Block copolymer and its manufacturing method

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

Research on immobilizing functional substances has been carried out for a long time, and metal, photosensitizers, color formers, DNA, electron acceptors and electron donors, electron transmitters, 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, a method of encapsulating the clathrate compound typified by cyclodextrin or a porous material has been considered. The purpose of immobilizing the functional substance as described above was to synergistically and efficiently express the functions of the substance by allowing the functional substance to be concentrated in a specific place.

On the other hand, attempts to uniformly disperse functional substances have been made for a very long time, and fine powders such as silica, clay, and pigments having functional groups are encapsulated with a surfactant or a surfactant-type polymer. This is 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), and the like. A method of internally containing a water-soluble monomer in particles formed by a water-dispersible polymer has been developed.

Furthermore, as materials that apply these properties, materials are being developed that can carry the required amount of functional substances, such as DDS (drug delivery system), when and where they are needed. .. Materials such as water-dispersible star polymers and dendrimers (see, for example, Non-Patent Document 1) and amphipathic diblock copolymers (see, for example, Non-Patent Document 2 and Non-Patent Document 3) have been proposed. A reversible immobilization method in the amphipathic block copolymer is required to release the required amount of the functional material at will, when and where it is needed. In addition, it is an important factor that the amphipathic block polymer is always stably dispersed before and after immobilizing the functional substance. When hydrophobic interaction is used as the immobilization method (see, for example, Non-Patent Document 4), the functional substances aggregate in the polymer micelle formed by the amphipathic block copolymer due to association or the like, and the polymer is polymerized. It is difficult to molecularly disperse functional substances in micelles. Therefore, it is not possible to release the functional substance quantitatively. In order to disperse the molecule, it is advantageous to use a method of immobilizing the functional molecule by an ionic bond or a coordination bond (see, for example, Non-Patent Document 5), but in this case, the functional molecule is immobilized. Since the morphology in the polymer micelle changes before and after, the dispersion stability of the polymer micelle in the system deteriorates.

<nplcit num="1"><text>Angew.Chem.Int.Ed.Engl., 1990,29,138-175</text></nplcit><nplcit num="2"><text>ACS.polym.Mater.Sci.Eng., 1998,79,278-279</text></nplcit><nplcit num="3"><text>J.Am.Chem.Soc.,1999,121,11247-11248</text></nplcit><nplcit num="4"><text>J.Contrl.Rel.,1993,24,119-132</text></nplcit><nplcit num="5"><text>Macromolecules, 1999,32,1140-1146, WO02002 / 026241</text></nplcit>

<p> The problem to be solved by the present invention is that it is possible to fix or release substances having various functions by reversible interaction, and even if changes such as morphology in particles occur before and after that, It is an object of the present invention to provide a block copolymer capable of forming a polymer micelle that can be used without deteriorating the dispersion stability in a solution system, and a method for producing the same.</p>

<p> As a result of diligent studies to solve the above problems, the present inventors have overcome the above problems with block copolymers having hydrophilic blocks, hydrophobic blocks, and blocks capable of reversibly interacting with functional substances. We have found what we can do and have completed the present invention.</p><p> That is, in the present invention, a block (X) composed of a polyalkylene ether, a block (Y) composed of a poly (N-acylalkyleneimine) having an acyl group having 3 or more carbon atoms, and an acyl possessed by the block (Y). It is composed of a block (Z) composed of a poly (alkyleneimine) having an acyl group different from the group or a poly (alkyleneimine) having no acyl group, and the block (Y) and the block (Z) are directly connected to each other. However, block copolymers having a number average degree of polymerization of each block in the range of 5 to 10000 are provided.</p><p> Further, in the present invention, a cyclic imino ether monomer (b) is subjected to living cationic polymerization on a polyalkylene ether derivative having a halogen atom or a sulfonic acid ester group at one end or both ends of the polyalkylene ether (a), and then the above. By cationically polymerizing a cyclic imino ether monomer (c) different from the cyclic imino ether monomer (b), a polyalkylene ether block (A), a poly (N-acylalkylene imine) block (B), and the poly ( A method for producing a block copolymer composed of a poly (N-acylalkyleneimine) block (C) having an acyl group different from that of the N-acylalkyleneimine block (B), and the poly (N-acylalkyleneimine) block (N-acylalkyleneimine) block ( Provided is a method for producing a block copolymer in which an acyl group in either the block of B) or the poly (N-acylalkyleneimine) block (C) is selectively hydrolyzed to form a poly (alkyleneimine) chain.</p>

<p> The present invention is a block 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 block copolymer having a hydrophilic block, a hydrophobic block, and a block capable of reversibly interacting with a functional substance, and the nanoscale formed by its stable self-assembling function. Block copolymer. Therefore, the block copolymer of the present invention can be obtained by introducing a medical diagnostic agent, a cancer therapeutic agent, a photofunctional substance, a catalytic functional substance, a dye, a metal ink, etc. into a block capable of reversibly interacting with a functional substance. It is possible to efficiently express each function, and it is effective as an advanced material in a wide range of fields.</p><p> The block copolymer of the present invention is composed of three types of blocks that interact with a functional substance in addition to a hydrophilic block and a hydrophobic block, and is a ternary block copolymer consisting of blocks having three different roles. Is. 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, it is possible to maximize the self-assembling ability of the block copolymer. It is a block copolymer that can easily form nanoscale polymer micelles with or without functional substances.</p><p> Further, in the polymer micelle, a medical diagnostic agent, a cancer therapeutic agent, a photofunctional substance, a catalytic functional substance, a dye, a metal ink material, etc. are introduced into a block that interacts with the functional substance of the block copolymer that forms the polymer micelle. Therefore, it is possible to efficiently express each function, and it is effective as an advanced material in a wide range of fields.</p>

The block copolymer of the present invention comprises a block (X) composed of a polyalkylene ether, a block (Y) composed of a poly (N-acylalkyleneimine) having an acyl group having 3 or more carbon atoms, and the block (Y). It is composed of a block (Z) composed of a poly (alkyleneimine) having an acyl group different from the acyl group having an acyl group or a poly (alkyleneimine) having no acyl group, and the block (Y) and the block (Z). Are directly connected, and the number average degree of polymerization of each block is in the range of 5 to 10000.

