JP2015044920A - Polymeric boron compound and its use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a boron compound excellent in retention in blood, tumor accumulation properties and/or the content of the boron compound loaded into each structure or a polymer micelle and capable of enhancing a therapeutic effect by a neutron beam capture therapy.SOLUTION: The boron compound is a polymeric boron compound formed by covalently bonding a boron ion cluster through a chloro methylene group of a polyethylene-glycols b-poly chloro methylene styrene (PEG-b-PCMA) block copolymer, and a polyion composite of the copolymer and a specified polycation chargeable compound.

Description

  The present invention relates to a polymerized boron compound and use thereof, and more specifically to a block copolymer carrying a low molecular boron compound such as a plurality of boron ion clusters in a molecule and use in the medical field.

Boron neutron capture therapy (BNCT) is a form of radiotherapy that kills cancer tissue with α particles and ⁷ Li particles generated by the capture reaction of ¹⁰ B nuclei and thermal neutrons. This therapy is attracting attention as a next-generation radiotherapy that makes effective use of the principles of both chemotherapy and radiotherapy and enables irradiation selectively in cells. In order to effectively carry out this therapy, it is necessary to provide a boron compound with improved accumulation in cancer tissue and reduced toxicity.

  From this point of view, a therapy using a combination of low molecular weight compounds borocaptate (BSH) and boronophenylalanine (BPA) is currently used clinically, but these drugs are rapidly excreted from the kidney. Therefore, it is necessary to devise a technique for increasing the accumulation in cancer tissues. In addition, liposomes encapsulating BSH, etc. (see Non-Patent Document 1 and Non-Patent Document 2), and stable liposomes are formed by covalently binding lipids or PEGylated lipids to cage-like boron ion clusters (such as nido carborane). Ionic boron cluster lipids (see Non-Patent Document 3 and Non-Patent Document 4) have also been proposed. However, it has been suggested that encapsulated boron compounds have a tendency to leak and toxicity problems. On the other hand, a compound obtained by covalently bonding a carborane modified with an appropriate functional group to provide a boron-rich compound in a dendrimer frame structure, a linear block copolymer obtained by polymerizing a polymerizable carborane-containing monomer, Polymer constructions of polymerized carborane functionalized styrene monomers, followed by dendrimer growth on the carborane, and copolymers of silyl protected oxonorbornene imide carborane and Boc protected oxo norbornene imidoamide have also been proposed (Non-Patent Documents). 5, Non-Patent Document 6 and Non-Patent Document 7). However, these polymerized boron compounds also leak carborane in the bloodstream, and polymer micelles formed from these tend to collapse micelles due to dissociation of blocks. On the other hand, the inventors who are partly in common with the present inventors are parent-hydrophobic block copolymers, in the polymer micelle of the copolymer carrying a polymerizable group at the end of the hydrophobic segment. After enclosing a polymerizable bifunctional carborane or monofunctional carborane, each polymerizable group was polymerized, and a structure in which carborane was covalently bonded in a polymer micelle was proposed (Patent Document 1 or Non-Patent Document 8, Non-Patent Document). Reference 9). These structures are known to be capable of accumulating boron compounds at high concentrations in cancer tissues and having high biocompatibility.

JP2011-63562A

Yanagie H. et al. et al. , Br. J. et al. Cancer, 63, 522-526 (1991) Shelly K. et al. , Proc. Natl. Acad. Sci. USA, 89, 9039-9043 (1992) Nakamura H. et al. et al. , Chem Commun 7: 1910-1911 (2004). Maruyama K.M. et al. , J. et al. Controlled Release 98: 195-207 (2004) Matthew C.I. et al. , Macromol. Symp. 196, 201- 211 (2003) S. Rahima Benhabbour et al. , Macromolecules, published on Web 07/04/2007 PAG EST: 10.1 Simon Y. Macromolecules, published on Web. 07/06/2007 PAGE EST: 2.6 Sumitani S. et al. , React Funct Polym 71, 684-693 (2011) Sumitani S. et al. , Biomaterials 33, 3568-3577 (2012)

  As described above, in the prior art, various modified boron compounds each capable of achieving the intended purpose are provided, but they are still in blood retention, tumor accumulation, and / or loaded into each construct or polymer micelle. In terms of the content of the boron compound that can be produced, it is not always satisfactory. Accordingly, an object of the present invention is to provide a polymerized boron compound having more excellent characteristics.

