JP6872216B2 - Hydrophilic polymer having iminodiacetic acid in the side chain and its use - Google Patents

Description

The present invention relates to a hydrophilic polymer having a chelating ability and its use, specifically, a complex or complex with a polyvalent metal ion or a boric acid derivative, and use of the complex or complex in the medical field. ..

Metal ions are expected in imaging such as MRI, PET, and Spec, and iron, Gd, and the like have already been used as contrast agents for MRI. Platinum is also an anticancer drug as cisplatin. Recently, anticancer agents have been developed by the Fenton reaction using divalent iron and divalent ruthenium. In addition, boron is in the stage of being clinically tested as neutron capture therapy (BNCT), which accumulates in tumors and kills cancer by a nuclear reaction with thermal neutrons. These boron and metal ions reduce their inherent toxicity by chelation with chelate molecules, etc., and take advantage of their higher uptake ability into tumors than those of normal cells to significantly incorporate them and exert their effects. There is.

However, since this kind of low molecular weight substance diffuses to normal cells to some extent, strong side effects become a problem. Therefore, although there are attempts to improve the therapeutic effect by encapsulating ferrocene in nanoparticles, immobilization of ferrocene by a physical trap causes leakage, which is far from solving the problem (see Non-Patent Document 1). In some cases, cisplatin is supported on the carboxyl group of a polyethylene glycol-b-polyglutamic acid (PEG-b-PGlu) block copolymer and made into nanoparticles to improve the anticancer effect (Non-Patent Document 2). .. However, the stability is not always perfect because the platinum metal is supported on the weak acid carboxylic acid.

On the other hand, vinylphenyl aliphatic carboxylic acid (N- (ar-vinylbenzyl) iminodiacetic acid, etc.) has been proposed as a chelating agent (Patent Document 1). In addition, by utilizing the stable complex-forming ability of iminodiacetic acid for polyvalent metal ions, a heavy metal adsorbent in which iminodiacetic acid is chemically modified on the surface of a cellulose fiber or an iminodiacetic acid residue is incorporated into the molecule. Chelating polymer compounds have also been proposed (eg, WO 2010/122954 A1). Further, it is also known that it is used for silica / polymer composite type iminodiacetic acid-based chelate adsorbent, adsorption separation of heavy metals, and the like (for example, Patent Document 3).

US 2,840,603 WO 2010/122954 A1 JP 2014-25779

Seong-Cheol Park, et. al. , Journal of Controlled Release 221, 37-47 (2016) Nishiyama Nobuhiro, et. al. , Bioconjugate chemistry, 14 (2), 449-57 (2003)

The present inventors have designed a wide variety of hydrophilic polymers for the purpose of providing materials that can be used for anticancer agents nanomedicine and biosensing, rather than as adsorbents for heavy metals. In particular, a poly (ethylene glycol) segment is used as a hydrophilic polymer having a certain chelating ability capable of forming nanoparticles by self-assembling by reaction with a polyvalent metal ion or a boric acid derivative in an aqueous medium. And a poly (styrene derivative) segment, a copolymer containing a segment in which an iminodiacetic residue is incorporated in the side chain allows polyvalent metals, boron compounds, etc. to be easily and stably supported, and stable nanoparticles. Was found to form. Further, as far as the present inventor knows, such a copolymer is a polymer compound not described in the prior art literature. Furthermore, such copolymers are such that the complex or complex with a polyvalent metal ion or boric acid derivative is stable for a long period of time in a physiological environment, for example in the presence of serum, and is suitable for specific treatments and imaging. It was also confirmed that it could be applied.

