.

  The terminal functional group of the diblock copolymer and the terminal functional group of polyethylene glycol used in the method for producing the triblock copolymer of the present invention may be changed to different types of terminal or terminal functional groups by performing a treatment such as reaction. There is no problem as long as the terminal of the diblock copolymer obtained as described above and the terminal functional group of polyethylene glycol can be converted into a triblock copolymer by reaction or a terminal functional group.

  When hydrolysis is carried out in the method for producing a triblock copolymer of the present invention, the obtained triblock copolymer may be subjected to hydrolysis reaction as it is, but in order to avoid side reactions during the hydrolysis reaction, It is preferred to purify the copolymer in the manner as described above.

  The hydrolysis in the production method of the triblock copolymer of the present invention can be carried out without any problem as long as it is a known and usual hydrolysis reaction. In general, an acid hydrolysis reaction and an alkaline hydrolysis reaction can be mentioned, but an enzyme-based hydrolysis reaction or the like can also be used. What is important is that the poly (N-acylalkyleneimine) block in the triblock copolymer is changed to a polyethyleneimine block without affecting the hydrophilic block and the hydrophobic block by the hydrolysis reaction. Considering the efficiency of the hydrolysis reaction, acid hydrolysis or alkali hydrolysis is preferable. The acid catalyst that can be used in the acid hydrolysis reaction is not limited as long as it is generally usable. As representative examples, hydrochloric acid, nitric acid, sulfuric acid and the like are preferable. In carrying out the alkaline hydrolysis reaction, a known and commonly used catalyst can be used. As typical examples, sodium hydroxide, potassium hydroxide, and the like are preferable. The amount of the catalyst is not a problem as long as it is a condition used for a general hydrolysis reaction. If a preferable example is given, it will be good to use 1-20 times mole with respect to the polymerization degree of the poly (N-acyl alkylene imine) block hydrolyzed, and 1-10 times mole is more preferable.

  As a representative method of the hydrolysis reaction, the triblock is added to a 2.5N hydrochloric acid aqueous solution containing 3 times the amount of hydrochloric acid with respect to the degree of polymerization of the poly (N-acylalkyleneimine) block in the triblock copolymer. The copolymer is mixed and dispersed in an ultrasonic cleaner for about 1 hour, and then reacted at 90 ° C. for 15 hours. After cooling, add to a large volume of acetone with stirring. The resulting precipitate is filtered, redispersed in a small amount of water, added again to acetone with stirring, reprecipitated, filtered and vacuum dried to obtain the triblock copolymer of the present invention.

  As described above, according to the method for producing a triblock copolymer of the present invention, a triblock copolymer having a hydrophilic block, a block capable of reversibly interacting with a functional substance, and a hydrophobic block can be easily obtained. It is possible to manufacture efficiently.

  Since the triblock copolymer of the present invention has a hydrophilic block and a hydrophobic block in addition to a block capable of reversibly interacting with a functional substance, the polymer is spontaneously dispersed when dispersed in a solvent such as water. A micelle can be formed. That is, in the triblock copolymer, a hydrophobic block is a core, and a poly (N-acylalkyleneimine) block that is a block capable of reversibly interacting with a functional substance, or a polyalkyleneimine is an intermediate layer, and a hydrophilic block To form a core-corona type polymer micelle that has a corona layer that can sufficiently move its molecular chain in water and can move freely, so it can maintain high dispersion stability in water. It becomes possible.

  When the block capable of reversibly interacting with the functional substance of the block copolymer of the present invention is a polyalkyleneimine block having no acyl group, it interacts with an ionic functional substance. For example, DNA, ionic dye, metal ion and the like. When these ionic functional substances are immobilized on the block by ionic bonds, the block is crystallized. However, as described above, the hydrophilic block and the hydrophobic block can each independently play a role of maintaining a stable associative force and dispersion stability, so that the dispersion stability in the system does not deteriorate. .

  Usually, when a functional substance such as DNA, metal, or dye forms a polymer micelle with a polymer having an interactable block, the functional substance is immobilized in or released from the triblock copolymer. When the functional substance is immobilized, the block that can interact with the functional substance does not form a crystal when the functional substance is immobilized, such as when the block crystallizes or releases the functional substance. Morphology changes in However, the triblock copolymer of the present invention has a hydrophilic block and a hydrophobic block that maintain dispersion stability in a solvent in addition to the block capable of interacting with the functional substance. Polymer micelles made of a copolymer can maintain excellent dispersion stability in solution regardless of such a change in morphology.