The block (X) made of polyalkylene ether constituting the block copolymer of the present invention (hereinafter, abbreviated as block (X)) is a block of a polymer in which alkylene chains are connected by oxygen atoms, and the alkylene chain is a straight chain. It may be in the form of a branch or in the form of a branch, and may have a branch such as a methyl group. Further, the block (X) is a block that plays a role as a hydrophilic block, and is not particularly limited as long as it does not impair its properties. Typical polyalkylene ethers include polyethylene glycol, polypropylene glycol and the like. In particular, the block (X) is the general formula (1).

<chemistry num="1"><img file="JP2005298542A_D0001.tif" /></chemistry>(In equation (1), n₁Is 2 or 3 and m₁Is in the range of 5 to 10000. ) Is preferable. As described above, in the above equation (1), n₁Does not impose any restrictions as long as the block (X) is hydrophilic, but n₁2 or 3 is preferable because it has excellent hydrophilicity, and n₁Polyethylene glycol having a value of 2 is particularly preferable. Also, in the above equation (1), m₁Is preferably in the range of 5 to 10000, preferably 5 to 1000.

The block (Y) (hereinafter abbreviated as block (Y)) composed of poly (N-acylalkyleneimine) having an acyl group having 3 or more carbon atoms constituting the block copolymer of the present invention has 3 carbon atoms. Any acyl group may be used as long as it is the above acyl group. Hydrocarbon-based acyl groups, fluorine-based acyl groups, etc. are not particularly limited. Further, the structure of the main chain of the block is a structure in which an alkylene chain is bonded with a nitrogen atom, and the alkylene chain may have branches such as a methyl group and an ethyl group as long as it has a structure that can be synthesized by living cationic polymerization. ..

The block (Y) includes the general formula (2).

<chemistry num="2"><img file="JP2005298542A_D0002.tif" /></chemistry>(In equation (2), R₁Represents an acyl group, n₂Is 2 or 3 and m₂Is in the range of 5 to 10000. ) Can be preferably used.

Specific examples of the block (Y) composed of poly (N-acylalkyleneimine) having an acyl group having 3 or more carbon atoms as represented by the above formula (2) are polypropionylethyleneimine and polypropionylpropyleneimine. , Poly (N-butylylethyleneimine), Poly (N-butylylpropyleneimine), Poly (N-isobutyrylethyleneimine), Poly (N-isobutyrylpropyleneimine), Poly (N-pivaloyl) Ethylene imine), poly (N-pivaloyl propylene imine), poly (N-lauroyl ethylene imine), poly (N-lauroyl propylene imine), poly (N-stearoyl ethylene imine), poly (N-stearoyl propylene imine) Poly (poly acylated with an aliphatic saturated carboxylic acid such as poly (N- (3- (perfluorooctyl) propionyl) ethyleneimine), poly (N-(3- (perfluorooctyl) propionyl) propyleneimine), etc. (Alkyleneimines),

Aliphatic unsaturateds such as poly (N- (meth) acryloylethyleneimine), poly (N- (meth) acryloylpropyleneimine), poly (N-oleoylethyleneimine), poly (N-oleoylpropyleneimine), etc. Poly (alkyleneimines) acylated with carboxylic acid,

Poly (N-benzoylethyleneimine), poly (N-benzoylpropyleneimine), poly (N-toluylethyleneimine), poly (N-toluiroylpropyleneimine), poly (N-naphthoylethyleneimine), poly ( Poly (alkyleneimine) acylated with aromatic carboxylic acids such as N-naphthoylpropylene imine), poly (N-cinnamoylethyleneimine), poly (N-cinnamoylpropyleneimine) and the like.

A block (Z) composed of a poly (alkyleneimine) having an acyl group different from the acyl group of the block (Y) or a poly (alkyleneimine) having no acyl group, which constitutes the block copolymer of the present invention (hereinafter, The block (Z) is abbreviated as a block (Z)) is a block that is directly connected to the block (Y). When the block (Z) has an acyl group, it is a poly (N-acylalkyleneimine) having an acyl group different from the acyl group of the block (Y). When the block (Z) has an acyl group, the acyl group may be any acyl group as long as it is an acyl group different from the acyl group of the block (Y), and is a hydrocarbon-based acyl group or a fluorine-based acyl group. There are no particular restrictions on the basics. When the block (Z) does not have an acyl group, the block (Z) is a block made of poly (alkyleneimine).

The structure of the main chain of the block (Z) constituting the block copolymer of the present invention is such that the alkylene chain is bonded with a nitrogen atom, and the alkylene chain may be linear or branched, and may have a methyl group or an ethyl group. Etc. may be branched.

The block (Z) constituting the block copolymer of the present invention is represented by the general formula (3).

<chemistry num="3"><img file="JP2005298542A_D0003.tif" /></chemistry>(In equation (3), R₂Is a hydrogen atom, or R in equation (2)₁Represents an acyl group different from the acyl group represented by, n₃Is 2 or 3 and m₃Is in the range of 5 to 10000. ) Can be preferably used. In the above equation (3), R₂When is a hydrogen atom, the block (Z) is a poly (alkyleneimine) having no acyl group, and R₂Is an acyl group, then R in equation (3)₁Represents a poly (alkyleneimine) having an acyl group different from the acyl group represented by.

Specific examples of the block (Z) as represented by the above formula (3) include poly (alkyleneimine) acylated with a saturated aliphatic carboxylic acid and an unsaturated fat exemplified in the above block (Y). Poly (alkyleneimine) acylated with group carboxylic acid, poly (alkyleneimine) acylated with aromatic carboxylic acid, etc., poly (ethyleneimine), poly (alkyleneimine) such as polypropyleneimin, etc. Poly (N-formylethyleneimine), poly (N-formylpropyleneimine), poly (N-acetylethyleneimine), poly (N-acetylpropyleneimine), etc. having an acyl group having 2 or less carbon atoms (N) -Acylalkyleneimine).

The block copolymer of the present invention is reversible because each of the above blocks (X), (Y), and (Z) has a reversible interaction with a hydrophilic, hydrophobic, or functional substance. By interaction, polymer micelles capable of immobilizing or releasing substances having various functions can be formed. As described above, the block (X) is a block having hydrophilicity. The block (Y) and the block (Z) differ in whether or not the block (Z) has an acyl group, and if both have an acyl group, the properties that can be taken by each of the acyl groups.