  The inventors of the present invention found that a polymer boron compound in which a boron ion cluster is covalently bonded via a chloromethylene group of a polyethylene glycol-b-polychloromethylenestyrene (PEG-b-PCMA) block copolymer is itself aqueous. Forming polymer micelles in a medium or in combination with a suitable polycationically charged compound to form polyion complex (PIC) micelles, and the polymer micelles thus formed are in blood retention and tumor accumulation And was able to be loaded with a high content of boron compounds. Furthermore, when a specific block copolymer is selected as the polycation chargeable compound when forming a PIC, active oxygen is usually generated by neutron irradiation in BNCT, causing inflammation and causing adverse effects on normal tissues. However, such adverse effects can be reduced or eliminated.

  Therefore, the present invention provides a polymerized boron compound represented by the following formula I as a means for solving the above problems.

In which A represents unsubstituted or substituted C ₁ -C ₁₂ alkoxy, and when substituted, the substituent represents a formyl group or a group of formula R ¹ R ² CH—, wherein R ¹ and R ² is _{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 -
L ₁ represents a bond or a linking group,
L ₂ represents a bond or a linking group,
X is the total number of X, and at least 3% of n is represented by the following formulas (a), (b) and three types (c):

A residue of a boron compound selected from the group consisting of: When X is other than the above residues, X is a hydrogen atom, a halogen (eg, chloro, bromo) atom or a hydroxyl group;
Where
m represents an integer of 15 to 10,000, and n represents an integer of 3 to 3,000.

  In addition, when the boron compound residue is anion-chargeable, a complex comprising a compound of formula I and a polycation-chargeable compound, particularly a polycation represented by the following formula II is also provided.

In which A represents unsubstituted or substituted C ₁ -C ₁₂ alkoxy, and when substituted, the substituent represents a formyl group or a group of formula R ¹ R ² CH—, wherein R ¹ and R ² is _{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 -
L ₁ represents a bond or a linking group,
L ₃ represents —CH ₂ —NH— or —CH ₂ —NH—CH ₂ —,
Y is the total number of Y, and at least 50% of n is 2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl, 2,2,5,5-tetramethylpyrrolidine-1-oxyl- 3-yl, 2,2,5,5-tetramethylpyrrolin-1-oxyl-3-yl and 2,4,4-trimethyl-1,3-oxazolidine-3-oxyl-2-yl, 2,4, A residue of a cyclic nitroxide radical compound selected from the group consisting of 4-trimethyl-1,3-thiazolidin-3-oxyl-2-yl and 2,4,4-trimethyl-imidazolindin-3-oxyl-2-yl; And when Y is other than the above residues, -L ₃ -Y is a methyl, methyl halide or hydroxymethyl group,
m represents an integer of 15 to 10,000, and n represents an integer of 3 to 3,000.

  Polyethylene glycol-poly (styrene bearing boron ion clusters) block copolymer represented by formula I of the present invention, in particular, polyethylene glycol-poly (borocaptate-supported styrene) copolymer and cationic charge represented by formula II The polyionic complex (PIC) of a sex compound forms stable micelles in an aqueous medium, exhibits excellent retention in blood, and has the property of being collected in a tumor with high efficiency when administered in blood. Thus, the PIC accumulated in the tumor can effectively kill cancer cells by neutron irradiation. In addition, since the PIC retains the ability to erase active oxygen species and reactive radical species (ROS), which is a function normally possessed by the polycation chargeable compound represented by the formula II, it is usually generated by neutron irradiation. Inflammation caused by ROS can be suppressed, BNCT has a good prognosis, and a high therapeutic effect can be expected. FIG. 1 shows a conceptual diagram for demonstrating the configuration and operation of a specific embodiment of the present invention.

<Detailed Description of the Invention>
Various terms used herein have meanings commonly used in the art unless otherwise specified. In the context of the present invention, for example, when referring to “supported” or “supported” or “bonded” in styrene or borocaptate-supported styrene that supports boron ion clusters, the corresponding group or compound moiety is bound by a covalent bond. Means that

“Chargeable” as referred to a cation or anion chargeable group means a group or moiety that can have a corresponding ionic charge, respectively, when the compound of Formula I or II is dissolved or dispersed in an aqueous medium. .

