Accumulative boron-10 agents capable of rapid, selective and localized targeting of tumor tissue for boron neutron capture therapy

Abstract

To provide a 10B medicine that can be selectively accumulated on a tumor tissue by a low dosage and in a short time, and is applicable to BNCT.SOLUTION: An accumulative 10B medicine includes a compound containing a peptide that can be selectively bonded to a tumor vascular endothelial cell, and 10B, is administered to a subject afflicted with cancer by an amount of 300 to 600 mg per administration, where the medicine is accumulated such that 10 B concentration in a cancer-afflicted tissue of the subject becomes 1 ppm or more after the administration.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] The present invention relates to a method for the production of boron neutron capture therapy using a boron-containing compound having a high accumulation rate and capable of selectively and locally targeting tumor tissue in a short period of time. 10 Regarding drug B. [Background technology]

[0002] The challenge with current anti-cancer drug treatments is that highly cytotoxic drugs are administered systemically. The key to reducing side effects such as cytotoxicity and achieving a high anticancer effect is to deliver a high concentration of anticancer drug only to the cancer in as short a time as possible. On the other hand, boron-10 nuclei (boron-10; 10 Boron neutron capture therapy (BNCT) involves irradiating a target (such as a tumor) with neutrons and taking advantage of the short range (on the order of micrometers) of the secondary nuclides generated to selectively kill nearby cancer cells. However, since BNCT is expected to have a highly localized effect on the self-destruction of cancer cells within a range of several μm, targeting the cancer tissue is an issue. In other words, to achieve BNCT effectively, 10 The key is how selectively B can be taken up by cancer cells. For example, in tumor nests that have developed in parts of an organ that cannot be removed, it is expected that B can selectively kill cancer cells while minimizing damage to the organ, making it applicable to tumors that cannot be removed by surgical treatment. In addition, neutrons can only reach a depth of about 7 to 8 cm in the human body, so they have little effect on cancer cells. 10 The higher the B uptake efficiency, the greater the range of cancer types and organs that can be treated with BNCT, and the more effective it is for cancer treatment.

[0003] On the other hand, Non-Patent Document 1 discloses that a peptide that specifically binds to tumor vasculature and does not target normal pulmonary vasculature was searched for using a phage library, and a peptide having the amino acid sequence IFLLWQR (hereinafter simply referred to as "IF7") was obtained. It was confirmed that the IF7 phage binds to recombinant annexin 1, and that geldanamycin derivative-bound IF7 suppressed tumor growth.

[0004] Patent Document 1 also discloses a composition containing a component for cancer treatment covalently bound directly or via a linker to the carboxy terminus containing IF7, and specifically discloses the anticancer activity of a composition containing a compound in which geldanamycin is bound to IF7, and a composition containing a compound in which the anticancer drug SN-38 is bound to IF7. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 6184101 [Non-patent literature]

[0006] [Non-Patent Document 1] Proc Natl Acad Sci USA.,Vol.108,No.49,Page.19587-19592(2011) Summary of the Invention [Problem to be solved by the invention]

[0007] However, the compound in which geldanamycin is bound to IF7 and the compound in which SN-38 is bound to IF7 described in Patent Document 1 can only be applied to certain cancers (e.g., colon cancer), and sufficient anticancer activity was not obtained even when applied to a wide variety of cancers. Furthermore, no anticancer activity was obtained when anticancer drugs other than geldanamycin and SN-38 were bound to IF7. This is thought to be because binding to IF7 changes the conformation of the anticancer drug, and although the anticancer drug exhibits anticancer activity after being metabolized and undergoing structural changes, when bound to IF7 it is not metabolized or undergoes structural changes, and therefore the anticancer activity is not obtained. Therefore, the invention described in Patent Document 1 has problems in that it is difficult to apply to a wide variety of cancers and that its anticancer activity is limited. On the other hand, in order to achieve a groundbreaking therapeutic effect against refractory cancers through BNCT treatment, it is necessary to develop a compound that is more effective than conventional drugs. 10 Drug B development 10 B is required to have (1) local accumulation and (2) short-term accumulation properties at the same time.

[0008] The present invention has been made in consideration of the above-mentioned problems of the conventional technology, and is capable of selectively accumulating in tumor tissue in a short period of time at a low dose, and is applicable to BNCT. 10 The purpose is to provide B drugs. [Means for solving the problem]

[0009] The present inventors have discovered a peptide capable of selectively binding to tumor vascular endothelial cells. 10 They found that a compound containing B can accumulate rapidly and selectively in tumor tissue at low doses, and that its application to BNCT has few side effects, is minimally invasive, and can selectively exert an anti-cancer effect on tumor tissue. In addition, when applied to BNCT, the above compounds reach the tumor via tumor vascular endothelial cells and are therefore taken up by the tumor itself. 10 Not only B but also tumor blood vessels or cells were taken up 10 We found that B may indirectly inhibit tumor growth by destroying tumor blood vessels. The present invention has been completed based on these findings. That is, the present invention is as follows.

[0010] (1) A peptide capable of selectively binding to tumor vascular endothelial cells 10 B, and the compound is administered to a subject suffering from cancer in an amount of 300 to 600 mg / dose, and after the administration, 10 Accumulation of B to a concentration of 1 ppm or more 10 B drug. (2) In the cancer-affected tissues of the above subjects 10Accumulation as described in (1) above, in which the B concentration is accumulated to 20 ppm or more. 10 B drug. (3) In the cancer-affected tissue within 10 to 30 minutes after administration 10 The accumulation property described in (1) or (2) above, including the time when the B concentration becomes 20 ppm or more. 10 B drug. (4) The accumulation-promoting agent according to any one of (1) to (3) above, wherein the administration is by injection. 10 B drug. (5) The compound 10 B-containing group, 10 B-containing group is Lp- 10 boronophenylalanine radical, 18 Fluoro 10 Boronophenylalanine group or 10 The accumulating agent according to any one of (1) to (4) above, which is a borocaptate group. 10 B drug. (6) The accumulation-promoting peptide according to any one of (1) to (5) above, wherein the peptide is a peptide capable of selectively binding to annexin 1. 10 B drug.