The block (Z) is a block made of poly (alkyleneimine) having no acyl group, specifically, the following formula (3a).

<chemistry num="4"><img file="JP2005298542A_D0004.tif" /></chemistry>(In equation (3a), n₄, M₄Are each n₃, M₃Is similar to. ), The block (Z) serves as a block having a reversible interaction with a functional substance, and the block (Y) serves as a hydrophobic block. Fulfill.

The block (Z) is composed of a poly (alkyleneimine) having an acyl group different from the acyl group of the block (Y), specifically, the following formula (3b).

<chemistry num="5"><img file="JP2005298542A_D0005.tif" /></chemistry>(In equation (3b), R₂'Is R in equation (2)₁Represents an acyl group different from the acyl group represented by, n₅, M₅Are each n₃, M₃Is similar to. ), The acyl group of the block (Y) and the acyl group of the block (Z), which has a strongly hydrophobic acyl group, play the role of a hydrophobic block. The remaining block acts as a block that has a reversible interaction with the functional substance.

Since it is preferable that the combination of the block (Y) and the block (Z) has different properties, the block (Z) is made of poly (alkyleneimine) having no acyl group. Can be preferably used. Further, even when the block (Z) has an acyl group, it is preferable that the properties of each block are clearly different.

A preferable example is shown below in the case where the block (Y) constituting the block copolymer of the present invention is the block represented by the above formula (2) and the block (Z) is the block represented by the above formula (3).

As described above, in the above equation (2), R₁Represents an acyl group, and in the above formula (3), R₂Is a hydrogen atom, or R in equation (2)₁It represents an acyl group different from the acyl group represented by, and is a block (Z) that can play a role as a hydrophobic block or a block that can interact with a functional substance, respectively, and each role is as described above. (2) Medium, R₁And in the above equation (3), R₂It depends on the combination with. However, in the above formula (3), R₂When is a hydrogen atom, the above formula (2) serves as a hydrophobic block, and the above formula (3) serves as a block capable of interacting with a functional substance.

To explain the preferable relationship between (Y) and (Z) among general combinations, R in the above equation (3)₂And R in the above equation (2)₁The relationship with R in the above equation (2)₁It can be mentioned that the hydrophobic property of is stronger. For example, R in the above equation (3)₂When is a hydrogen atom, R in the above equation (2)₁Is often an acyl group having 3 or more carbon atoms, and the block (Y) represented by the above formula (2) is a hydrophobic block and the block (Z) represented by the above formula (3). ) Should be a block that can interact with the functional substance.

To give a more detailed combination of (Y) and (Z), R in the above equation (2)₁And R in the above equation (3)₂In combination with R₁/ R₂Is a combination of an acyl group / hydrogen atom with 3 or more carbon atoms, a formyl group, or an acetyl group, R₁/ R₂Or R₂/ R₁Is either a propionyl group / acyl group with 4 or more carbon atoms, a saturated aliphatic acyl group or an unsaturated aliphatic acyl group / aromatic acyl group, or a combination of a non-fluorinated acyl group / an acyl group having fluorine. Preferably, R₁/ R₂Is particularly preferably a combination of an acyl group / hydrogen atom, a formyl group, or an acetyl group having 3 or more carbon atoms.

n₂, N₃The preferred range for is 2 or 3. It is desirable to control the properties of block (Y) and block (Z) by changing the type of each acyl group. n₂, N₃If the range of is too large, the influence of the alkyleneimine moiety, which is the main chain, becomes stronger than the influence of the properties of the acyl group, so that the properties of the block cannot be controlled even if the type of the acyl group is changed. Is a concern.

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, etc., and is generally m.₁, M₂And m₃Is preferably an integer in the range of 5 to 10000, preferably 5 to 1000, respectively. And m₁, M₂And m₃The value of is very important and must be determined to maintain dispersion stability in the solvent without depending on the morphological changes of the polymeric micelles before and after immobilization or release of the functional material. is there. In other words, it is a value that should be set according to the application, purpose, type of R, type of functional substance to be immobilized, etc., and if it indicates a generally conceivable range, m₁: m₂: m₃= 100: 1 ~ 10000: 1 ~ 10000 can be considered preferable.

In the block copolymer of the present invention, the order of the binary block copolymer consisting of two components in which the block (Y) and the block (Z) are directly bonded to the block (X) is, for example, (YZ), (ZY), ( YZY), (ZYZ) and the like are bonded, and it is particularly preferable that the binary block copolymer represented by (YZ) and (ZY) is bonded to the block (X).

Among such block copolymers, the general formula (i) X (YZ)_p1, Or X (ZY)_p2, (I) (X in the formula is a block (X) made of polyalkylene ether, Y is a block made of poly (N-acylalkyleneimine) having an acyl group having 3 or more carbon atoms (Y), said block (Y). ) Represents a block (Z) composed of a poly (alkyleneimine) having an acyl group different from the acyl group or a poly (alkyleneimine) having no acyl group, and the number average degree of polymerization of each block is 5 independently. In the range of ~ 10000, p₁, P₂Represents an integer of 1 or 2. ) Can be preferably used because the block copolymer represented by) can efficiently express the functions of each block.

Among the block copolymers represented by the above formula (i), p₁Or p₂Triblock copolymers of 1, especially the following equation (4)

<chemistry num="6"><img file="JP2005298542A_D0006.tif" /></chemistry>

Or the following formula (5)

<chemistry num="7"><img file="JP2005298542A_D0007.tif" /></chemistry>(In equations (4) and (5), n₁, M₁Is n in equation (1)₁, M₁Similar to R₁, N₂, M₂Is R in equation (2)₁, N₂, M₂Similar to n₄, M₄Is n in equation (3a)₄, M₄Is similar to. )

Or, the following formula (6)

<chemistry num="8"><img file="JP2005298542A_D0008.tif" /></chemistry>

Or, the following formula (7)

<chemistry num="9"><img file="JP2005298542A_D0009.tif" /></chemistry>(In equations (6) and (7), n₁, M₁Is n in equation (1)₁, M₁Similar to R₁, N₂, M₂Is R in equation (2)₁, N₂, M₂Similar to R₂', n₅, M₅Is R in equation (3b)₂', n₅, M₅Is similar to. ) Is preferable because the degree of polymerization of each block can be controlled more precisely and the polymer micelles having a more uniform grain system can be produced.