Defined for L ₁ and L ₂ of formula I "linking group" can be of any divalent group as long as it does not impair the effects of the present invention described above, the L ₁ is (CH _{2) c S, (CH 2} ) c S (CH 2) d, (CH 2) c NH, (CH 2) c NH (CH 2) d, (CH 2) c NHCO, (CH 2) c NHCO ( _{CH 2) d, - (CH} 2) c NHC (= S) NH, (CH 2) c NHC (= S) NH (CH 2) d -, (CH 2) c NHC (= O) NH, (CH _{2) c NHC (= O)} NH (CH 2) d, (CH 2) c OCO, (CH 2) c OCO (CH 2) d, (CH 2) c O, (CH 2) c O (CH 2 _{) d, (CH} 2) selected from the group consisting of _c, where c and d are independently Integer from 1 to 5, preferably 2 to 4, more preferably 2. These vary mainly depending on the method of connecting the polyethylene glycol segment and the poly (styrene ion bearing boron ion cluster) segment. On _the other hand, _{the L 2, CH 2, CONH,} NHCO, may be mentioned _{NHCO (CH 2) 2 (CH} 2 CH 2 O) e (CH 2) NHCO (C 4 H 2 NO 2) or the like. Here, e is an integer of 1-12.

  X can be at least 3%, preferably 10%, more preferably 20%, most preferably 30% or more of n, the total number of X. Moreover, when X is represented by the formula (a) or (b), the residue exhibits anion chargeability, and can form a PIC with a cation chargeability compound as described above. In the present specification, when the term “residue” is used, the formulas (a) and (b) and the like are taken as examples to mean the remaining part from which a small part such as a hydrogen atom has been eliminated from the molecule of the corresponding boron ion cluster. Since the residue represented by the formula (a) shows a stronger anion chargeability, it is more preferable in forming PIC.

  M in Formula I is generally an integer from 15 to 10,000, preferably from 20 to 1000, more preferably from 40 to 500, and most preferably from 100 to 300. In general, n is an integer of 3 to 3,000, preferably 5 to 40, more preferably 6 to 30, and most preferably 7 to 20.

  The cationically chargeable compound is a compound that is known in the art to be able to form a PIC with a nucleic acid, and may optionally be PEGylated, such as poly (L-lysine), polyethyleneimine, poly It can be allylamine, polydimethylaminoethyl (meth) acrylate, and the like. The molecular weight of PEG when PEGylated can be a converted value of the number of repeating units represented by m in the above formula I or formula II, and the number of cation-chargeable groups is the boron compound of formula II It can correspond to the number of residues.

The block copolymer represented by Formula II provided by some of the present inventors has a structure that is almost common in the polymer backbone with the block copolymer of Formula I, and is represented by Formula I. Forms a stable PIC in an aqueous medium with a polymerized boron compound, and in each copolymer, the polyethylene glycol segment is used as an outer shell or shell, and carries an ion binding moiety or a residue of a boron ion cluster or a cyclic nitroxide radical compound It is understood to result in micelles with a polymer chain segment as a core. While the polyethylene glycol segment is easily soluble and super mobile in aqueous media, the micelles are stable in aqueous media because the latter polymer segments are poorly soluble or insoluble. In order to form such stable micelles, the ratio of the boron compound residue of Y of formula I to the imino group of L ₂ of formula II is 2: 1 to 1: 8, preferably 1.5: 1. ˜1: 6, more preferably 1: 1 to 1: 4. Regarding the micelle of the present invention, the term “nanoparticle” means that the particle size is in the nanometer order when the particle size of the corresponding micelle in the aqueous medium is measured by a dynamic light scattering method.

  The “aqueous medium” mentioned above or in the context of the present invention is water, in particular deionized or pure water, physiological saline, an aqueous solution buffered with a suitable buffer (for example, phosphate buffer), and further mixed with water. It can be a mixed solution of an organic solvent (for example, N, N-dimethylformamide, dimethyl sulfoxide, etc.).

  The polycation chargeable compound represented by the formula II is described in WO 2009 / 133647A1 or JP2012-111700A and is known per se. The contents of these patent documents are incorporated herein by reference.

In Formula II, A, L ₁ , m and n are as defined for Formula I, L ₃ is —CH ₂ —NH— or —CH ₂ —NH—CH ₂ —, and Y is preferably Is

Here, R ′ represents a methyl group.