[0011] (7) A peptide capable of selectively binding to annexin 1 10 and a compound containing a B-containing group, 10 B-containing group is Lp- 10 boronophenylalanine radical, 18 Fluoro 10 Boronophenylalanine group or 10 Borocaptate group, accumulation 10 B drug. (8) The peptide according to (6) or (7) above, wherein the peptide comprises an amino acid sequence IFLLWQR (amino acids 1 to 7 of SEQ ID NO: 1), an amino acid sequence IFLLWQRX (amino acids 1 to 8 of SEQ ID NO: 1), an amino acid sequence IFLLWQRXX (amino acids 1 to 9 of SEQ ID NO: 1), an amino acid sequence IFLLWQRXXX (amino acids 1 to 10 of SEQ ID NO: 1), an amino acid sequence IFLLWQRXXXX (amino acids 1 to 11 of SEQ ID NO: 1), or an amino acid sequence IFLLWQRXXXXX (amino acids 1 to 12 of SEQ ID NO: 1), wherein each X is independently a polar or charged amino acid, and one or two amino acids of IFLLWQR in each of the amino acid sequences may be substituted. 10 B drug.

[0012] (9) The peptide 10 The accumulating group according to any one of (1) to (8), wherein the B-containing group is bonded via a linker. 10 B drug. (10) The above 10 B-containing group is Lp- 10 Boronophenylalanine group or 18 Fluoro 10 A boronophenylalanine group, 10 The B-containing group is bonded to the linker via an ester bond, or the linker contains an ester bond. 10 B drug. (11) The above 10 B-containing group 10 The accumulating agent according to (9), which is a borocaptate group and the linker does not contain an ester bond. 10 B drug. (12) The accumulation property according to any one of (9) to (11), wherein the linker is a linker represented by the following formula (i) or (ii): 10 B drug. [ka] (In the above formula, * and ** each represent a bond.) (13) The compound according to any one of (1) to (12), which is a compound having a structure represented by the following formula (i-1) or (ii-1): 10 B drug. [ka] (In the above formula, * and ** respectively represent binding sites for a peptide capable of selectively binding to tumor vascular endothelial cells.) (14) The accumulation method according to any one of (1) to (13), which is for use in BNCT. 10 B drug. (15) The accumulation property described in (14) above, which is used for irradiating with neutrons within 60 minutes after administration. 10 B drug. (16) 2×10 6 / cm 2 The accumulation property described in (14) or (15) is used for irradiating neutron irradiation at a dose of s or more. 10 B drug.

[0013] The present invention also relates to the following: (17) The accumulation-promoting agent according to (1), wherein the dosage per administration to the subject is 5 to 9 mg per unit body weight (1 kg) of the subject. 10 B drug. (18) The accumulation characteristic according to any one of (1) to (17) above. 10 Cancer treatments, including B drugs. (19) The accumulation characteristic according to any one of (1) to (17) above. 10 Boron neutron capture therapy, which involves administering 300-600 mg of B agent to a subject suffering from cancer. (20) A method for treating cancer, comprising the above (19) boron neutron capture therapy. Effect of the Invention

[0014] Accumulation of the present invention 10 Agent B is suitable for BNCT because it can accumulate rapidly and selectively (preferably at high concentrations) in tumor tissue at a low dose. Accumulation of the present invention 10The B agent can reduce the neutron dose to normal tissue that does not need to be irradiated with neutrons, has fewer side effects, is minimally invasive, and can exert a local killing effect on tumor tissue. [Brief description of the drawings]

[0015] [Figure 1A] This figure shows the 10B concentration (ppm) in each organ of tumor-bearing mice 5, 10, and 20 minutes after administration of 100 μL (175 μg) of IF7-10BPA or IF7-10BSH, prepared at 7 mg / kg, into the tail vein of tumor-bearing mice. [Figure 1B] This figure shows the 10B concentration (ppm) in each organ of tumor-bearing mice 5, 10, and 20 minutes after administration of 100 μL (175 μg) of IF7-10BPA or IF7-10BSH, prepared at 7 mg / kg, into the tail vein of tumor-bearing mice. [Diagram 2] This figure shows the 10B concentration (ppm) in each organ of tumor-bearing mice 20, 40, and 60 minutes after administration of 10BPA-fructose (100 mg / kg) at 100 μL (2000 μg) into the tail vein of tumor-bearing mice. [Figure 3A] This figure shows a violin plot of the 10B concentration (ppm) in each organ of tumor-bearing mice 5, 10, 20, and 40 minutes (including 60 minutes in the case of 100 mg / kg) after administration of IF7-10BPA prepared at 7 mg / kg or 10BPA prepared at 7 or 100 mg / kg into the tail vein of tumor-bearing mice. [Figure 3B] This figure shows a violin plot of the 10B concentration (ppm) in each organ of tumor-bearing mice 5, 10, 20, and 40 minutes (including 60 minutes in the case of 100 mg / kg) after administration of IF7-10BPA prepared at 7 mg / kg or 10BPA prepared at 7 or 100 mg / kg into the tail vein of tumor-bearing mice. [Figure 3C] This figure shows a violin plot of the 10B concentration (ppm) in each organ of tumor-bearing mice 5, 10, 20, and 40 minutes (including 60 minutes in the case of 100 mg / kg) after administration of IF7-10BPA prepared at 7 mg / kg or 10BPA prepared at 7 or 100 mg / kg into the tail vein of tumor-bearing mice. [Figure 4A] FIG. 1 shows a violin plot of 10B concentrations (ppm) in each organ of tumor-bearing mice 5, 10, 20, and 40 minutes after administration of IF7-10BSH or 10BSH, prepared at 7 mg / kg, into the tail vein of tumor-bearing mice. [Figure 4B] FIG. 1 shows a violin plot of 10B concentrations (ppm) in each organ of tumor-bearing mice 5, 10, 20, and 40 minutes after administration of IF7-10BSH or 10BSH, prepared at 7 mg / kg, into the tail vein of tumor-bearing mice. [Figure 5A] FIG. 1 shows the results of a hot group in which IF7-10BSH or IF7-10BPA was administered to tumor-bearing mice and then neutron-irradiated 40 minutes later, and a cold group in which neutrons were not irradiated. [Figure 5B] FIG. 1 shows the results of a hot group in which IF7-10BSH or IF7-10BPA was administered to tumor-bearing mice and then neutron-irradiated 40 minutes later, and a cold group in which neutrons were not irradiated. [Figure 6A] This figure shows the results of the hot group, which was administered IF7-10BPA or 10BPA to cancer-bearing mice and then irradiated with neutrons 40 minutes later, and the cold group, which was not irradiated. [Figure 6B] This figure shows the results of the hot group, which was administered IF7-10BPA or 10BPA to cancer-bearing mice and then irradiated with neutrons 40 minutes later, and the cold group, which was not irradiated. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The following describes in detail the embodiments of the present invention. However, the present invention is not limited to the following embodiments and can be implemented with appropriate modifications within the scope of the object of the present invention. In addition, in this specification, "~" means from above to below unless otherwise specified.