  In addition, since the triblock polymer of the present invention has a block capable of interacting with a functional substance, a functional substance such as DNA, metal, or dye can be fixed to the block. Immobilized polymeric micelles can be formed. Therefore, the polymer micelle comprising the triblock polymer of the present invention can be usefully used in the fields of medical diagnostic agents, cancer therapeutic agents, photofunctional substances, catalytic functional substances, dyes, photolithographic materials and the like.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. ¹ H-NMR was measured by a dynamic light scattering method using Lamda 300, (300 MHz) manufactured by JEOL Ltd., and the particle size was measured using a Microtrac UPA150 manufactured by Nikkiso Co., Ltd.

Example 1
[Living radical polymerization]
Put a magnetic stirrer in a two-necked eggplant flask, weigh 65 mg (0.42 mmol) of 2,2-bipyridyl and 60 mg (0.42 mmol) of copper bromide, then attach a three-way cock and a stopper and seal tightly. The inside was sufficiently purged with nitrogen by repeatedly performing vacuum degassing. Next, 2.0 ml (17 mmol) of styrene, 2 ml of toluene, and 47 μl (0.35 mmol) of 1- (bromoethyl) benzene were respectively added to the flask using a syringe while flowing nitrogen gas from a three-way cock. After sealing, the mixture was stirred in an oil bath at 110 ° C. for 24 hours.

The resulting reaction solution was cooled, diluted in 50 g of chloroform, and treated with an alumina column. The obtained treatment liquid was concentrated with an evaporator, dropped into 100 g of ethanol, and purified by reprecipitation. After filtration, it was washed twice with ethanol and dried in vacuum. The yield was 83%. Each peak was assigned by ¹ H-NMR spectrum to confirm the structure of the product (1.4 ppm: CH _{2 of} polystyrene (hereinafter referred to as PSt) main chain, 1.8 ppm: CH of PSt main chain, 4. 4 ppm: CH adjacent to PSt terminal bromine, 6.3 to 7.3 ppm: phenyl group of PSt). From this, it was confirmed that the obtained product was terminal brominated polystyrene.

[Living cationic polymerization]
Put a magnetic stirrer in a two-necked eggplant flask, weigh 1.3 g (0.24 mmol) of the above-mentioned terminal brominated polystyrene, attach a three-way cock and a stopper, seal tightly, and repeat the vacuum degassing enough Was replaced with nitrogen. Next, 1 ml (12 mmol) of methyloxazoline (hereinafter referred to as MOZ) and 10 ml of N, N-dimethylacetamide (hereinafter referred to as DMA) were added into the flask using a syringe while flowing nitrogen gas through a syringe. . After sealing, the mixture was stirred in an oil bath at 100 ° C. for 24 hours. The obtained reaction solution was cooled, sampled at 5 g, added to 200 g of hexane with stirring, and precipitated. The precipitate adhering to the wall of the container was separated by decantation and dissolved in 10 g of methanol. This was added with stirring to a mixed solvent of 200 g of hexane and reprecipitated. The dispersed reprecipitate was filtered and vacuum-dried at 80 ° C. The yield was 70%. Each peak was assigned by ¹ H-NMR spectrum to confirm the structure of the product (1.5 ppm: CH ₂ of PSt main chain, 1.8 ppm: CH of PSt main chain, 2.1 ppm: polyacetylethyleneimine) Acetyl group (hereinafter referred to as PAEI), 3.5 ppm: CH ₂ CH ₂ of PAEI main chain, 6.3 to 7.3 ppm: phenyl group of PSt). Thus, the obtained product was a PSt-PAEI diblock copolymer, and the composition of each block was PSt: PAEI = 46: 54.

[Condensation reaction]
In a two-necked eggplant flask, 0.46 g (0.24 mmol) of polyethylene glycol monomethyl ether (Mn2000), 0.082 g (0.59 mmol) of potassium carbonate, and 2 ml of DMA were weighed, and the atmosphere was replaced with nitrogen gas. And stirred for 2 hours. This is designated as Solution A. In addition, 5.8 g of the above reaction solution after living cationic polymerization was weighed into a 50 ml eggplant flask, 0.23 g (1.18 mmol) of sodium tosylate was added, the atmosphere was replaced with nitrogen gas, and the mixture was stirred at 60 ° C. for 2 hours. After cooling the solution, it was added to the above solution A and reacted at 100 ° C. for 24 hours with stirring. After cooling, it was diluted with 10 g of chloroform and filtered. Chloroform was distilled off with an evaporator, and the concentrated solution was added to 200 g of hexane with stirring and reprecipitated. After filtration, the precipitate was dissolved in 10 g of chloroform and reprecipitated again in hexane. After filtration, it was vacuum dried. The yield was 50%. ¹ performs assignment of each peak by H-NMR spectra confirmed the structure of the product (1.5 ppm: PSt main chain of _CH 2, 1.8 ppm: PSt main chain of CH, 2.1 ppm: acetyl group of PAEI , 3.5 ppm: PAEI main _CH 2 _CH 2 chain, 3.7ppm: _CH 2 _CH 2 polyethylene glycol (hereinafter referred to as PEG), 6.3~7.3ppm: phenyl group PSt). Thus, the obtained product was a PSt-PAEI-PEG triblock copolymer.