  The polymerized boron compound represented by the formula I is, for example, boron having an appropriate functional group supported as necessary via the chloromethyl group of the corresponding PEG-b-poly (chloromethylstyrene) copolymer. Ion clusters (Nakamura H. et al., Org. Biochem., 10, 1374-1380 (2010), Mier, W. et al., Z. Anorg. Allg. Chem. 630, 1258-1262, (2004)). Can be produced by conjugation using a condensation or substitution reaction known per se. By changing such reaction conditions, it is possible to adjust the content of boron compound residues at X in n repeating units. The starting copolymer can be obtained by the method described in WO 2009 / 133647A1. Alternatively, instead of introducing a boron compound into the poly (chloromethylstyrene) moiety used in the production of the copolymer, a boron compound residue was introduced in advance through the chloromethyl group of the chloromethylstyrene monomer. The polymerized boron compound of formula I can be produced by carrying out a polymerization reaction using the modifying monomer.

  The polyion complex (PIC) of an anionically chargeable compound of formula I and a cationically chargeable compound of formula II that can be produced in this way forms a polyion complex by electrostatic interaction in an aqueous medium. Can be prepared. In the production of such a PIC, these compounds can associate to form micelles that are molecular assemblies. Whether or not such micelles can be formed can be confirmed by measuring the particle size using a particle size measuring device or the like by a dynamic light scattering method.

  The polymeric boron compound of formula I is a physiologically acceptable excipient ordinarily used in the art, either alone or in combination with a PIC of a cationically charged compound of formula II Pharmaceutical formulations can be prepared with diluents.

Such excipients or diluents can be, but are not limited to, aqueous media such as the buffered saline described above, and the micelles can be applied, for example, in a lyophilized state. Forms such as monosaccharides (sucrose, glucose etc.), disaccharides (lactose etc.), reducing sugars, polysaccharides (starch etc.), sugar alcohols (sorbitol, xylitol, erythritol, mannitol, maltitol, lactitol, etc.) It can be used to prepare a suitable pharmaceutical preparation in the form of a mixture. These are preferably prepared as parenteral agents. Parenteral administration can be performed by intravenous, intraarterial, subcutaneous or intramuscular administration, or local embedding.

The conceptual diagram which shows the structure and effect | action of the specific aspect of this invention 1 is a 1H NMR spectrum of PEG-b-PMBSH obtained in Production Example 1. 3 is a graph showing the results of evaluation of PIC micelle retention in blood and tumor accumulation in Test 1. FIG. It is a graph which shows the transition (left figure) of the size of the cancer tissue after the neutron irradiation by Test 2, and the change (right figure) of the body weight of a mouse | mouth. In the figure, (-♦-) represents a treatment according to the present invention, and (-Δ-) represents a treatment using a conventional technique.

  Hereinafter, the present invention will be described in more detail with reference to specific examples, but is not meant to limit the present invention thereto.

Production Reference Example 1: Synthesis of polyethylene glycol-b-polychloromethylstyrene (PEG-b-PCMS) block copolymer 4 g polyethylene glycol having a thiol group at one end (MeO-PEG-SH, Mn: 5000) ) And 66 mg azobisisobutyronitrile were added to the reaction vessel. Next, after evacuating the reaction vessel, the operation of blowing nitrogen gas was repeated three times to fill the reaction vessel with nitrogen. 20 ml toluene and 2 ml chloromethylstyrene (CMS) were added to the reaction vessel, heated to 60 ° C. and stirred for 24 hours. The reaction mixture was washed three times with polyethylethylstyrene (PCMS) using diethyl ether, which is a good solvent, and then freeze-dried with benzene to obtain 4.274 g of the desired compound.

Production Reference Example 2: Synthesis of block polymer having nitroxy radical (PEG-b-PMNT) In a reaction vessel, 2.67 g PEG-b-PCMS was dissolved in 102.64 ml dimethyl sulfoxide (DMSO) to obtain 2.716 g. 30.86 ml of DMSO in which (4-amino-TEMPO) was dissolved was added and stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was washed 3 times with 2-propanol and then lyophilized with benzene to obtain 2.74 g of the desired compound.