[0017] <Anti-cancer drugs> Integration of the present invention 10 The B agent is a peptide that can selectively bind to tumor vascular endothelial cells. 10B, and the compound is administered to a subject suffering from cancer in an amount of 300 to 600 mg / dose, and after the administration, 10 Accumulate so that the B concentration becomes 1 ppm or more (preferably 20 ppm or more). Integration of the present invention 10 The B agent is a peptide that can selectively bind to tumor vascular endothelial cells. 10 By including a compound containing B, 10 Even though the single dose of 300-600 mg is less than that of formulation B, 10 It can be accumulated so that the B concentration becomes 1 ppm or more (preferably 20 ppm or more), which is suitable for BNCT. In addition, the integration of the present invention 10 When applied to BNCT, drug B reaches the tumor via tumor vascular endothelial cells, and is thus not taken up by the tumor itself. 10 B Not only the drug but also the above substances that are taken up into the tumor blood vessels or cells 10 B agents can indirectly inhibit tumor growth by destroying tumor blood vessels. Therefore, the integration of the present invention 10 B drug is a drug that induces high concentrations in tumor tissue. 10 The concentration of B (eg, 20 ppm or more) may be a requirement, or it may not be a requirement (ie, 1 to 20 ppm).

[0018] The subject is not particularly limited as long as it is suffering from cancer, but examples include mammals suffering from cancer (e.g., humans, pigs, cows, mice, rats, etc.), and preferably humans suffering from cancer (subjects or patients).

[0019] The dosage per administration to the subject is 300 to 600 mg, preferably 400 to 500 mg, from the viewpoint of achieving the effect of killing cancer tissue by BNCT at a low dosage in order to suppress side effects. In addition, the dose per administration to the subject was a low dose of 5-9 mg per unit body weight (1 kg) to suppress side effects, but it was found that the amount of the drug in the cancer-affected tissue was sufficient. 10It can be accumulated so that the B concentration is 1 ppm or more (preferably 20 ppm or more), and preferably, even if it is 6 to 8 mg, it can be accumulated so that it is 1 ppm or more (preferably 20 ppm or more).

[0020] In cancer-affected tissue 10 Unless otherwise specified, the value of the B concentration is the value measured by prompt gamma ray analysis (PGA method) under the conditions described in the Examples below. In the above cancer-affected tissues 10 From the viewpoint of the killing effect of BNCT on cancer tissue, the B concentration is preferably 2 ppm or more, 3 ppm or more, 4 ppm or more, or 5 ppm or more, more preferably 6 ppm or more, 7 ppm or more, 8 ppm or more, 9 ppm or more, or 10 ppm or more, even more preferably 11 ppm or more, 12 ppm or more, 13 ppm or more, 14 ppm or more, or 15 ppm or more, even more preferably 20 ppm or more, particularly preferably 25 ppm or more, even particularly preferably 30 ppm or more, particularly preferably 35 ppm or more, and most preferably 40 ppm or more. In cancer-affected tissue 10 There is no particular upper limit to the B concentration as long as the effect of the present invention is not impaired. 10 An example of a B concentration less than 20 ppm is 19 ppm or less, typically 18 ppm or less, and preferably 17 ppm or less. 10 When the B concentration is 20 ppm or more, it is, for example, 200 ppm or less, typically 150 ppm or less, preferably 100 ppm or less, more preferably 80 ppm or less, even more preferably 70 ppm or less, and particularly preferably 60 ppm or less.

[0021] Here, "accumulation" means selectively moving toward or localizing in cancer-affected tissues relative to other tissues or normal tissues in a subject, including selective localization in cancer-affected tissues relative to other tissues or normal tissues, and 1.2 times or more accumulation relative to other tissues or normal tissues. 10 It is preferable that the concentration of B is localized at 1.5 times or more. 10It is more preferable that the concentration of B is localized in the 10 It is more preferable that the concentration of B is localized in the B concentration, and that the concentration is three times or more. 10 It is particularly preferable that the concentration of B is localized in the 10 It is most preferable that it is localized in the B concentration. There is no particular upper limit, but an example is 50 times or less, and typically 30 times or less.

[0022] From the viewpoint of allowing the compound to be rapidly accumulated in cancer-affected tissues and enabling rapid application of BNCT, the compound is accumulated in the cancer-affected tissues within 5 to 60 minutes (preferably 5 to 50 minutes, more preferably 10 to 40 minutes, even more preferably 15 to 30 minutes, particularly preferably 15 to 25 minutes, and even more preferably 15 to 20 minutes) after the administration. 10 It is preferable to include a period during which the B concentration becomes 1 ppm or more (preferably 20 ppm or more).

[0023] The administration method may be any of parenteral administration, inhalation administration, oral administration, and direct administration (DDD = Direct Drug Delivery). From the viewpoint of allowing the compound to accumulate rapidly in cancer-affected tissues and enabling rapid application of BNCT, parenteral administration is preferred, and injection administration such as intravenous injection, subcutaneous injection, intraperitoneal injection, intramuscular injection, etc., or intravenous infusion, or direct administration to the affected area using an endoscope or catheter is more preferred, with intravenous injection being even more preferred.

[0024] In the case of parenteral administration, 10The form of killing of cancer tissue by B-agent includes sterile aqueous or non-aqueous solutions, suspensions, emulsions, etc. Examples of non-aqueous solvents that may be included include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), injectable organic esters (e.g., ethyl oleate), etc. Aqueous carriers that may be included include water, alcoholic / aqueous solutions, emulsions or suspensions (including saline and buffered media). Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (e.g., based on Ringer's dextrose), etc. Preservatives and other additives may also be present, such as, for example, antibacterial agents, antioxidants, chelating agents, and inert gases, etc. In the case of oral administration, 10 Forms of the B drug include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets, and may contain thickeners, flavorings, diluents, emulsifiers, dispersing aids, or binders.