Therefore, the present invention provides a copolymer and its use comprising a polymer segment having an aminodiacetate group introduced into the side chain and a polyethylene glycol) segment (sometimes referred to simply as PEG). Although not limited to, the inventions of the main aspects include those described in the following [1] to [8].
[1] A block copolymer comprising a poly (ethylene glycol ) segment and a poly [di (carboxymethyl) aminomethylstyrene] segment.
[2] The block copolymer according to [1], and the copolymer is represented by the following formula I.
Formula I:

During the ceremony
A represents an unsubstituted or substituted C ₁ -C ₁₂ al-kill, substituents when substituted, represents a formyl group or the formula R ₁ R ₂ CH- group, wherein, R ₁ and R ₂ independently C ₁ -C ₄ alkoxy or R ₁ and R ₂ are -OCH ₂ CH ₂ O together _{-, - O (CH 2)} 3 O- or -O (CH _{2) 4} O- and represent,
L is the formula

Selected from the groups represented by, or also bonded,-(CH ₂ ) _c S-, -CO (CH ₂ ) _c S-,-(CH ₂ ) _c NH-,-(CH ₂ ) _c CO Selected from the group consisting of −, −CO−, −OCOO−, −CONH− ,
The di (carboxymethyl) amino group in the formula is present at least in the total number of n, and if not present, the amino group can be an H, halogen atom or hydroxy group.
Y is H, SH or S (C = S) -Ph, where Ph represents phenyl which may be substituted with 1 or 2 methyls or methoxys.
b is an integer of 2 to 6
c is an integer from 1 to 5
m represents an integer of 2 to 10,000
n represents an integer of 2 to 500.
In the above definition of L, when there is a directionality, it is understood that it exists in the formula I with the stated directionality. Hereinafter, the same applies to formulas other than I.
[3] A complex of the copolymer according to [1] or [2] and a multivalent metal ion.
[4] One or 2 polyvalent metal ions selected from the group consisting of Ga (III), Gd (III), Cu (II), Fe (II), Mn (II) and Zn (II) ions. is the ion more kinds, complex according to [3].
[5] An ester-forming complex of the di (carboxymethyl) group of the copolymer according to [1] or [2] and phenylboronic acid.
[6] The complex or complex according to any one of [3] to [5], which exists as particles having an average particle size of nanometer size in an aqueous medium.
[7] A preparation for suppressing tumor growth, which is the complex according to [4] and contains a complex in which a metal ion is Fe (II) as an active ingredient.
[8] A preparation for suppressing tumor growth for use in neutron capture therapy, which comprises the complex according to [5] as an active ingredient.

In the present invention, a block copolymer containing a poly (ethylene glycol ) segment and a poly [di (carboxymethyl) aminomethylstyrene] segment is a stable complex or composite with various metal ions or boric acid derivatives in an aqueous medium. It was confirmed that body micelles or particles were formed, and that such complexes or complexes exhibited a tumor growth inhibitory effect. Therefore, new biomaterials useful at least in the medical field can be provided. Specifically, in this complex or complex (or chelate-type polymer compound), as shown in FIG. 1 as a schematic diagram, a material having a chelating ability is introduced as a polyanion, and various metal ions are chelated. It can be introduced by, and can be used for treatment and imaging. Further, phenylboronic acid and boric acid other than existing drugs such as borophenylalanine (BPA) can be easily and stably encapsulated via an ester bond, and can be expected as a drug for BNCT.

The conceptual diagram of the complex or composite of the block copolymer of this invention and a polyvalent metal ion or a boron compound. ¹ H-NMR spectrum of PEG-b-PAAMS (acidic) ¹ H-NMR spectrum of PEG-b-PECAMS ¹ H-NMR spectrum of PEG-b-PAAMS (neutral) Measurement results of dynamic light scattering of Fe (II) -containing PEG-b-PAAMS nanoparticles Photograph to replace the figure showing chelated nanoparticles encapsulating various ions Measurement results of particle size and scattering intensity related to the presence or absence of 10% serum of chelated nanoparticles encapsulating various ions Measurement results of dynamic light scattering of Mn (II) and Zn (II) -encapsulated nanoparticles ¹ H-NMR spectrum of phenylboronic acid-introduced PEG-b-PAAMS Measurement Results of Dynamic Light Scattering of PEG-b-PAAMS Boron Complex (ZA (d. Nm)) Cytotoxicity of PEG-b-PAAMS boron complex to HepG2 Tumor growth pattern by administration of chelated polymer to cancer-bearing mice Weight change pattern due to administration of chelated polymer to cancer-bearing mice Tumor growth inhibitory effect of Fe (II) -encapsulating nanoparticles (Fe (II) NP) -administered group Weight change pattern of Fe (II) -encapsulating nanoparticles (Fe (II) NP) -administered group Survival curve of Fe (II) -encapsulating nanoparticles (Fe (II) NP) -administered group Cytotoxicity of chelated polymers PEG-b-PAAMS and Fe (II) encapsulated nanoparticles (Fe (II) NP) Cytotoxicity in the presence or absence of hydrogen peroxide and Fe (II) -encapsulating nanoparticles (Fe (II) NP)