Production Example 1: Synthesis of a block polymer (PEG-b-PMBSH) containing boron 2 g BSH (mercaptoundecahydrododecaborate) and 228.58 mg sodium hydride (NaH) were added to a reaction vessel. Next, after the inside of the 300 ml reaction vessel was evacuated, the operation of blowing nitrogen gas was repeated three times to fill the reaction vessel with nitrogen. 25 ml of 1,3-dimethyl-2-imidazolidinone (DMI) was added to the reaction vessel and stirred at room temperature for 5 hours. Next, 55 ml of DMI in which 1.604 g PEG-b-PCMS was dissolved was added to the reaction vessel, and further stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was purified by repeating ultrafiltration 5th floor and freeze-dried to obtain 1.632 g of the purified desired compound. Whether the target compound was obtained was evaluated by nuclear magnetic resonance or high performance liquid chromatography. FIG. 2 shows the NMR spectrum showing the result of nuclear magnetic resonance and the assignment of each part.
1NMR measurement conditions:
Magnetic field: 400MHz
Solvent: D ₂ O
Temperature: Room temperature Scan: 64

Production Example 2: Preparation of PIC micelle 2.7 g PEG-b-PMNT was dissolved in 5 ml of 1M HCl aqueous solution to completely protonate the amino group of the PMNT chain, and then recovered by freeze-drying. Next, 1.039 mg of protonated PEG-b-PMNT block copolymer and 0.251 mg of PEG-b-PMBSH were dissolved in 0.5 ml of phosphate buffer (10 mM, pH 6), respectively. Each polycation and polyanion were mixed at a concentration of 20 μg / mL (amino group of BSH / PMNT chain = 1: 4) to prepare PIC micelles. It was confirmed that PIC micelles were formed by dynamic light scattering.

Test 1: Retention in blood and accumulation in tumor: 200 μl of the PIC micelle-containing solution was administered to tumor-bearing mice by tail vein injection, and after 1 to 72 hours, the animals were sacrificed under anesthesia, dissected and analyzed for blood, Each organ such as a tumor was taken out and dissolved in nitric acid and hydrogen peroxide. Thereafter, the amount of boron in the tissue was evaluated using ICP-MS. The results are shown in FIG. Here, PIC micelle is tail vein administration at a dose of 1.8 mg / kg ^{B 10} to tumor-bearing mice.

  As shown in FIG. 3, when the pharmacokinetics of PIC micelles was confirmed, it showed a high blood retention, and the particles gradually accumulated in the tumor with the passage of time. After 48 hours, the boron concentration reached the maximum (2.03 μg / g organization), and it can be confirmed that 5.51 ID% / g accumulation 72 hours later. The ratio of the boron compound in the tumor to the blood (T / B ratio) reached 2 or more after 72 hours. Therefore, according to the present invention, it is possible to accumulate boron compounds in cancer tissues with high efficiency.

Test 2: Evaluation of BNCT using PIC micelles In order to confirm the therapeutic effect of neutron capture therapy using the material of the present invention (the PIC micelles described above), PIC micelles were administered to tumor-bearing mice by tail vein injection. 8 × 10 ¹² neutrons / cm ² of neutron irradiation was performed for 40 minutes. The change in tumor size was measured over about 2 weeks, and the therapeutic effect was evaluated. In order to compare the effects, evaluation was performed using 5 groups including a reference experiment. Sample groups are as follows. The results are shown in FIG.
・ PIC micelle (with irradiation)
・ PIC micelle (no irradiation)
・ BSH (with irradiation, conventional technology)
・ Saline (with irradiation)
・ Saline (no irradiation)

  When the transition of the size of the cancer tissue was examined over 13 days after the irradiation, the growth of the cancer tissue of the PIC micelle group (with irradiation) according to the present invention was effectively suppressed. On the other hand, in the group not irradiated, cancer tissue grew greatly in 13 days. From this, it can be seen that the suppression of the growth of cancer tissue is the effect of neutron irradiation. Even when irradiation is carried out by administration of only physiological saline without administration of a drug, the growth of cancer tissue is somewhat suppressed, but it is insufficient. Although the growth of cancer tissue is also suppressed in the BSH (with irradiation) group which is a conventional technique, it can be seen that the use of the material according to the present invention is overwhelmingly superior (see FIG. 4). . This is considered to be because the boron compound according to the present invention was efficiently accumulated in the cancer tissue, and inflammation was suppressed by removing reactive oxygen species, thereby suppressing the growth of the cancer tissue.

