Compound and antitumor agent

Abstract

Provided is a compound that can be used as an antitumor agent and exhibits improved biocompatibility. The compound according to the present disclosure comprises a bile acid and a polymer chain. The polymer chain is formed from a biocompatible cationic polymer.

Description

Compounds and antitumor agents

[0001] The present invention relates to compounds and antitumor agents.

[0002] Previously, research has been conducted into the use of bile acid-modified polymers to specifically induce cell death in tumor cells (see, for example, Non-Patent Document 1). Such compounds aggregate in the acidic environment surrounding tumor cells, destroying the cell membrane and causing tumor cell death. The compound disclosed in Non-Patent Document 1 has a cationic functional group introduced at the polymer end. This allows the compound to be delivered to tumor cells by taking advantage of the negatively charged nature of tumor cells.

[0003] Noriya Matsuzaki and Yudai Shioji, "Creation of molecular blocks that induce cell death by self-assembly in response to the cancer microenvironment," Polymer preprints, Japan, 67th, Vol. 67, p. 67, 2018

[0004] The cationic functional group introduced in Non-Patent Document 1 was a (2-aminoethyl)trimethylammonium group. This functional group is not highly biocompatible, making it difficult to use the compound disclosed in Non-Patent Document 1 as an antitumor agent without modification.

[0005] An object of one aspect of the present invention is to provide a compound that can be used as an antitumor agent and has improved biocompatibility.

[0006] The present invention includes the following aspects. <1> A compound comprising a bile acid bound to a polymer chain, wherein the polymer chain is a biocompatible cationic polymer. <2> The compound according to <1>, wherein the bile acid is one or more selected from the group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, salts thereof, and conjugated forms thereof. <3> The compound according to <1> or <2>, wherein the polymer chain of the compound is mainly composed of chitosan. <4> An antitumor agent comprising the compound according to any one of <1> to <3>.

[0007] According to one aspect of the present invention, there is provided a compound which can be used as an antitumor agent and has improved biocompatibility.

[0008] 1 is a diagram showing an overview of a compound according to one embodiment of the present invention. The upper panel is a schematic diagram of the chemical structure of chitosan modified with ursodeoxycholic acid (CS-UDCA). The lower panel is a schematic diagram showing the pH-dependent changes of CS-UDCA. 2 is a diagram showing the mechanism by which a compound according to one embodiment of the present invention damages tumor cells. 3 is a diagram showing the structure of CS-UDCA. The upper panel is a chemical formula showing the synthetic pathway of CS-UDCA. The lower panel is a diagram showing the mechanism by which a compound according to one embodiment of the present invention damages tumor cells. １ 1H-NMR spectra showing the results of analysis. 1H-NMR spectra showing the zeta potential of CS-UDCA. 1H-NMR spectra showing the effect of pH change. 1H-NMR spectra showing the volumetric particle size distribution of CS-UDCA. 1H-NMR spectra showing the effect of pH change. 1H-NMR spectra showing the effect of pH change. 1H-NMR spectra showing the results of tumor cell injury by CS-UDCA. The left panel is a microscopic image of cells after incubation with CS-UDCA. The right panel is a graph showing cell viability after incubation with CS-UDCA. The top panel is a microscopic image showing tumor cell injury by chitosan modified with deoxycholic acid (CS-DCA). The bottom panel is a microscopic image showing tumor cell injury by the compound (4-PEG-DCA50-AETMA50) disclosed in Non-Patent Document 1. 1H-NMR spectra showing the chemical formula of the synthetic route of chitosan modified with deoxycholic acid via a succinic anhydride-derived linker (CS-S-DCA). This figure shows the results of tumor cell injury caused by CS-S-DCA. This figure shows the results of tumor cell injury caused by various bile acids. The upper panel shows the IC at pH 6.3 or 7.5. ５０ The bottom panel shows the IC at pH 7.4. ５０ IC at pH 6.3 ５０ 1 is a graph showing the ratio of tumor volume to tumor mass in the 100% control group. 2 is a graph showing the results of in vivo tumor treatment with CS-S-DCA. 3 is a graph showing the change in tumor volume over time. 4 is a graph showing the results of in vivo tumor treatment with CS-S-DCA. 5 is a graph showing the change in mouse body weight over time.

[0009] An embodiment of the present invention will be described below. However, the present invention is not limited to the configurations described below. The present invention can be modified in various ways within the scope of the claims. The technical scope of the present invention also extends to embodiments or examples obtained by appropriately combining multiple technical means disclosed in this specification. In this case, multiple technical means may be disclosed across multiple embodiments or examples.