Detailed description of the invention

In the invention of the aspect [1], the block copolymer containing a poly (ethylene glycol ) segment and a poly [di (carboxymethyl) aminomethylstyrene] segment is polyvalent in an aqueous medium for the purpose of the present invention. Those capable of forming a complex with a metal or an ester with phenylboronic acid and forming nanoparticles by self-assembly are preferable. In the present specification, the aqueous medium refers to water (including filtered water, distilled water, reverse osmosis water, ion-exchanged water, tap water, etc.), physiological saline, buffered physiological saline, and the like. In addition, although the nanoparticles are not bound by theory, in the case of a complex, as shown in FIG. 1, the block copolymer is crosslinked by chelating via a polyvalent metal ion, and the poly [di (carboxy) is used. By forming a water-insoluble core derived from the [methyl) aminomethylstyrene] segment, while PEG forms a water-soluble or hydrophilic shell, the average particle size is several when measured by dynamic light scattering. It means polymeric micelle-like particles exhibiting nanometers to several hundreds of nanometers, generally 5 nm to 200 nm, preferably 10 to 100, more preferably 15 to 60. In the ester with phenylboronic acid, the hydrophilic group di (carboxymethyl) amino group is converted to a hydrophobic group, so that the polymer-like micelle is similar to the so-called hydrophilic-hydrophobic block copolymer. Is understood to form. Even in the latter case, the average particle size is not substantially different from that in the case of the complex.

In the invention of the aspect of [2], the copolymer represented by the formula I also has a complex with a polyvalent metal or an ester with phenylboronic acid in an aqueous medium in the same manner as described in the above [1]. Those capable of forming and self-assembling to form nanoparticles are preferred. The description of nanoparticles and others is the same as described in [1] above.

In formula I, with variable groups, abbreviations, etc., m is generally an integer of 2 to 10,000, preferably an integer of 12 to 5,000, more preferably an integer of 14 to 1,000, and even more. It can preferably be an integer of 20 to 400, where n is generally an integer of 2 to 500, preferably an integer of 4 to 100, more preferably an integer of 6 to 60, and even more preferably an integer of 6 to 30. Can be.

Y is generally hydrogen, SH or S (C = S) -Ph, and is converted from the latter two groups by a method well known in the art, as long as it is in line with the object of the present invention. It can also be another group or part.

Of the total number of n, there are at least 1, preferably 4, more preferably 6, and even more preferably 10 di (carboxymethyl) amino groups in the formula, and most preferably all of the total number of n is the amino group. If present, the amino group can be an H, halogen atom or hydroxy group, and at least one alkyl as a part of each of the above groups or groups is a straight chain or a branched chain. And, but not limited to, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, nonyl, undecyl, etc. be able to.