(Example 2)
[Acid hydrolysis reaction]
In a 100 ml eggplant flask, 0.4 g of PSt-PAEI-PEG triblock copolymer (acetylethyleneimine unit (hereinafter abbreviated as AEI): 1.8 mmol) synthesized in Example 1 was weighed and 2.2 g of 5N HCl aqueous solution (HCl: 10.5 mmol) was added, and a magnetic stirrer was added to make a stopper. The mixture was dispersed by treating with an ultrasonic cleaner for 1 hour, and then stirred at 90 ° C. for 10 hours. After cooling, the reaction solution was concentrated with an evaporator, and the concentrated solution was added to 200 g of acetone with stirring. The resulting precipitate was filtered and dissolved in 10 g of water. Again, the mixture was added to 200 g of acetone with stirring and reprecipitated, followed by filtration. It vacuum-dried at 60 degreeC and obtained the target PSt-PEI-PEG triblock copolymer. The yield was 90%. Each peak was assigned by ¹ H-NMR spectrum, and the structure of the product was confirmed, such as the disappearance of the 2.1 ppm acetyl group-derived peak. The composition of each block is that part of the product is dissolved in water and placed in a dialysis tube, dialyzed overnight with 0.5% aqueous ammonia, the aqueous ammonia is replaced with water, and the water is replaced again after 8 hours. Thereafter, ethanol was added to the aqueous solution in the dialysis tube, the solvent was distilled off with an evaporator, and the obtained was further obtained from ¹ H-NMR spectrum of a sample which was vacuum-dried at 70 ° C. for 15 hours. PSt: PEI: PEG = 38: 35: 27. Each peak of the ¹ H-NMR spectrum of the sample dialyzed with aqueous ammonia is described as follows: 1.5 ppm: CH ₂ of PSt main chain, 1.8 ppm: CH of PSt main chain, 3.5 ppm: polyethyleneimine (hereinafter referred to as PEI) The main chain is CH ₂ CH ₂ , 3.7 ppm: PEG CH ₂ CH ₂ , 6.3 to 7.3 ppm: PSt phenyl group.

(Example 3)
[Living radical polymerization, living cationic polymerization, and condensation reaction]
In [Living radical polymerization] of Example 1, 40 μl (0.35 mmol) of 2- (iodoethyl) benzene was used instead of 1- (bromoethyl) benzene. The yield was 86%. Each peak was assigned by ¹ H-NMR spectrum, and the structure of the product was confirmed (1.4 ppm: CH _{2 of} polystyrene (hereinafter referred to as PSt) main chain, 1.8 ppm: CH of PSt main chain, 3. 9 ppm: CH adjacent to PSt terminal iodine, 6.3-7.3 ppm: phenyl group of PSt). From this, it was confirmed that the obtained product was terminally iodinated polystyrene.

In [Living Cationic Polymerization] of Example 1, the same procedure as in Example 1 was performed except that the above-mentioned terminal iodinated polystyrene was used instead of terminal brominated polystyrene. ^{From the 1} H-NMR spectrum, a peak similar to the result of [Living Cationic Polymerization] in Example 1 was observed. The composition of each block was PSt: PAEI = 53: 47.

In [Condensation reaction] in Example 1, the same procedure as in [Condensation reaction] in Example 1 was carried out except that 5.8 g of the reaction solution after living cationic polymerization was added as it was to the aforementioned solution A. The yield was 58%. ^{From the 1} H-NMR spectrum, a peak similar to the result of [Condensation reaction] in Example 1 was observed.

Example 4
[Acid hydrolysis reaction]
0.4 g of PSt-PAEI-PEG triblock copolymer synthesized in Example 3 (except that an acetylethyleneimine unit was used, this was performed in the same manner as in [Acid hydrolysis reaction] in Example 2. The yield was 87%. From the ¹ H-NMR spectrum of the sample dialyzed with aqueous ammonia, the composition was PSt: PEI: PEG = 41: 34: 25, which was the same as the result of [Acid hydrolysis reaction] in Example 2. A peak was observed.