Next, a method for producing the block copolymer of the present invention will be described. In the method for producing a block copolymer of the present invention, a cyclic imino ether monomer (b) is subjected to living cationic polymerization on a polyalkylene ether derivative having a halogen atom or a sulfonic acid ester group at one end or both ends of the polyalkylene ether (a). Then, a cyclic imino ether monomer (c) different from the cyclic imino ether monomer (b) is cationically polymerized. The block copolymer obtained is a polyalkylene ether block (A), a poly (N-acylalkyleneimine) block (B), and a poly (B) having an acyl group different from that of the poly (N-acylalkyleneimine) block (B). It consists of N-acylalkyleneimine) block (C).

The polyalkylene ether (a) used in the production method of the present invention is a polyalkylene ether block (A) in the obtained block polymer, and is also used as an initiator for living cationic polymerization. As the polyalkylene ether (a), for example, polyethylene glycol, polypropylene glycol or the like can be used, and the polyalkylene ether block (A) provided by the polyalkylene ether (a) is the block copolymer of the present invention described above. It corresponds to the block (X) inside.

In the production method of the present invention, the polyalkylene ether (a) is used as a polyalkylene ether derivative having a halogen atom or a sulfonic acid ester group at one end or both ends thereof. As the halogen contained in the polyalkylene ether derivative at one end or both ends, a chlorine atom, a bromine atom, an iodine atom and the like can be mentioned as preferable examples. 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, and a 2-nitrobenzenesulfonic acid ester group. Examples thereof include 2,4-dinitrobenzene sulfonic acid ester groups. Of these, the sulfonic acid ester group is preferable because it has a high ability to initiate cationic polymerization, and the p-toluenesulfonic acid ester group is particularly preferable.

As the polyalkylene ether derivative having a halogen or sulfonic acid ester group at one end or both ends, a commercially available compound may be used as it is, after treatment such as purification, or the polyalkylene ether terminal. There is no problem even if a compound obtained by synthesizing a halogen or a polyalkylene ether having a sulfonic acid ester group by treating the hydroxyl group of the above by a reaction is used.

The method for synthesizing a polyalkylene ether having a halogen or a sulfonic acid ester group by treating the hydroxyl group at the terminal of the polyalkylene ether by a reaction may be carried out by any known and commonly used method. To exemplify the case of using polyethylene glycol, polyethylene glycol having a hydroxyl group at one end is dissolved in chloroform, and the same amount of pyridine as the hydroxyl group is added. While stirring this in a nitrogen atmosphere, a chloroform solution in which p-toluenesulfonic acid chloride is dissolved is slowly added dropwise while cooling. After the heat generation has subsided, the temperature is raised to 40 ° C and the reaction is carried out for 4 hours. The reaction solution is washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate solution, and water, and then dried over sodium sulfate. The obtained chloroform solution is concentrated, added dropwise to a large amount of hexane, and precipitated. By vacuum drying this, polyethylene glycol having a p-toluenesulfonic acid ester group at one end can be synthesized.

Further, when the polyalkylene ether derivative has a halogen atom or a sulfonic acid ester group at only one end, the other one end may have a structure that does not lose the hydrophilicity of the polyalkylene ether (a). For example, a structure such as a hydrogen atom, a methyl group, or an ethyl group is preferable.

In the production method of the present invention, the cyclic imino ether monomer (b) and the cyclic imino ether monomer (c) are different from each other. The cyclic imino ether monomer (b) and the cyclic imino ether monomer (c) are cationically polymerized to form a poly (N-acylalkyleneimine) block (B) and a poly (N-acylalkyleneimine) block (N-acylalkyleneimine). C).

As the cyclic imino ether monomer (b) and the cyclic imino ether monomer (c), known and commonly used ones can be used without any problem. Of these, an oxazoline monomer and an oxazoline monomer can be preferably used, and examples of these monomers include poly (N-formylalkyleneimine) such as 2-oxazoline, 2-oxazoline, 2-methyl-2-methyloxazoline and 2-methyl-2-oxazine. ) Or a monomer that gives a poly (N-acylalkyleneimine) having an acyl group having 2 or less carbon atoms, such as poly (N-acetylalkyleneimine).

Monomers that give poly (N-acylalkyleneimine) having an acyl group having 3 or more carbon atoms, such as 2-ethyl-2-oxazoline and 2-ethyl-2-oxazine.

2-propyl-2-oxazoline, 2-propyl-2-oxazoline, 2-isopropyl-2-oxazoline, 2-isopropyl-2-oxazoline, 2- (t-butyl) -2-oxazoline, 2- (t-butyl) ) -2-Oxazoline, 2-Undecyl-2-oxazoline, 2-Undecyl-2-oxazoline, 2-Heptadecyl-2-oxazoline, 2-Heptadecyl-2-oxazoline and other 2-alkyl-2-oxazolines or 2 -Alkyl-2-oxazolines, 2-vinyl-2-oxazolines, 2-vinyl-2-oxazolines, 2- (2-propenyl) -2-oxazolines, 2- (2-propenyl) -2-oxazolines, 2- Allyl-2-oxazoline, 2-allyl-2-oxazoline, 2-α-methylvinyl-2-oxazoline, 2-α-methylvinyl-2-oxazoline, 2- (9-heptadecenyl) -2-oxazoline, 2- Gives poly (N-acylalkyleneimine) having an acyl group having 4 or more carbon atoms such as 2-aryl-2-oxazolines such as (9-heptadecenyl) -2-oxazoline or 2-aryl-2-oxazolines. monomer,

Cyclic imino ethers that provide poly (N-acylalkyleneimine) having a fluorine-containing acyl group such as 2- (2-perfluorooctylethyl) -2-oxazoline and 2- (2-perfluorooctylethyl) -2-oxazine. monomer,

2-Phenyl-2-oxazoline, 2-phenyl-2-oxazoline, 2-tolyl-2-oxazoline, 2-tolyl-2-oxazoline, 2-naphthyloxazoline, 2-naphthyloxazine, 2-styryl-2-oxazoline, Examples include a monomer that gives a poly (N-acylalkyleneimine) having an aromatic acyl group such as 2-styryl-2-oxazine.