The copolymer represented by the formula I may be produced by any method. However, but not limited to, the formula described in WO 2009/133647 A1 or WO 2016/052463 A1 based on the disclosure of the present inventors, etc .:

In the formula, A, L, Y, m and n are synonymous with those defined for formula I, and X is a block copolymer represented by a halogen atom, particularly chlorine, bromine and iodine (particularly). When X is chlorine, it is abbreviated as PEG-PCMS below) and formula:

Iminodiacetic acid or its di-C _1-6 alkyl ester represented by is a non-reactive organic solvent in the presence of a hydrolyzate, an organic amine compound, ethyl diisopropylamine, etc., for example, dimethyl formamide (DMF). , Dioxane, dimethyl sulfoxide, etc., at a temperature from room temperature to the boiling point of the organic solvent for 5 to 24 hours, the latter can then be produced by hydrolyzing the ester.

Alternatively, in the method for producing, for example, PEG-PCMS described in WO 2009/133647 A1 or WO 2016/052463 A1, instead of chloromethylstyrene used as a starting material monomer, di (carboxymethyl) aminomethyl By using styrene, a copolymer of formula I can also be produced.

Inventions of Aspects [3]-[6] The complexes described in [3]-[6] are in an aqueous medium via chelation as shown in FIG. 1, as described for [2]. Those having an average particle size of nanometer-sized particles are preferable. Therefore, if the copolymer and the metal ion are contained in a proportion that causes such chelation, the proportion is not limited, but the total di (carboxy) in the copolymer. The copolymer and the metal ion are contained so that the methyl) amino group-to-metal ion is generally 4: 1, preferably 3: 1, and more preferably 2: 1. On the other hand, it is desirable that the complex contains a di (carboxymethyl) amino group to phenylboronic acid in a ratio of 1 to 2: 2 to 1, and at least a half ester bond is formed.

Such a complex can be produced by mixing the corresponding copolymer with a metal compound that can be ionized in an aqueous medium at room temperature for several minutes, for example, 5 minutes to several hours, for example, 2 hours. The reaction mixture thus obtained is a semipermeable membrane, for example, a Spectra / Por (registered trademark) Diarysis Micrane (nominal flat width = 45 mm, diameter = 29 mm, vol / lens = 6.4 mL / cm, MWCO = 3,500). By using and dialyzing against water, nanoparticles for polymer micelles as described above can be provided. Such nanoparticles may be lyophilized and subsequently prepared for use. On the other hand, the ester-forming complex can be prepared in a dehydrated or dry organic solvent (for example, DMF) via an ester-forming reaction between the copolymer and phenylboronic acid. Such a reaction may be carried out at a temperature from room temperature to 100 ° C. for 6 to 24 hours without limitation. The reaction solution thus obtained can be dialyzed against water using the semipermeable membrane as described above to provide the desired ester complex as the nanoparticles described above. This complex can also be lyophilized for subsequent use.

Regarding [7], as described in Non-Patent Document 1, the ferrous (Fe (II)) ion is hydrogen peroxide (H ₂ O ₂ ), which can be said to be a mild oxidizing agent, as can be called a Fenton reaction. Is known to be converted to hydroxyl radicals, which are highly reactive and highly cytotoxic. According to the present invention, the above-mentioned complex in which the radical metal ion is Fe (II) can be stably present as nanoparticles under physiological conditions, and can be adapted to an aqueous environment. , Hydrogen peroxide normally highly expressed in the vicinity of the tumor can be converted into active hydroxyl radical (.OH radical) or the like in the living body through the Fenton reaction to bring about a tumor-killing cell or tumor growth inhibitory effect. Therefore, according to the present invention, there is provided a tumor growth-suppressing preparation comprising the complex according to [4], wherein the metal ion is Fe (II) as an active ingredient.

Such a preparation may contain a carrier or an excipient which is commonly used in the art as long as the object of the present invention is met. Examples of such carriers include sterilized water, buffered sterilized water, and the like, and excipients include polysorbate, polyethylene glycol of various molecular weights, monosaccharides or disaccharides or their reduced products, maltitol, xylitol, and the like. , Etc. can be mentioned. The complex contained in such a preparation can be solubilized or homogeneously dispersed in water as polymer micelle-like nanoparticles, and thus is not limited, but is conveniently parenteral to the living body, particularly intravenous. It can be administered intramuscularly, intramuscularly, or subcutaneously. Such a dose can be appropriately determined by a person skilled in the art, particularly a specialist, in consideration of the results of tests on laboratory animals and the like. However, the complex can also be included as an active ingredient in oral formulations.