[0025] Peptides that can selectively bind to tumor vascular endothelial cells 10 Compounds containing B The compound can selectively bind to tumor vascular endothelial cells by binding to an amino acid residue (preferably, the side chain of the amino acid residue) at any position constituting the peptide. 10 It is preferable that B is bonded directly or via a linker to B. The bond may be any bond such as a covalent bond, an ionic bond, a coordinate bond, or a bond due to intermolecular forces, but a covalent bond is preferable in terms of bond stability.

[0026] ( 10 B) The above compound 10 It is preferable that the peptide contains a B-containing group, and the B-containing group is a group that can selectively bind to tumor vascular endothelial cells. 10It is more preferable that the B-containing group is bonded directly or via a linker. 10 The B-containing group is 10 Although B may be itself, it is preferable that B is represented by the following formula (a): 10 Boronophenylalanine group, represented by the following formula (b): 10 From the viewpoint of imaging the distribution of the anticancer agent of the present invention in the body by positron emission tomography (PET), 18 Radiolabeled with F 18 Fluoro 10 It may also be a boronophenylalanine group (for example, the following formula (c)). [ka] (In the above formula, * indicates a bond.)

[0027] and an amino acid residue at any position constituting a peptide capable of selectively binding to tumor vascular endothelial cells. 10 Examples of the embodiment in which the B-containing group is directly bonded include the following examples (a) to (e), but the present invention is not limited to these. Represented by the above formula (a) 10 Boronophenylalanine group or the above formula (c) 18 Fluoro 10 A boronophenylalanine group; (A) an amide bond with a lysine residue having an amino group in the side chain at any position constituting the above peptide; (a) a thioester bond with a cysteine ​​residue having a thiol group in its side chain at any position constituting the peptide; (c) an ester bond with a serine or threonine residue having a hydroxyl group in the side chain at any position constituting the above peptide; (D) Represented by the above formula (b) 10 a disulfide bond between a borocaptate group and a cysteine ​​residue having a thiol group in the side chain at any position constituting the peptide; (E) Represented by the above formula (b) 10A thioester bond between a borocaptate group and an aspartic acid residue or glutamic acid residue having a carboxyl group in the side chain at any position constituting the above peptide. etc. The above amide bond, thioester bond, ester bond, and disulfide bond can be formed by any organic chemical method.

[0028] (Peptides capable of selectively binding to tumor vascular endothelial cells) The peptide capable of selectively binding to tumor vascular endothelial cells is not particularly limited as long as it can selectively bind to tumor vascular endothelial cells, but is preferably a peptide capable of selectively binding to annexin 1. Annexin 1 has been identified as a specific tumor endothelial cell surface marker, and is known to be specifically expressed in tumor vascular endothelial cells (Oh, P. et al. Nature 2004; 429: 629-35). The present invention also relates to a peptide capable of selectively binding to annexin 1. 10 and a compound containing a B-containing group, 10 B-containing group is Lp- 10 Boronophenylalanine group or 10 The borocaptate group is 10 It also concerns B drugs.

[0029] Examples of the above-mentioned peptide capable of selectively binding to annexin 1 include a peptide having 7 to 15 amino acids (preferably 7 to 13 amino acid residues, more preferably 7 to 12 amino acid residues, and even more preferably 8 to 11 amino acid residues) containing the amino acid sequence IFLLWQR, in which one or two amino acids of IFLLWQR may be replaced by any amino acid. More specific examples of the peptide capable of selectively binding to annexin 1 include peptides comprising the amino acid sequence IFLLWQR (amino acids 1 to 7 of SEQ ID NO: 1), the amino acid sequence IFLLWQRX (amino acids 1 to 8 of SEQ ID NO: 1), the amino acid sequence IFLLWQRXX (amino acids 1 to 9 of SEQ ID NO: 1), the amino acid sequence IFLLWQRXXX (amino acids 1 to 10 of SEQ ID NO: 1), the amino acid sequence IFLLWQRXXXX (amino acids 1 to 11 of SEQ ID NO: 1), or the amino acid sequence IFLLWQRXXXXX (amino acids 1 to 12 of SEQ ID NO: 1), wherein each X is independently a polar or charged amino acid, and one or two amino acids of IFLLWQR in each of the amino acid sequences may be substituted (preferably not substituted).

[0030] For example, each X may be independently selected from any set of five of the amino acids C, R, K, S, T, H, D, E, N, Q, and M, any set of four of all of the amino acids, any set of three of all of the amino acids, any set of two of all of the amino acids, or any one of all of the amino acids. For example, each X may be independently selected from the set of three amino acids C, R, and K. Examples of the above peptide capable of selectively binding to annexin 1 include IFLLWQRCRR (SEQ ID NO: 2), IFLLWQRKRR (SEQ ID NO: 3), IFLLWQRCR (SEQ ID NO: 4), IFLLWQRCRRRR (SEQ ID NO: 5), and the like.

[0031] The above peptide 10 B (preferably 10 The position at which the aryl group (B-containing group) is bonded directly or via a linker may be any amino acid residue in the peptide, and examples thereof include the 6th to 12th amino acid residues (preferably the side chains of these amino acid residues) in each of the amino acid sequences, preferably the 7th to 11th amino acid residues in each of the amino acid sequences, more preferably the 8th to 10th amino acid residues in each of the amino acid sequences, and even more preferably the 8th or 9th amino acid residues in each of the amino acid sequences.

[0032] The peptides may have various modifications.Modifications may be used to change or improve the properties of the peptides.For example, the disclosed peptides may be N-methylated, O-methylated, S-methylated, C-methylated, or combinations of one or more amino acids.

[0033] The amino and / or carboxy termini of the peptides may be modified. Modifications of the amino terminus include methylation (e.g., -NHCH3 or -N(CH3)2), acetylation (e.g., with acetic acid or its halogenated derivatives (e.g., α-chloroacetic acid, α-bromoacetic acid, or α-iodoacetic acid), addition of a benzyloxycarbonyl (Cbz) group, or blocking the amino terminus with any blocking group including a carboxylate functionality defined by RCOO- or a sulfonyl functionality defined by R-SO2- (where R is selected from the group consisting of alkyl, aryl, heteroaryl, alkylaryl, etc.), and similar groups. One skilled in the art may also incorporate a desamino acid at the N-terminus (resulting in the absence of an N-terminal amino group) to reduce susceptibility to proteases or restrict the conformation of the peptide compound. In a preferred embodiment, the N-terminus is acetylated with acetic acid or acetic anhydride.