In the production method of the present invention, two types of cyclic imino ether monomers as exemplified above are used as the cyclic imino ether monomer (b) and the cyclic imino ether monomer (c), respectively, and each cyclic imino ether monomer is used. , The above-mentioned polyalkylene ether derivative is subjected to living cationic polymerization to form poly (N-acylethyleneimine) blocks (B) and (C). Here, a cyclic imino ether monomer that imparts a poly (N-acylalkyleneimine) block having an acyl group having 3 or more carbon atoms to at least one of the cyclic imino ether monomers (b) and (c) to be used is used. By doing so, the block copolymer of the present invention described above can be obtained. At this time, when a cyclic iminoether monomer that gives a poly (N-acylalkyleneimine) block having an acyl group having 3 or more carbon atoms is used as the cyclic iminoether monomer (b), poly (N-acylalkyleneimine) is used. Cyclic imine ether monomer which corresponds to the block (Y) in the block copolymer of the present invention described above and provides a poly (N-acylalkyleneimine) block having an acyl group having 3 or more carbon atoms. Is used as the cyclic iminoether monomer (c), the poly (N-acylalkyleneimine) block (C) corresponds to the block (Y) in the block copolymer of the present invention described above. If any of the cyclic iminoether monomers used is a cyclic iminoether monomer that provides a poly (N-acylalkyleneimine) block having an acyl group having 3 or more carbon atoms, the resulting poly (N-acylalkyleneimine) is obtained. Imine) Either block (B) or (C) may be block (Y).

As a combination of the cyclic imino ether monomers (b) and (c), the obtained poly (N-acylalkyleneimine) blocks (B) and (C) can interact with the hydrophobic block or the functional substance, respectively. A combination that can preferably play a role as a block, that is, a combination that satisfies the above-mentioned relationship between the block (Y) and the block (Z) of the block polymer of the present invention is preferable. Further, a combination capable of easily hydrolyzing either one of the obtained poly (N-acylalkyleneimine) blocks (B) and (C) is also suitable.

As an example of a specific preferable combination, a monomer giving a poly (N-acylalkyleneimine) having an acyl group having 3 or more carbon atoms and a poly (N-formylalkyleneimine) or a poly (N-acetylalkyleneimine) are given. Combination with a monomer, a monomer giving a poly (N-acylalkyleneimine) having an acyl group having 4 or more carbon atoms and (C) a monomer giving a poly (N-propionylalkyleneimine), an aromatic acyl group or A combination of a monomer giving a poly (N-acylalkyleneimine) having a fluorine-containing acyl group and a monomer giving a poly (N-acylalkyleneimine) having a saturated aliphatic acyl group or an unsaturated aliphatic acyl group, containing fluorine Examples thereof include a combination of a monomer giving a poly (N-acylalkyleneimine) having an acyl group and a monomer giving a poly (N-acylalkyleneimine) having an aromatic acyl group. Further, the combination of the monomers shown above may be a cyclic imino ether monomer (b) or a cyclic imino ether monomer (c).

Next, the method of cationic polymerization will be described in detail. Using the above-mentioned polyalkylene ether derivative as an initiator, the cyclic imino ether monomer (b) is subjected to living cationic polymerization to form a polyalkylene ether block (A) and a poly (N-acylalkyleneimine) block (B). Synthesize the diblock copolymer. 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. Examples include acetonitrile, cyanobenzene, phenylacetonitrile, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP) and the like. The amount of poly (N-acylalkyleneimine) (b) relative to the polyalkylene ether derivative is such that the cyclic imino ether monomer is 1 to 10000 mol when the degree of polymerization of the alkylene ether unit in the polyalkylene ether is 100. Is desirable.

As described above, in order for the polymer micelles formed by the block copolymer of the present invention to maintain high dispersion stability in solution, the composition ratio of each block is an important factor, and the composition ratio is the functional substance to be introduced or , It is known that it is strongly affected by the solvent to be dispersed. That is, the amount of the cyclic imino ether monomer to be added must be determined in consideration of the balance with the degree of polymerization of the hydrophobic block described later. Polymerization is possible at a polymerization reaction temperature of 40 ° C or higher, but considering the shortening of the polymerization time, the type of polymerization solvent, and the fact that side reactions do not occur, 60 is used for low boiling point solvents such as acetonitrile. In the case of a high boiling point solvent having a boiling point of more than 140 ° C and up to 80 ° C, the reaction is preferably carried out at 80 to 140 ° C.

Specific examples of the living cationic polymerization method are shown below. Attach a three-way cock to one of the two-necked flask containing the stir bar, and seal the other with a stopper. The inside of the flask is degassed under reduced pressure and replaced with nitrogen. As the gas that can be used here, an inert gas is generally used, and nitrogen gas, argon gas and the like are preferable. Using a syringe, the above-mentioned aprotic solvent such as N, N-dimethylacetamide and 2-phenyl-2-oxazoline (POZ) are put into the flask from a three-way cock. Open the stopper while overflowing the nitrogen gas, and add polyethylene glycol having p-toluenesulfonylated at one end. The flask is sealed and reacted at 100 ° C for 48 hours while stirring in an oil bath.

After this, a case where a cyclic iminoether monomer different from 2-phenyl-2-oxazoline, which is a cyclic iminoether monomer already living-cationically polymerized, for example, 2-methyl-2-oxazoline (MOZ) is cationically copolymerized is described below. As described above, the diblock copolymer obtained may be purified before that, or cation copolymerization may be continued as it is without any problem. When performing purification treatment, care must be taken because the p-toluenesulfonyl group at the end of the diblock copolymer will be removed if the treatment is performed with a strong acid or strong base. Any known and conventional treatment method that does not dissociate the other terminal p-toluenesulfonyl group can be used without any problem.