In [8], the tumor growth inhibitory preparation for use in neutron capture therapy, which contains the complex according to [5] as an active ingredient, also contains the complex of [7] as an active ingredient. It can be prepared and administered to the living body in the same manner as the inhibitory preparation. In addition, since the complex can stably exist as nanoparticles in a physiologically aqueous environment, it can stay in the tumor tissue via the so-called EPR effect, and thus it is effective in neutron capture therapy. Can be inferred.

Hereinafter, the present invention will be described in more detail based on specific examples, but it is not intended to limit the present invention to these examples. In the following examples, PEG-b-polychloromethylstyrene (PEG-b-PCMS) obtained by the method described in the examples of WO 2016/052463 A1 based on the disclosure of the present invention was used. .. Therefore, in the structural formula of the copolymer described later, the description of the linking group of the PEG segment and the poly [di (carboxymethyl) aminomethylstyrene] (PAAMS) segment is omitted, but more appropriately, those segments are omitted. It should be understood that there is paraxylylene in between.

<Example 1> Synthesis method of poly (ethylene glycol) -b-poly [di (carboxymethyl) aminomethylstyrene] (PEG-b-PAAMS) 1

To a 50 mL eggplant-shaped flask, 1 g of PEG-b-PCMS (MW: PEG: 5KDa, CMS degree of polymerization 18), 2 g of iminodiacetic acid, 3 g of ethyldiisopropylamine, and 10 mL of DMF were added and reacted at 100 ° C. for 1 day. The mixture was placed in a MWCO 3,500 dialysis bag, dialyzed against water at pH 3 for 24 hours, and then lyophilized to give a dry polymer. ^{FIG. 2 shows a 1} H-NMR spectrum of the obtained polymer DMSO-d6 solution.

<Example 2> Synthesis of poly (ethylene glycol) -b-poly [di (ethoxycarbonylmethyl) aminomethylstyrene] (PEG-b-PECAMS)

To a 50 mL eggplant-shaped flask, 2 g of the same PEG-b-PCMS used in Example 1, 5 g of diethyl iminodiacetic acid, and 10 mL of DMF were added, and the mixture was reacted at 50 ° C. C for 1 day. The mixed solution was precipitated in 500 mL of cold 2-propanol, filtered and dried under reduced pressure to obtain a polymer. ^{FIG. 3 shows a 1} H-NMR spectrum of the obtained polymer DMSO-d6 solution.

<Example 3> Synthesis method of poly (ethylene glycol) -b-poly [di (carboxymethyl) aminomethylstyrene] (PEG-b-PAAMS) 2
700 mg of PEG-b-PECAMS was dissolved in 20 mL of DMF in a 50 mL eggplant-shaped flask, 0.5 g of sodium hydroxide and 10 mL of water were added, and the mixture was reacted at room temperature for 4 days. The reaction mixture was dialyzed against water in the same manner as above, and then freeze-dried to obtain a polymer. ^{FIG. 4 shows a 1} H-NMR spectrum of the obtained polymer DMSO-d6 solution.

<Example 4> Preparation of Fe (II) -containing nanoparticles 50 mg of PEG-b-PAAMS synthesized in Example 3 and _{12 mg of FeCl 2} were dissolved in 10 mL of water, stirred for 10 minutes, and water in the same manner as above. Was dialyzed against. FIG. 5 shows the results of dynamic light scattering measurement. Particles having a particle size of 57 nm were obtained.