[0034] Carboxy-terminal modifications include replacing a free acid with a carboxamide group or forming a cyclic lactam at the carboxy terminus to introduce structural constraints. One skilled in the art can also cyclize the disclosed peptides or incorporate desamino or descarboxy residues at the termini of the peptides, such that the terminal amino or carboxyl groups are absent, to reduce susceptibility to proteases or restrict the conformation of the peptide. Functional groups at the C-terminus of the disclosed peptides include amide, lower alkyl amide, di(lower alkyl) amide, lower alkoxy, hydroxy, and carboxy, as well as lower ester derivatives thereof, and pharma- ceutically acceptable salts thereof.

[0035] Those skilled in the art will appreciate that the naturally occurring side chains of the genetically encoded amino acids (or stereoisomeric D amino acids) can be modified with other side chains, such as groups (e.g., alkyl, lower (C 1~6) alkyl, cyclic 4-, 5-, 6-, 7-membered alkyl, amide, lower alkylamide di(lower alkyl)amide, lower alkoxy, hydroxy, and carboxy, and their lower ester derivatives), and 4-, 5-, 6-, 7-membered heterocyclic groups. In particular, proline analogs in which the ring size of the proline residue is changed from 5 members to 4-, 6-, or 7 members may be used. The cyclic groups may be saturated or unsaturated, and if unsaturated, may be aromatic or non-aromatic. The heterocyclic groups preferably contain one or more nitrogen, oxygen, and / or sulfur heteroatoms. Examples of such groups include furazanyl, furyl, imidazolidinyl, imidazolyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl (e.g., morpholino), oxazolyl, piperazinyl (e.g., 1-piperazinyl), piperidyl (e.g., 1-piperidyl, piperidino), pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl (e.g., 1-pyrrolidinyl), pyrrolinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyl (e.g., thiomorpholino), and triazolyl. These heterocyclic groups may be substituted or unsubstituted. When a group is substituted, the substituent may be alkyl, alkoxy, halogen, oxygen, or substituted or unsubstituted phenyl.

[0036] One of skill in the art can also readily modify the above peptides by phosphorylation and other methods (eg, as described in Hruby, et al. (1990) Biochem J. 268:249-262).

[0037] ((Linker)) An amino acid residue (preferably a side chain of the amino acid residue) at any position constituting a peptide capable of selectively binding to tumor vascular endothelial cells 10 B (preferably 10 The bond to the B-containing group may be via a linker as described above. Examples of the linker include linkers having 1 to 20 carbon atoms (preferably having 2 to 15 carbon atoms, more preferably having 3 to 10 carbon atoms) which may or may not contain a keto group, an ether bond, a thioether bond, an amide bond, a divalent succinimide group and / or a divalent maleimide group.

[0038] first, 10 Regarding the bond between the B-containing group and the linker, the following examples (F) to (I) can be mentioned, but the present invention is not limited to these. (F) Represented by the above formula (a) 10 Boronophenylalanine group or the above formula (c) 18 Fluoro 10 an amide bond formed between a boronophenylalanine group and an amino group of an optional linker; (G) Represented by the above formula (a) 10 Boronophenylalanine group or the above formula (c) 18 Fluoro 10 an ester bond formed between a boronophenylalanine group and a hydroxyl group of an arbitrary linker; (H) Represented by the above formula (b) 10 Examples of the bond include a thioether bond formed between a borocaptate group and a maleimide group carried by an arbitrary linker.

[0039] (I) In addition, the above formula (a) 10 Boronophenylalanine group or the above formula (c) 18 Fluoro 10 The boronophenylalanine group and any aminoalkyl alcohol (preferably an aminoalkyl alcohol having 1 to 5 carbon atoms) are used to form an ester bond to obtain a compound represented by the above formula (a). 10 Boronophenylalanine group or the above formula (c) 18 Fluoro 10 An amino group can be introduced at the terminus of the boronophenylalanine group. Thereafter, a linker having an N-hydroxysuccinimide activated ester group and a linker having an amino group at the terminal represented by the above formula (a) are added.10 Boronophenylalanine group or the above formula (c) 18 Fluoro 10 It can also be reacted with a boronophenylalanine group to form an amide bond. The above amide bond, thioether bond, thioester bond, ester bond, and disulfide bond can be formed by any organic chemical method.

[0040] Next, with regard to the bond between an amino acid residue at any position constituting a peptide capable of selectively binding to tumor vascular endothelial cells and a linker, examples of (K) to (L) below can be mentioned, but the present invention is not limited to these. (k) an amide bond between an N-hydroxysuccinimide activated ester group of an arbitrary linker and a lysine residue having an amino group in the side chain at any position constituting the above peptide; (l) a thioether bond between a maleimide group of an arbitrary linker and a cysteine ​​residue having a thiol group in the side chain at an arbitrary position constituting the above peptide; (S) a thioester bond between an N-hydroxysuccinimide activated ester group of an arbitrary linker and a cysteine ​​residue having a thiol group in the side chain at an arbitrary position constituting the above peptide; (c) an ester bond between an N-hydroxysuccinimide activated ester group of an arbitrary linker and a serine or threonine residue having a hydroxyl group in the side chain at an arbitrary position constituting the above peptide; etc. The above amide bond, thioether bond, thioester bond, and ester bond can be formed by any organic chemical method.

[0041] An amino acid residue (preferably a side chain of the amino acid residue) at any position constituting a peptide capable of selectively binding to tumor vascular endothelial cells 10 B (preferably 10 Preferred examples of the linker linking the aryl group and the B-containing group include linkers represented by the following formula (i) or (ii), but the present invention is not limited thereto. [ka] (In the above formula, * and ** each represent a bond.)

[0042] The bond * in the above formulae (i) and (ii) is a thioether bond with a cysteine ​​residue at any position constituting the above peptide, or 10 It is preferred to form a thioether bond with the borocaptate group. The bond ** in the above formulae (i) and (ii) is an amide bond with a lysine residue at any position constituting the above peptide, or 10 Boronophenylalanine group or the above formula (c) 18 Fluoro 10 It is preferred to form an ester bond with the boronophenylalanine group. The bond ** in the above formulae (i) and (ii) is a thioester bond with a cysteine ​​residue at any position constituting the peptide, or a bond represented by the above formula (b). 10 It is also preferred to form a thioester bond with the borocaptate group.