(Example 5)
[Living radical polymerization, living cationic polymerization, and condensation reaction]
In the method shown in Example 1, instead of 2.0 ml (17 mmol) of styrene for living radical polymerization, 1.9 ml (17 mmol) of methyl methacrylate (hereinafter referred to as MMA) was used, and terminal bromine of living cationic polymerization was used. The same procedure as in Example 1 was performed except that 1.2 g (0.24 mmol) of the terminal brominated polymethyl methacrylate was used instead of 1.3 g (0.24 mmol) of the modified polystyrene. Yield 52%. Each peak was assigned by ¹ H-NMR spectrum in the same manner as in Example 1, and the structure of the product was confirmed (1.2 ppm: methyl group of PMMA, CH ₂ , (1.5 ppm, 2.0 ppm): PMMA. Main chain CH ₂ , 2.1 ppm: acetyl group of PAEI, 3.5 ppm: CH ₂ CH ₂ of PAEI main chain, 3.6 ppm: methyl ester group of PMMA, 3.7 ppm: CH ₂ CH _{2 of} PEG).

(Example 6)
[Acid hydrolysis reaction]
In the method shown in Example 2, instead of adding 0.4 g of PSt-PAEI-PEG triblock copolymer (AEI: 1.8 mmol) and adding 2.2 g of 5N HCl aqueous solution (HCl: 10.5 mmol), Except that 0.4 g (AEI: 1.8 mmol) of the PMMA-PAEI-PEG triblock copolymer synthesized in Example 5 was weighed and 2.2 g (HCl: 10.7 mmol) of 5N HCl aqueous solution was added. Performed exactly as in 2. Yield was 80%, ¹ H-NMR spectrum was assigned to each peak in the same manner as in Example 2 to confirm the structure of the product (1.2 ppm: methyl group of PMMA, CH ₂ , (1.5 ppm, 2.0 ppm): CH _{2 of} PMMA main chain, 3.5 ppm: CH ₂ CH ₂ of PAEI main chain, 3.6 ppm: methyl ester group of PMMA, 3.7 ppm: CH ₂ CH _{2 of} PEG). The obtained product was a PEG-PBEI-PEI triblock copolymer, and the composition of each block determined by treatment with aqueous ammonia was PMMA: PEI: PEG = 41: 34: 25.

(Application 1)
2.0 mg of the PSt-PEI-PEG triblock copolymer obtained in Example 2 was dispersed in 5 g of water, stirred for 1 hour in an oil bath at 80 ° C. while stirring with a magnetic stirrer, and then 1 hour in an ultrasonic cleaner. Processed. After standing for 24 hours, the particle size of the obtained colloidal particles was measured. The number average particle size was 70 nm. When tetraphenylporphyrin-sodium tetrasulfonate (TSPP) was added to the obtained colloidal particle dispersion, it was confirmed that TSPP was suitably immobilized.

(Application example 2)
In the above PSt-PEI-PEG triblock copolymer dispersion aqueous solution, 0.7 mg (TSPP (mol) / EI unit (mol) = 1/10) of tetraphenylporphyrin-sodium tetrasulfonate (hereinafter abbreviated as TSPP) as a dye. And stirred at room temperature for 24 hours using a magnetic stirrer. The dispersed aqueous solution was put into a dialysis tube (SPECTRUM Spectra / Por; MWCO: 3500) and dialyzed in water. The water was changed 3 times every 8 hours. After the dispersion aqueous solution was allowed to stand for 24 hours from the dialysis tube, the particle size of the obtained colloidal particles was measured. The number average particle size was 80 nm. When tetraphenylporphyrin-sodium tetrasulfonate (TSPP) was added to the obtained colloidal particle dispersion, it was confirmed that TSPP was suitably immobilized.

Claims (7)

A triblock copolymer represented by the following formula (1).

(In the formula (1), X represents an ethylene glycol unit, Y represents a hydrophobic living radical polymerizable monomer unit, R represents a hydrogen atom or an acyl group, n ₁ is 2 or 3, and m ₁ is 5 to 10000, m ₂ is 5 to 10,000, and m ₃ is 5 to 10,000.) The triblock copolymer according to claim 1, wherein Y in the formula (1) is a polymer block selected from a repeating unit composed of styrenes and a repeating unit composed of (meth) acrylic acid esters. Y in the formula (1) is a styrene unit, a methyl (meth) acrylate unit, an ethyl (meth) acrylate unit, a butyl (meth) acrylate unit, a benzyl (meth) acrylate unit, or a 2-ethylhexyl (meth) acrylate unit. The triblock copolymer according to claim 1, which is a selected polymer block. The triblock copolymer according to claim 1, wherein a ratio of m ₁ , m ₂ and m _{3 in} the formula (1) is m ₁ : m ₂ : m ₃ = 100: 1 to 10000: 1 to 10,000. A polymeric micelle comprising the triblock copolymer according to any one of claims 1 to 4. A method for producing a triblock copolymer, in which a cyclic iminoether monomer (b) is subjected to living cationic polymerization to a hydrophobic polymer (a) having a halogen or sulfonic acid ester group at the terminal, and then reacted with polyethylene glycol (c) at the terminal. Furthermore, the manufacturing method of the triblock copolymer which hydrolyzes a polyoxazoline block.