<Example 5> Preparation of nanoparticles using various ions Ga (III), In (III), Gd (III), Cu (II), Fe (II), F
Composite nanoparticles of PEG-b-PAAMS with respect to e (III) were mixed (PEG-b-PAAMS: metal ion chloride 20 mM, metal ion: chelate molecule = 2: 1) and stirred at 37 ° C. for 1 hour. , Water was dialyzed in the same manner as above). FIG. 6 shows a photograph of the obtained solution.

The size, ion encapsulation amount and encapsulation rate are as follows.

<Example 6> Stability of metal ion encapsulation The stability of the metal ion-encapsulated nanoparticles (excluding In (III) and Fe (III)) prepared in Example 5 was stirred in the presence of 10% serum for 2 days. .. When dynamic light scattering measurement was performed, the particle size hardly changed even in the presence of serum, and the scattering intensity did not decrease, and it was extremely stable (see FIG. 7).

<Example 7> Encapsulation of Mn (II) and Zn (II) When metal ions were carried out with Mn (II) and Zn (II) in the same manner as in Example 5, a metal having a particle size of 45-50 nm was formed. Encapsulating particles were obtained (see FIG. 8).

<Example 8> Preparation of PEG-b-PAAMS boron complex (or complex) 100 mg of PEG-b-PAAMS, 100 mg of phenylboronic acid, 100 mg of activated molecular sieve, and 10 mL of dehydrated DMF are placed in a 30 mL flask at 80 ° C. It was allowed to react for one day. After the reaction, the molecular sieve is filtered off, and the filtrate is dialyzed against Spectra / Por (registered trademark) Dialysis Membrane (nominal flat width = 45 mm, diameter = 29 mm, vol / lens = 6.4 mL / cm, MWCO = 3,500). It was placed in a bag, dialyzed against water, and then lyophilized. Yield 75 mg. ^{1 1} H-NMR of the obtained polymer is shown in FIG. A 2 mg / mL aqueous solution was prepared, and the boron concentration was measured by IPC-MS and found to be 500 ppm. Dynamic light scattering measurements showed that the polymer was associated in water and had a particle size of 37 nm (see Figure 10).

<Example 9> PEG-b-PAAMS boron錯合of seeded HepG2 cells cytotoxicity 96-well plates to 1x10 ^4, 0.5mg / mL and 1.0 mg / mL to become as PEG-b-paams boron complex After adding the coalescence and incubating for 24 hours, the EST solution was added, and after 2 hours, UV absorption at 450 nm was measured and compared with the control, and a survival rate of 80% or more was confirmed in each case (see FIG. 11).

<Example 10> Toxicity and antitumor properties of chelate polymer (PEG-b-PAAMS) and its ester (PEG-b-PECAMS).

Sample group (6 animals per group):
1 PBS
2 PBS solution (25 mg) of the polymer (PEG-b-PAAMS) prepared in Example 1
/ ML)
3 PB the DMSO solution of the polymer (PEG-b-PECAMS) prepared in Example 2
Solution dialyzed against S (25 mg / mL)

^{1x10 6} Colon-26 cells were subcutaneously administered to Balb / C mice, and 7 days later, 100 μL of the above sample was intravenously injected (100 mb / Kg-BW, 0, 3, 6 days and 3 times). No significant difference was observed between the three administration groups in weight gain and tumor growth, and although no strong toxicity was observed by administration of this chelating agent, no antitumor activity was observed (see FIGS. 12 and 13).

<Example 11> Antitumor activity of Fe (II) -containing nanoparticles The Fe (II) -containing nanoparticles prepared in Example 4 were administered 7 days after ^{subcutaneously administering 1x10 6 Colon-26 cells to a Balb / C mouse.} It was administered from the tail vein (7.75 mg / mL, 100 μL, 31 mg / Kg-BW, administered three times a day, 3, 6 days). Particles with Fe (II) showed a significant tumor growth inhibitory effect and did not show significant weight loss (see FIGS. 14 and 15). In addition, it showed a high life-prolonging effect on the control (see FIG. 16).