[0043] It is known that actively growing cancer cells have increased phenylalanine metabolism and, because they are unable to synthesize phenylalanine within the cells, take up and use large amounts of phenylalanine from the blood. Therefore, the above formula (a) 10 boronophenylalanine radical, 18 Fluoro 10 Phenylalanine compounds derived (e.g., by free radicals) from boronophenylalanine groups (eg, formula (c) above) and the like can also be taken up in large amounts by cancer cells. Therefore, it is preferable that the compound is released from the compound in a form that allows it to migrate to the cell nucleus, where a greater cancer cell killing effect is expected, by the action of esterases and the like that are generally present within cells. In view of the above, the compound represented by the above formula (a) 10 boronophenylalanine radical,18 Fluoro 10 The boronophenylalanine group (e.g., formula (c) above) is bonded to the linker via an ester bond or to a linker represented by formula (a) above. 10 boronophenylalanine radical, 18 Fluoro 10 The boronophenylalanine group (e.g., the above formula (c)) is preferably linked to a peptide capable of selectively binding to tumor vascular endothelial cells via a linker containing an ester bond, and is represented by the formula (a): 10 boronophenylalanine radical, 18 Fluoro 10 It is more preferable that the boronophenylalanine group (e.g., the above formula (c)) is bound to a peptide that can selectively bind to tumor vascular endothelial cells via the linker represented by the above formula (i) by binding to the bond ** in the above formula (i).

[0044] on the other hand, 10 Borocaptate compounds (e.g., compounds represented by the above formula (b) 10 The dissociated or separated borocaptate group is 10 Per molecule of borocaptate compound 10 There are 12 B, and BNCT is expected to have a significant effect on killing cancer cells. 10 It is known that the borocaptate compound itself is generally difficult to be taken up by cells and tends to remain in the vicinity of cancer cells. So, 10 The B-containing group is represented by the above formula (b). 10 In the case of the borocaptate group, a peptide capable of selectively binding to tumor vascular endothelial cells and a compound represented by the above formula (b) are 10 The borocaptate group is preferably linked via a linker (preferably a linker not containing an ester bond) that is difficult to be cleaved by the action of esterases generally present in cells, and is preferably a linker represented by the above formula (b). 10 It is more preferable that the borocaptate group is bonded to a peptide capable of selectively binding to tumor vascular endothelial cells via a linker represented by formula (ii) above by binding to the bond * in formula (ii) above.

[0045] The peptide of the present invention capable of selectively binding to tumor vascular endothelial cells 10 Preferred examples of the compound containing B include compounds containing a structure represented by the following formula (i-1) or (ii-1), but the present invention is not limited thereto. [ka] (In the above formula, * and ** respectively represent binding sites for a peptide capable of selectively binding to tumor vascular endothelial cells.) The peptide of the present invention capable of selectively binding to tumor vascular endothelial cells 10 More preferred specific examples of the compound containing B include compounds represented by the following formula (1) or (2), but the present invention is not limited thereto. [ka] [ka]

[0046] <Other ingredients> The present invention 10 The B drug may or may not include a pharma- ceutically acceptable carrier. By "pharmacologically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject together with the anti-cancer agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the anti-cancer agent in which it is included. The carrier will naturally be selected, as would be well known to one of skill in the art, to minimize any degradation of the active ingredient (the compound) and to minimize any adverse side effects in the subject. The material may be in solution, suspension (e.g., incorporated into microparticles, liposomes, or cells).

[0047] Suitable carriers include those described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. AR Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of a pharma- ceutically acceptable salt is used in the anticancer agent to make the anticancer agent isotonic. Examples of the pharma- ceutically acceptable carrier include, but are not limited to, saline, Ringer's solution, and dextrose solution. The pH of the solution is preferably about 5 to about 8, and more preferably about 7 to about 7.5. Additional carriers include sustained release preparations, such as semipermeable matrices of solid hydrophobic polymers containing an antibody, where the matrices are in the form of shaped articles, such as films, liposomes, or microparticles. It will be apparent to one skilled in the art that certain carriers may be more preferable depending, for example, on the route of administration and the concentration of the composition being administered.

[0048] Pharmaceutical carriers are known to those of ordinary skill in the art. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH.

[0049] The present invention 10 In addition to the generally preferred compounds listed above, the B agent may contain carriers, thickeners, diluents, buffers, preservatives, surface active agents, and the like.

[0050] <Application> The anticancer agent of the present invention is suitable for BNCT because it can be rapidly and selectively accumulated in tumor tissue at high concentrations at a low dose. Neutron irradiation in BNCT is preferably performed within 60 minutes after the administration, more preferably within 40 minutes after the administration, even more preferably within 30 minutes after the administration, and particularly preferably within 20 minutes after the administration. There is no particular lower limit for the start of neutron irradiation, but an example is 5 minutes or more after the administration, and 10 minutes or more is preferable. There is no particular limit to the neutron exposure dose (flux). For example, 2×10 6 / cm 2 s or more (preferably 1×10 7 / cm 2 s or more, preferably 1×10 8 / cm 2 s or more, more preferably 1×10 9 / cm 2 s or more, particularly preferably 1×10 10 / cm 2 s or more, particularly preferably 1×10 11 / cm 2 s or more, most preferably 1×10 12 / cm 2 From the viewpoint of PGA measurement sensitivity, the resolution improves as the flux increases above this range. Therefore, there is no particular upper limit for the flux, but in practice, for example, 1×10 13 / cm 2 ·s or less, 8×10 12 / cm 2 ·s or less is preferable, 6×10 12 / cm 2 ·s or less is preferable, 5×10 12 / cm 2 ·s or less is even more preferable.

[0051] There is no particular limit to the physical dose of neutrons. For example, the total of thermal neutrons, epithermal neutrons, fast neutrons and gamma rays is 5E -1 There is no particular upper limit to the physical dose, but the total amount may be, for example, 5 Gy or less.

[0052] <Target> The present invention 10Cancers to which B agents can be applied include, but are not limited to, lymphoma (Hodgkin's and non-Hodgkin's), carcinoma, carcinoma of solid tissue, squamous cell carcinoma, adenocarcinoma, sarcoma, glioma, high grade glioma, blastoma, neuroblastoma, plasmacytoma, histiocytoma, melanoma, adenoma, hypoxic tumor, myeloma, AIDS-related lymphoma or sarcoma, metastatic cancer, or cancer in general.