Specifically, polyethylene glycol (PEG), poly (N-benzoylethyleneimine) (PBEI) diblock copolymer, and 2-methyl, which is a cyclic iminoether monomer different from 2-phenyl-2-oxazoline. The living cation copolymerization reaction of -2-oxazoline can be reacted in the same manner as the living cation polymerization described above, whereby polyethylene glycol block, poly (N-benzoylethyleneimine) block, and poly (N-acetylethylene) can be reacted. A triblock copolymer consisting of an imine) (PAEI) block is obtained. To show a specific example of the case where 2-methyl-2-oxazoline is continuously cationically polymerized after the above-mentioned living cationic polymerization reaction is completed, the flask in the completed reaction state is cooled to room temperature, and the nitrogen gas line is laid on three sides. Attach to one of the cocks and add 2-methyl-2-oxazoline into the flask from the three-way cock using a syringe while gently flowing nitrogen gas. At this time, N, N-dimethylacetamide may be added as needed. When adding, add with a syringe from a three-way cock while gently flowing nitrogen gas in the same manner. Then, the nitrogen gas is stopped, the flask is closed tightly, and the reaction is carried out at 100 ° C. for 96 hours while stirring in an oil bath. The reaction time varies depending on the concentration of the polymer and the monomer, the reaction temperature, etc., but in the latter half of the living cation copolymerization reaction, the clay of the polymerization reaction solution increases, and so on, the reaction is generally carried out for a long time.

According to the method described above, the polyalkylene ether block (A), the poly (N-acylalkyleneimine) block (B), and the poly having an acyl group different from that of the poly (N-acylalkyleneimine) block (B). A block copolymer composed of a (N-acylalkyleneimine) block (C) can be obtained. As described above, each block of the block copolymer is a poly having an acyl group different from the block (X), the block (Y), or the block (Y) of the block (Z) in the block copolymer of the present invention. It corresponds to the (alkyleneimine) block.

In the block copolymer of the present invention, the block copolymer in which the block (Z) is a poly (alkyleneimine) block having an acyl group different from that of the block (Y) can be produced by the above method. Next, a method for producing a block copolymer in which the block (Z) is a block (Z) made of poly (alkyleneimine) having no acyl group will be described.

The production method comprises a polyalkylene ether block (A), a poly (N-acylalkyleneimine) block (B), and a poly (B) having an acyl group different from that of the poly (N-acylalkyleneimine) block (B). After obtaining a block copolymer composed of an N-acylalkyleneimine block (C) by the above-mentioned production method, the poly (N-acylalkyleneimine) block (B) or the poly (N-acylalkyleneimine) block (N-acylalkyleneimine) block ( The acyl group in any of the blocks of C) is selectively hydrolyzed to obtain a poly (alkyleneimine) block (D).

In the method for producing a block copolymer of the present invention, the block that is selectively hydrolyzed to form a poly (alkyleneimine) block is the block (B) or (C) having a stronger hydrophilicity of the acyl group, or It is the block with weaker hydrophobicity, and as described above, which block is hydrolyzed differs depending on the combination of (B) and (C). For example, if the acyl group of the block (B) is more hydrophobic, the block (B) is not hydrolyzed and the block (C) is selectively hydrolyzed to the poly (alkyleneimine) block (D). Become. The block (D) is a block corresponding to a poly (alkyleneimine) block having no acyl group among the blocks (Z) in the block copolymer of the present invention.

In the method for producing block copolymers of the present invention, the selectivity of hydrolysis changes depending on the difference in hydrophilicity or hydrophobicity of each acyl group of blocks (B) and (C). .. There is no particular problem even if the difference is small. The acyl group with the stronger hydrophilicity or the weaker hydrophobicity is hydrolyzed. If the difference is small, some of the acyl groups of the non-hydrolyzable block acyl groups may be hydrolyzed, but this may interfere with the functions of the block copolymer and the dispersion stability of the polymer micelles formed. There is nothing to do. It is preferable to use a combination in which the difference in hydrophilic strength or the difference in hydrophobic strength of each acyl group of the block (B) and the block (C) is large. Examples of preferred acyl group combinations are formyl groups, or combinations of acetyl groups with acyl groups with 3 or more carbon atoms, propionyl groups with acyl groups with 4 or more carbon atoms, saturated aliphatic acyl groups or Examples thereof include a combination of an unsaturated aliphatic acyl group and an aromatic acyl group or an acyl group having fluorine, or a combination of an aromatic acyl group and an acyl group having fluorine.

When hydrolysis is carried out in the method for producing a block copolymer of the present invention, the obtained block copolymer may be hydrolyzed as it is, but in order to avoid side reactions during the hydrolysis reaction, the block copolymer is purified. It is preferable to do so. As the purification method, a known and commonly used method can be used, and the purification method is not particularly limited. As an example, the reaction solution is added dropwise to a mixed solvent of ethyl acetate and hexane with stirring, and the resulting precipitate is filtered. The precipitate is dissolved and dispersed in a small amount of methanol, and again added dropwise and reprecipitated in a mixed solvent of ethyl acetate and hexane with stirring. This is a method for obtaining a purified product by filtering the precipitate and vacuum-drying it.

Specifically, the poly (N-acetyl) of a block copolymer composed of the polyethylene glycol block, the poly (N-benzoylethyleneimine) block, and the poly (N-acetylethyleneimine) block obtained as described above. The method of selectively hydrolyzing the acetyl group of the (ethyleneimine) block to synthesize a triblock copolymer having a poly (ethyleneimine) block can be carried out without any problem as long as it is a method used as a known and commonly used hydrolysis reaction. be able to. Generally, an acid hydrolysis reaction or an alkali hydrolysis reaction can be mentioned, but a hydrolysis reaction using an enzyme or the like can also be used. Importantly, as described above, this hydrolysis reaction selectively combines one selected block of triblock copolymer with a poly (ethyleneimine) block without interfering with the hydrophilic and hydrophobic segments on both sides. I have something to do.

Further, when selectively hydrolyzing one of the blocks (B) and (C), either one of (B) or (C) in the block copolymer before hydrolysis is used. It is preferable to use 1 to 20 times the molar amount of hydrochloric acid with respect to the degree of polymerization of the N-acylalkyleneimine unit of the block to be selectively hydrolyzed.

For example, in the block copolymer composed of the polyethylene glycol block, the poly (N-benzoylethyleneimine) block, and the poly (N-acetylethyleneimine) block described above, the poly (N-acetylethyleneimine) block The triblock copolymer was mixed in a 2.5N hydrochloric acid aqueous solution containing 3 times the degree of polymerization of the N-acetylethyleneimine unit, dispersed in an ultrasonic washer for 1 hour, and then dispersed at 90 ° C for 15 hours. React for time. After cooling, add to a large amount of acetone with stirring. The triblock copolymer of the present invention can be obtained by filtering the produced precipitate, dissolving it in water, adding it to acetone again with stirring, reprecipitating it, filtering it, and vacuum-drying it.