<Example 12> Cytotoxicity of Fe (II) -containing nanoparticles Cell toxicity of 96- ^{well microplates 10 4} / well HeLa cells were seeded and cultured for 24 hours, then the culture solution was removed, the following sample was added, and the cells were cultured for 24 hours. did. After that, the cell viability was determined by WST measurement. As shown in FIG. 17, it was confirmed that the polymer and Fe (II) -containing nanoparticles also showed no cytotoxicity under these conditions.

Sample 1 PEG-b-PAAMS (10 mg / mL, 100 mg / mL solution diluted 10-fold with serum)
2 PEG-b-PAAMS (5 mg / mL, 100 mg / mL solution diluted 20-fold with serum)
3 Fe (II) -containing nanoparticles used in Example 11 (1.55 mg / mL, the solution used in the above animal experiment diluted 5-fold with serum)

<Example 13> Cytotoxicity of Fe (II) -containing nanoparticles by Fenton reaction 10 ⁴ / well HeLa cells were seeded on a 96-well microplate, cultured for 24 hours, and then the culture solution was removed, and the following sample was removed. Was added and cultured for 24 hours. After that, the cell viability was determined by WST measurement. As shown in FIG. 18, H ₂ O ₂ ^{alone showed no cytotoxicity at 3} × 10 3 mol / L, whereas it showed remarkable cytotoxicity in the presence of Fe (II) -containing nanoparticles and showed an effect. In the coexistence test, Fe (II) -containing nanoparticles (1.55 mg / mL, the solution used in the above animal experiment was diluted 5-fold with serum).

The block copolymer of the present invention can provide a complex or complex as nanoparticles stable under physiological conditions with a polyvalent metal ion or a boron compound, and such nanoparticles exhibit a tumor growth inhibitory effect. Therefore, the present invention is available in the medical field.

Claims (8)

A block copolymer comprising a poly (ethylene glycol) segment and a poly [di (carboxymethyl) aminomethylstyrene] segment. A block copolymer according to claim 1, wherein the block copolymer the copolymer is characterized by being represented by the following formula I.
Formula I:

During the ceremony
A represents an unsubstituted or substituted C _1- C ₁₂ alkyl, and the substituent when substituted represents a formyl group or a formula R ₁ R ₂ CH- group, where R ₁ and R ₂ are independent. to C ₁ -C ₄ alkoxy or R ₁ and R ₂ are -OCH ₂ CH ₂ O together _{-, - O (CH 2)} 3 O- or -O (CH _{2) 4} O- and represent,
L is the formula

Selected from the groups represented by, or also bonded,-(CH ₂ ) _c S-, -CO (CH ₂ ) _c S-,-(CH ₂ ) _c NH-,-(CH ₂ ) _c CO Selected from the group consisting of −, −CO−, −OCOO−, −CONH−,
The di (carboxymethyl) amino group in the formula is present at least one in the total number of n, and if not present, the amino group can be H, a halogen atom or a hydroxy group, where Y is H. , SH or S (C = S) -Ph, where Ph represents phenyl which may be substituted with 1 or 2 methyls or methoxys.
b is an integer of 2 to 6
c is an integer from 1 to 5
m represents an integer of 2 to 10,000
n represents an integer of 2 to 500. A complex of the copolymer according to claim 1 or claim 2 and a multivalent metal ion. One or more polyvalent metal ions selected from the group consisting of Ga (III), Gd (III), Cu (II), Fe (II), Mn (II) and Zn (II) ions. The complex according to claim 3, which is an ion. An ester-forming complex of the di (carboxymethyl) group of the copolymer according to claim 1 or 2 and phenylboronic acid. The complex or complex according to any one of claims 3 to 5, wherein the complex or complex exists as particles having an average particle size of nanometer size in an aqueous medium. The preparation for suppressing tumor growth, which is the complex according to claim 4, which comprises a complex in which a metal ion is Fe (II) as an active ingredient. A tumor growth-suppressing preparation for use in neutron capture therapy, which comprises the complex according to claim 5 as an active ingredient.

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