[0053] More specifically, the cancer includes lymphoma, B-cell lymphoma, T-cell lymphoma, mycosis fungoides, Hodgkin's disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of the head and neck, kidney cancer, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), neuroblastoma / glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, squamous cell carcinoma of the mouth, throat, larynx, and lung, colon cancer, cervical cancer, cervical carcinoma, breast cancer, and epithelial cancer, renal cancer, genitourinary cancer, lung cancer, esophageal carcinoma, gastric cancer, head and neck carcinoma, colon cancer, hematopoietic cancer; testicular cancer; colon and rectal cancer, or pancreatic cancer. EXAMPLES

[0054] The present invention will be described in more detail below by showing examples, but the scope of the present invention is not limited to these examples.

[0055] <Synthesis Example 1> [ka] A peptide represented by the amino acid sequence IFLLWQRCRR (SEQ ID NO: 2) was chemically synthesized by the 9-fluorenylmethoxycarbonyl method (Fmoc method). 2000 mg of the peptide obtained above and 3000 mg of the compound represented by the above formula were mixed, and N-(6-maleimidocaproyloxy)succinimide (EMCS) was added dropwise to crosslink the cysteine ​​thiol group of the peptide with the terminal amino group of the compound represented by the above formula with EMCS to obtain a compound represented by the following formula (1) (hereinafter, simply referred to as "IF7- 10 The researchers obtained 420 mg of BPA (also known as 'BPA'). [ka]

[0056] <Synthesis Example 2> A peptide represented by the amino acid sequence IFLLWQRKRR (SEQ ID NO: 3) was chemically synthesized using the tert-butoxycarbonyl method (Boc method). 2000 mg of the peptide obtained above, 10 3000 mg of sodium borocaptate was mixed, and N-(6-maleimidocaproyloxy)succinimide (EMCS) was added dropwise to bind the amino group of the lysine of the peptide. 10 The thiol group of sodium borocaptate was crosslinked with EMCS to obtain a compound represented by the following formula (2) (hereinafter, simply referred to as “IF7- 10 The researchers obtained 415 mg of BSH. [ka]

[0057] [Tumor accumulation test] <Examples 1 and 2> The IF7- synthesized in the above Synthesis Example 1 in tumor-bearing mice (tumor diameter 7 mm) inoculated with mouse bladder cancer cells MBT2 in the thigh 10 BPA and IF7- synthesized in the above Synthesis Example 2 10 The tumor accumulation ability of BSH was tested. IF7- 10 BPA, IF7- 10 BSH was administered at 100μL (175μg) into the tail vein of the tumor-bearing mice, and the results were analyzed in each organ of the tumor-bearing mice 5, 10, and 20 minutes after administration.10 The B concentration (ppm) was measured by the PGA method.

[0058] Figure 1A shows IF7- 10 BPA, and IF7- 10 BSH was administered in the tail vein of the tumor-bearing mice at 100μL (175μg) for 5, 10, and 20 minutes after administration. 10 FIG. 1 shows the B concentration (ppm). As is clear from the results shown in Fig. 1A and B, IF7- 10 BPA and IF7- 10 For both BSHs, the brain, lungs, heart, liver, kidneys, bladder, stomach, intestines, spleen, skin, muscles, and blood were 10 B concentration was less than 20 ppm, whereas 20 minutes after administration, tumor tissue-specific concentrations of at least 25 ppm were observed in tumor-bearing mice. 10 It is clear that B is accumulating. Therefore, IF7- 10 BPA and IF7- 10 Both BSHs can be selectively accumulated in tumor tissues quickly (20 minutes) and at high concentrations (25 ppm or more) at low doses (7 mg / kg). 10 It can be seen that it is suitable as drug B.

[0059] <Comparative Example 1> In addition, as Comparative Example 1, a compound represented by the above formula (a) was added to the 2'-position of β-D-fructopyranose. 10 Compounds esterified with boronophenylalanine groups (hereinafter simply referred to as " 10 The tumor accumulation ability was also tested using BPA-fructose. The dose was increased to 100 mg / kg. 10 BPA-fructose was administered in 100μL (increased to 2000μg) via the tail vein of tumor-bearing mice, and the results were analyzed in each organ of tumor-bearing mice 20, 40, and 60 minutes after administration. 10 The B concentration (ppm) was measured by ICP-AES. Figure 2 shows 10BPA-fructose was administered at 100μL (2000μg) into the tail vein of tumor-bearing mice, and the results were analyzed in each organ of the tumor-bearing mice 20, 40, and 60 minutes after administration. 10 FIG. 1 shows B concentration (ppm). As is clear from the results shown in Figure 2, 10 BPA-fructose did not accumulate in the tumor tissue even 20, 40, or 60 minutes after administration, and it was found that there was no significant difference compared to other organs.

[0060] <Example 3 and Comparative Examples 2 and 3> Example 3 The results are shown in Table 1. The amount of the tumor in each organ of the tumor-bearing mice 5, 10, and 20 minutes after administration to the tail vein of the tumor-bearing mice 10 In addition to B concentration, the tumor-bearing mice's organs after 40 minutes 10 The B concentration in each organ of the tumor-bearing mice was also measured in the same manner as in Example 1, except that the n number for each data point was 3 or more, and the measurement results were shown in a violin plot. 10 The B concentration was measured, and the results are shown in Figure 3A. Comparative Example 2 IF7- 10 Instead of BPA, 10 Boronophenylalanine ( 10 The same procedure as in Example 3 was repeated except that BPA was administered to each organ of the tumor-bearing mice. 10 The B concentration was measured, and the results are shown in a violin plot in Figure 3B. Comparative Example 3 10 The same procedure as in Comparative Example 2 was repeated except that the BPA concentration was changed from 7 mg / kg to 100 mg / kg. 10 The B concentration was measured, and the results are shown in a violin plot in Figure 3C. (result) As is clear from the results shown in Figures 3A-C, IF7- 10 Example 3, which used BPA, 10 Compared with Comparative Examples 2 and 3, which used BPA, 10 It can be seen that accumulation of B tends to be high shortly after administration, especially 20 minutes. Also, 10Compared with Comparative Example 3, which had a BPA concentration of 100 mg / kg, IF7- 10 In the tumor of Example 3 using BPA 10 It can be said that the B concentration is comparable.