According to the above-mentioned production method of the present invention, a block copolymer having a hydrophilic block, a hydrophobic block, and a block capable of interacting with a functional substance can be easily obtained by a known conventional polymerization method and a hydrolysis reaction. It can be manufactured.

Since the block copolymer of the present invention has a hydrophilic block and a hydrophobic block in addition to a block that can interact with a functional substance, it self-organizes polymer micelles when dispersed in a solvent such as water. can do. For example, p-toluenesulfonylated polyethylene glycol and 2-methyl-2-oxazoline were living-cationically polymerized, and then a triblock copolymer was obtained by cation-copolymerizing 2-phenyl-2-oxazoline to synthesize a central poly (N-acetyl). When a triblock copolymer composed of a polyethylene glycol block, a poly (ethyleneimine) (PEI) block, and a poly (N-benzoylethyleneimine) block obtained by hydrolyzing an ethyleneimine) block with hydrochloric acid is dispersed in water, the result is described. The triblock copolymer self-assembles to form the following polymeric micelles. The triblock copolymer has a poly (N-benzoylethyleneimine) block, which is a hydrophobic block, as a core, a poly (ethyleneimine) block, which is a block capable of interacting with a functional substance, as an intermediate layer, and a hydrophilic block. A certain polyethylene glycol block forms a core-corona type polymer micelle in which the molecular chain is sufficiently expanded in water to form a corona layer capable of free molecular movement, so that high dispersion stability in water is achieved. It becomes possible to hold.

The block that can interact with the functional substance of the block copolymer of the present invention is (Y) or (Z), and the acyl group of (Y) or (Z) has a strong hydrophilicity or a weak hydrophobicity. Acts as a block that can interact with functional substances. One example is that the oxygen of the acetyl group of the poly (N-acetylalkyleneimine) block interacts with the metal. When combined with poly (N-benzoylalkyleneimine) as a hydrophobic block, the metal does not interact with the oxygen of the benzoyl group in that combination. That is, in the block copolymer, a block made of polyalkylene ether serves as a hydrophilic block, poly (N-acetylalkyleneimine) serves as a block that interacts with a metal, and poly (N-benzoylalkyleneimine) serves as a hydrophobic block. Can be fulfilled independently.

Further, when the block (Z) capable of interacting with the functional substance of the block copolymer of the present invention is a poly (alkyleneimine) having no acyl group, it interacts with the ionic functional substance. For example, DNA, ionic dyes, metal ions and the like. When these ionic functional substances are immobilized on the block by ionic bonding, the block crystallizes. However, as described above, polyalkylene ether can play a role as a hydrophilic block and poly (N-acylalkyleneimine) can play a role as a hydrophobic block independently, so that the dispersion stability in the system may deteriorate. Absent.

Normally, when a functional substance such as DNA, metal, or dye forms a polymer micelle with a polymer having interactable blocks, the functional substance is immobilized in or released from the block copolymer. At that time, the block capable of interacting with the functional substance is contained in the polymer micelle, for example, the block crystallizes when the functional substance is immobilized, or does not form a crystal due to the release of the functional substance. Morphology changes. However, since the triblock copolymer of the present invention has a hydrophilic segment and a hydrophobic segment that are factors that determine dispersion stability in a solvent, in addition to a block that can interact with a functional substance, the block. Polymeric micelles composed of copolymers can maintain excellent dispersion stability in solution regardless of such morphological changes.

Further, since the block polymer of the present invention has a block capable of interacting with a functional substance, a functional substance such as DNA, a metal, or a dye can be fixed to the block, and therefore these functional substances are fixed inside. It is possible to form polymer micelles. Therefore, the polymer micelle made of the block 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, photolithography materials and the like.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

(Example 1) [Tosylation reaction of polyethylene glycol]

Put magnetic stirrer in a 100 ml three-necked eggplant flask, and weigh 10 g (ethylene glycol unit (hereinafter abbreviated as EG): 5.1 mmol) of polyethylene glycol monomethyl ether (hereinafter abbreviated as PEGM) having a number average molecular weight (Mn) of about 2000. After taking and dissolving by adding 15 g of chloroform, 4 g (51 mmol) of pyridine was added and stirred. The flask was equipped with an introduction pipe for introducing nitrogen gas and an exhaust pipe for exhausting gas, and the remaining mouth was plugged together. Separately, 4.9 g (25.5 mmol) of tosyl loride was weighed in an Erlenmeyer flask, and 15 g of chloroform was added and dissolved.

A chloroform solution of tosyl lolide was added dropwise while stirring a three-necked eggplant flask containing PEGM or the like in an ice bath. After the dropping, it was confirmed that the exotherm had subsided, the temperature was raised to 40 ° C, and the reaction was carried out for 4 hours. After completion of the reaction, 30 g of chloroform was added to dilute the mixture, and the mixture was transferred to a separating funnel. Then, the chloroform solution was washed twice with 300 g of 2.5 N HCl aqueous solution, twice with 300 g of 10% sodium hydrogen carbonate aqueous solution, and twice with 300 g of water. The obtained chloroform solution was dried over sodium sulfate, filtered, and then concentrated on an evaporator. This was added to hexane with stirring to precipitate and vacuum dried at room temperature for 15 hours. The yield was 81%.¹Each peak was assigned from the H-NMR spectrum, and it was confirmed that the compound was the target compound. (2.4ppm: methyl group in tosyl group, 3.3ppm: methyl group at PEGM terminal, 3.6ppm: EG chain of PEG, 7.3 ~ 7.8ppm: benzene ring in tosyl group)

[Living cationic polymerization]