  By using PIC micelles according to the present invention, the amount of drug accumulation in cancer tissue required for BNCT could be reduced to approximately 20-25% compared to the conventional technology. This is because in the conventional method, the drug is rapidly discharged from the cancer tissue, and thus an effect that is not considered to be a high drug accumulation amount cannot be obtained. Reducing drug dosage is also highly desirable for treatment. From the results of this test, it can be understood that the present invention is much superior to the conventional method.

Claims (10)

A polymerized boron compound represented by the following formula I.
In which A represents unsubstituted or substituted C ₁ -C ₁₂ alkoxy, and when substituted, the substituent represents a formyl group or a group of formula R ¹ R ² CH—, wherein R ¹ and R ² is _{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 -
L ₁ represents a bond or a linking group,
L ₂ represents a bond or a linking group,
X is the total number of X, and at least 3% of n is represented by the following formulas (a), (b) and three types (c):
A residue of a boron compound selected from the group consisting of, and when X is other than the above residues, X is a hydrogen atom, a halogen atom or a hydroxyl group,
Where
m represents an integer of 15 to 10,000, and n represents an integer of 3 to 3,000.   The polymerized boron compound according to claim 1, wherein X is represented by the formula (a) or (b). The linking group of L ₁ is (CH ₂ ) _c S, (CH ₂ ) _c S (CH ₂ ) _d , (CH ₂ ) _c NH, — (CH ₂ ) _c NH (CH ₂ ) _d , (CH ₂ ) _c NHCO, (CH ₂ ) _c NHCO (CH ₂ ) _d , (CH ₂ ) _c NHC (═S) NH, (CH ₂ ) _c NHC (═S) NH (CH ₂ ) _d , (CH ₂ ) _c NHC ( ═O) NH, (CH ₂ ) _c NHC (═O) NH (CH ₂ ) _d , (CH ₂ ) _c OCO, (CH ₂ ) _c OCO (CH ₂ ) _d , (CH ₂ ) _c O, (CH ₂ ) _c O (CH ₂ ) _d , (CH ₂ ) _c , wherein c and d are each independently an integer of 1 to 5, and the linking group of L ₂ is CH ₂ , CONH, NHCO, NHCO (CH ₂ ) ₂ (CH ₂ CH ₂ O) _e (CH ₂ ) NHCO (C ₄ H Selected from the group consisting of ₂ NO _2), where e is an integer from 1 to 12 A compound according to claim 1 or 2.   A complex comprising the compound according to claim 1, wherein X is represented by the formula (a) or (b), and a polycation chargeable compound. The complex according to claim 4, wherein the polycation chargeable compound is represented by the following formula II.
In which A represents unsubstituted or substituted C ₁ -C ₁₂ alkoxy, and when substituted, the substituent represents a formyl group or a group of formula R ¹ R ² CH—, wherein R ¹ and R ² is _{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 -
L ₁ represents a bond or a linking group,
L ₃ represents —CH ₂ —NH— or —CH ₂ —NH—CH ₂ —,
Y is at least 50% of the total number of Y is 2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl, 2,2,5,5-tetramethylpyrrolidine-1-oxyl- 3-yl, 2,2,5,5-tetramethylpyrrolin-1-oxyl-3-yl and 2,4,4-trimethyl-1,3-oxazolidine-3-oxyl-2-yl, 2,4, A residue of a cyclic nitroxide radical compound selected from the group consisting of 4-trimethyl-1,3-thiazolidin-3-oxyl-2-yl and 2,4,4-trimethyl-imidazolindin-3-oxyl-2-yl; And when Y is other than the above residues, -L ₃ -Y is a methyl, methyl halide or hydroxymethyl group,
m represents an integer of 15 to 10,000, and n represents an integer of 3 to 3,000. Y is the following formula
The complex according to claim 5, wherein R ′ represents a methyl group.   The complex according to any one of claims 4 to 6, wherein the complex is a nanoparticle in one or both of a polyion complex form and a polymer micelle form in an aqueous medium.   A pharmaceutical preparation comprising the compound according to any one of claims 1 to 3 and a physiologically acceptable excipient.   A pharmaceutical preparation comprising the complex according to any one of claims 4 to 7 and a physiologically acceptable excipient.   10. A pharmaceutical formulation according to claim 8 or 9, which is used for boron neutron capture therapy.