[0061] <Example 4 and Comparative Example 4> Example 4 The results are shown in Table 1. The amount of the tumor in each organ of the tumor-bearing mice 5, 10, and 20 minutes after administration to the tail vein of the tumor-bearing mice 10 In addition to B concentration, the tumor-bearing mice's organs after 40 minutes 10 The B concentration in each organ of the tumor-bearing mice was also measured in the same manner as in Example 2, except that the n number for each data point was 3 or more, and the measurement results were shown in a violin plot. 10 The B concentration was measured, and the results are shown in Figure 4A. Comparative Example 4 IF7- 10 Instead of BSH, use the same concentration of mercaptoundecahydrododeca. 10 Borate ( 10 The same procedure as in Example 4 was repeated except that BSH was administered to each organ of the tumor-bearing mice. 10 The B concentration was measured, and the results are shown in a violin plot in Figure 4B. (result) As is clear from the results shown in Fig. 4A and B, IF7- 10 Example 4 using BSH 10 Compared with Comparative Example 4, which used BSH, 10 It can be seen that the accumulation of B tends to be equal or greater 10 to 40 minutes after administration.

[0062] [Neutron irradiation test] <Examples 5 and 6> Example 5 The mouse bladder cancer cell line MBT2 was inoculated into the thigh of tumor-bearing mice, and IF7- 10 Tumor volumes (mm3) of mice were measured over the following 21 days for the group that was irradiated with neutrons for 30 minutes under the following conditions (hot group) and the group that was not irradiated (cold group). 3 The results are shown in FIG. 5A. In the figure, * indicates p<0.05. (1) Neutron fluence (cm -2 ·s -1 ) 2.1E +12 (2.1×10 12 )~4.6E +12 (2) Physical dose (Gy) Thermal neutron: 2.8E -1 ~6.1E -1 Epithermal neutrons: 3.0E -2 ~6.5E -2 Fast neutron: 2.1E -1 ~4.6E -1 Gamma rays: 3.6E -1 ~4.9E -1 Total 8.9E -1 ~1.5E 0

[0063] Example 6 IF7- 10 IF7- instead of BPA 10 The mice were administered in the same manner as in Example 5, except that BSH was administered. The hot group was irradiated with neutrons 40 minutes after administration, and the cold group was not irradiated. The tumor volume (mm 3 ) was measured. The results are shown in Figure 5B. (result) As is clear from the results shown in Fig. 5A and B, IF7- 10 BPA, IF7- 10 After BSH administration, the hot group showed no IF7- 10 BPA, IF7- 10 It can be seen that a tumor volume regression effect was achieved compared to the cold group after BSH administration.

[0064] <Example 7 and Comparative Example 5> Example 7 The above mouse bladder cancer cell line MBT2-bearing mice were treated with IF7- 10 The hot group was irradiated with neutrons 40 minutes after BPA was administered at a dose of 7 mg / kg into the tail vein, and the cold group was not irradiated. The tumor volume (mm3 The results are shown in Figure 6A. As is clear from the results shown in Fig. 6A, IF7- 10 After BPA administration, the hot group showed IF7- 10 It can be seen that a tumor volume regression effect was achieved compared to the cold group after BPA administration. Also, 10 Boronophenylalanine ( 10 The tumor volume regression effect in the hot group in Comparative Example 5 below, in which IF7- 10 It can be said that the tumor volume regression effect in the hot group after BPA administration was greater.

[0065] Comparative Example 5 IF7- 10 Instead of BPA 10 The mice were administered in the same manner as in Example 7, except that BPA was administered. The hot group was irradiated with neutrons 40 minutes after administration, and the cold group was not irradiated. The tumor volume (mm 3 ) was measured. The results are shown in Figure 6B. As is evident from the results shown in FIG. 6B, 10 After BPA administration, the hot group 10 Compared to the cold group after BPA administration, a tumor volume regression effect was observed, but the effect was not as great as in Example 7.

Claims

1. A peptide capable of selectively binding to tumor vascular endothelial cells １０ A compound having a B-containing group bonded via a linker １０ A drug B, the peptide is capable of selectively binding to annexin 1, the peptide comprises an amino acid sequence IFLLWQRX (amino acids 1-8 of SEQ ID NO:1), an amino acid sequence IFLLWQRXX (amino acids 1-9 of SEQ ID NO:1), or an amino acid sequence IFLLWQRXXX (amino acids 1-10 of SEQ ID NO:1), where each X is independently selected from the group consisting of the three amino acids C, R, and K, and no amino acid substitutions are made among IFLLWQR in each of the amino acid sequences; The above １０ The B-containing group is L-p- １０ boronophenylalanine radical, １８ Fluoro １０ Boronophenylalanine group or １０ is a borocaptate group, (a) the 10 B-containing group is an L-p- 10 boronophenylalanine group or an 18 fluoro 10 boronophenylalanine group, and the 10 B-containing group is bonded to the linker via an ester bond, or the linker contains an ester bond and is a linker having 1 to 20 carbon atoms which may or may not contain an amide bond, a divalent succinimide group and / or a divalent maleimide group, or (b) The integratable polymer, in which the 10 B-containing group is a 10 borocaptate group, the linker does not contain an ester bond, and the linker is a linker having 1 to 20 carbon atoms which may or may not contain an amide bond, a divalent succinimide group, and / or a divalent maleimide group. １０ Drug B.

2. The position to which the linker is attached is the side chain position of the 8th or 9th amino acid residue in each of the amino acid sequences. １０ Drug B.

3. The accumulating 10 B agent according to claim 1, which is administered to a subject suffering from cancer and accumulates in a cancer-affected tissue of said subject such that the 10 B concentration in said cancer-affected tissue becomes 1 ppm or more after said administration.

4. In the cancer-affected tissue of the subject １０ The accumulation property according to claim 3, wherein the accumulation is performed so that the B concentration becomes 20 ppm or more. １０ Drug B.

5. The accumulation|accumulation property of Claim 1, wherein the said linker is a linker represented by the following formula (i) or (ii): １０ Drug B. 【Chemistry 1】 (In the above formula, * and ** each represent a bond.) 6. The accumulating 10 B agent of claim 1, wherein the peptide is IFLLWQRCRR (SEQ ID NO: 2), IFLLWQRKRR (SEQ ID NO: 3), IFLLWQRCR (SEQ ID NO: 4) or IFLLWQRCRRRRR (SEQ ID NO: 5).

7. The accumulation assay according to claim 1, wherein the cancer is at least one cancer selected from the group consisting of bladder cancer, brain cancer, prostate cancer, melanoma, breast cancer, and colon cancer. １０ Drug B.

8. The accumulating 10 B agent of claim 1 for use in positron emission tomography (PET).

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