A magnetic stirrer was placed in a two-necked eggplant flask, and a three-way cock and a co-plug were attached to close the flask, and vacuum degassing was repeated to sufficiently replace the inside with nitrogen. Weigh 1.5 g (EG unit: 34 mmol) of the above-mentioned tosylated polyethylene glycol (hereinafter abbreviated as PEG-Ts), open the stopper, quickly put the weighed PEG-Ts into the flask, and then put nitrogen again. Substitution was performed. Next, using a syringe, 3 ml (34 mmol) of methyloxazoline (hereinafter abbreviated as MOZ) and 30 ml of N, N-dimethylacetamide (hereinafter abbreviated as DMA) were added into the flask while flowing nitrogen gas from a three-way cock. .. After sealing, the mixture was stirred in an oil bath at 100 ° C for 22 hours. After cooling, 4.7 g (34 mmol) of phenyloxazoline (hereinafter abbreviated as POZ) was added into the flask using a syringe while flowing nitrogen gas from the three-way cock. After sealing, the mixture was stirred in an oil bath at 100 ° C. for 111 hours. After cooling, the obtained reaction solution was added to a mixed solvent of 150 g of ethyl acetate and 150 g of hexane with stirring, and precipitated. The precipitate adhering to the wall of the vessel was separated by decantation and dissolved in 15 g of methanol. This was added to a mixed solvent of 350 g of ethyl acetate and 350 g of hexane with stirring, and reprecipitated. The dispersed reprecipitates were filtered and vacuum dried at 80 ° C. The yield was 89%.¹Each peak was assigned by 1 H-NMR spectrum, and the structure of the product was confirmed (2.1 ppm: PAEI acetyl group, 3.6 ppm: PEG, 7.0 to 7.7 ppm: PBEI benzoyl group). From this, the obtained product was a PEG-PAEI-PBEI triblock copolymer, and the composition of each block was PEG: PAEI: PBEI = 31: 32: 37.

(Example 2) [Acid hydrolysis reaction]

1.7 g of PEG-PAEI-PBEI triblock copolymer synthesized as in Example 1 (acetylethyleneimine unit (hereinafter abbreviated as AEI): 5.7 mmol) was weighed in a 100 ml eggplant flask, and 3.5 g of a 5N HCl aqueous solution (HCl: 17.1 mmol) was added, a magnetic stirrer was added, and the flask was stoppered. After treating with an ultrasonic cleaner for 1 hour to disperse, the mixture was stirred at 90 ° C for 10 hours. After cooling, the reaction solution was added to 200 g of acetone with stirring. The resulting precipitate was filtered and dissolved in 10 g of water. It was added again to 200 g of acetone with stirring, reprecipitated, and filtered. Vacuum dried at 60 ° C to give the desired PEG-PEI-PBEI triblock copolymer. The yield was 90%. Each peak was assigned by 1H-NMR spectrum, and the structure of the product was confirmed, such as the disappearance of the peak derived from the acetyl group at 2.1 ppm. The product obtained was a PEG-PAEI-PBEI triblock copolymer. The composition of each block is such that a 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 after 8 hours, the water is replaced again. , Ethanol was added to the aqueous solution in the dialysis tube, the solvent was distilled off with an evaporator, and the sample was vacuum-dried at 70 ° C for 15 hours.¹Obtained from 1 H-NMR spectrum. It was PEG: PEI: PBEI = 29: 32: 39. Samples dialyzed against ammonia water¹Explaining each peak of the H-NMR spectrum, it is 2.2 ppm: PEI, 2.8 ppm: PEG, 3.0 to 3.7 ppm: ethyleneimine of PBEI, and 7.0 to 7.7 ppm: benzoyl group of PBEI.

(Example 3) [Living cationic polymerization]

In the method shown in Example 1, 1.5 g of PEG-Ts, 3 ml of MOZ, and 30 ml of DMA were added to the flask, and the mixture was stirred at 100 ° C for 22 hours, then 4.7 g of POZ was added and stirred at 100 ° C for 111 hours. Instead, add 1.5 g of PEG-Ts (EG unit: 34 mmol), 4.7 g of POZ (34 mmol), and 30 ml of DMA to the flask, stir at 100 ° C for 22 hours, add 3 ml of MOZ (34 mmol), and add 3 ml of MOZ (34 mmol) for 105 hours at 100 ° C. Except for stirring, the procedure was exactly the same as in Example 1. Yield 93%.¹Each peak was assigned by the H-NMR spectrum in the same manner as in Example 1, and the structure of the product was confirmed. The product obtained was a PEG-PBEI-PAEI triblock copolymer, and the composition of each block was PEG: PBEI: PAEI = 30: 38: 32.

(Example 4) [Acid hydrolysis reaction]

In the method shown in Example 2, 1.7 g of the PEG-PAEI-PBEI triblock copolymer was weighed, and instead of adding 3.5 g of the 5N HCl aqueous solution, 1.7 g of the PEG-PBEI-PAEI triblock copolymer synthesized in Example 3 was added. The procedure was exactly the same as in Example 2 except that g (AEI: 5.7 mmol) was weighed and 3.5 g (HCl: 17.1 mmol) of a 5N HCl aqueous solution was added. Yield is 80%,¹Each peak was assigned by the H-NMR spectrum in the same manner as in Example 2, and the structure of the product was confirmed. The product obtained was a PEG-PBEI-PEI triblock copolymer, and the composition of each block obtained by treating with aqueous ammonia was PEG: PBEI: PEI = 29: 39: 32.

(Application Example 1) 2.0 mg of the PEG-PEI-PBEI triblock copolymer obtained in Example 2 was dispersed in 5 g of water, and the mixture was stirred with a magnetic stirrer for 1 hour in an oil bath at 80 ° C. Treated in a washer for 1 hour. After standing for 24 hours, the particle size was measured. The number average particle size was 40 nm. The particle size was measured by a dynamic light scattering method using a Microtrac UPA150 manufactured by Nikkiso Co., Ltd.

(Application Example 2) In the above PEG-PEI-PBEI triblock copolymer dispersion aqueous solution, the dye tetraphenylporphyrin-sodium tetrasulfonate (hereinafter abbreviated as TSPP) 0.7 mg (TSPP (mol) / EI unit (mol) = 1/10) was added, and the mixture was stirred at room temperature for 24 hours using a magnetic stirrer. The dispersed aqueous solution was placed in a dialysis tube (SPECTRUM Spectra / Por; MWCO: 3500) and dialyzed in water. Water was changed 3 times every 8 hours. After allowing the dispersed aqueous solution to stand for 24 hours from the dialysis tube, the particle size was measured and found that the number average particle size was 30 nm.