[0010] Unless otherwise specified in this specification, the expression "A to B" representing a range of numerical values ​​means "greater than or equal to A and less than or equal to B."

[0011] In the drawings accompanying this specification, polymer chain structures may be depicted as block copolymers (e.g., Figure 1), but it should be understood that these representations are for convenience and are actually intended to encompass random copolymers as well.

[0012] [1. Compound] One aspect of the present invention is a compound in which a bile acid is bound to a polymer chain. The structure and action of this compound will be explained with reference to exemplary Figures 1 and 2.

[0013] The upper panel of Figure 1 is a schematic diagram showing an example of a compound structure. In the example shown in the figure, the polymer chain is chitosan, and the bile acid is ursodeoxycholic acid (UDCA). It should be noted that the figure depicts a polymer chain in which units modified with glucosamine, N-acetylglucosamine, and bile acid are linked in blocks, but this is a convenient representation, and the units may be linked randomly.

[0014] The lower panel of Figure 1 is a schematic diagram showing the pH-dependent changes of the compound. In a neutral pH environment, the carboxyl groups of the bile acids are negatively charged, and the polymer chains are electrically neutral. On the other hand, in a weakly acidic pH environment, the carboxyl groups of the bile acids are electrically neutral, and the polymer chains are positively charged.

[0015] This change has two macroscopic effects (see Figure 2). First, in a weakly acidic environment, bile acids lose their charge, leading to their aggregation through hydrophobic interactions (both between bile acids in the same molecule and between bile acids in different molecules). Second, in a weakly acidic environment, the polymer chains acquire a positive charge, leading to electrostatic interactions that attract the entire compound to negatively charged targets.

[0016] Conversely, in a neutral environment, the charge conditions are reversed, so bile acids do not aggregate and the entire compound is not attracted to a negatively charged target.

[0017] The microenvironment of tumor tissue is known to be weakly acidic (pH = approximately 6.5) due to the hypoxic environment and metabolism specific to tumor cells (normal tissue is neutral (pH = approximately 7.4)). In addition, tumor cells express more glycoproteins on their surface than normal cells, and due to sialic acid contained in the sugar chains, tumor cells carry a greater negative charge than normal cells. Therefore, when compounds reach the microenvironment surrounding tumor tissue, they aggregate, significantly increasing their particle size and becoming positively charged, so that they are preferentially attracted to tumor cells by electrostatic interactions. As a result, the aggregated compounds destroy the cell membranes of tumor cells, leading to cell death. In this way, a compound according to one embodiment of the present invention exerts antitumor activity.

[0018] Hereinafter, each of the constituent parts of a compound according to one embodiment of the present invention will be described in detail.

[0019] [1.1. Polymer Chain] The polymer chain is biocompatible. A biocompatible material has substantially no adverse effects on the living body and can be used for medical purposes. Examples of conditions that a biocompatible material must meet include sufficiently low toxicity to cells and sufficiently low irritation to tissues.

[0020] The polymer chain is a cationic polymer. A cationic polymer refers to a polymer that is positively charged under certain conditions. Typically, a cationic polymer becomes electrically neutral when the surrounding pH exceeds a certain value, and becomes positively charged when the surrounding pH is below a certain value. Preferably, the polymer chain is electrically neutral in a neutral environment and positively charged in a weakly acidic environment. The lower limit of the acid dissociation constant (pKa) or base dissociation constant (pKb) of the cationic group contained in the polymer chain may be 6.5 or more, 6.6 or more, or 6.7 or more. The upper limit of the base dissociation constant (pKb) of the cationic group contained in the polymer chain may be 7.4 or less, 7.3 or less, or 7.2 or less.

[0021] The above-mentioned acid dissociation constant and base dissociation constant are preferably measured at a temperature close to that of a living body. In one embodiment, the acid dissociation constant and base dissociation constant are measured at 37°C.

[0022] An example of a polymer chain that satisfies these properties is chitosan. Chitosan is a compound in which many glucosamines are linked in a β1→4 bond. The basic unit structure of chitosan is shown in (1) below. Chitosan is usually obtained by deacetylating chitin. Chitin is a compound in which many N-acetylglucosamines are linked in a β1→4 bond. The basic unit structure of chitin is shown in (2) below.

[0023] Chitosan may contain an N-acetylglucosamine unit. In this specification, when the number of units represented by (1) is X and the number of units represented by (2) is Y, the value calculated by dividing X by (X + Y) × 100 is referred to as the degree of deacetylation (%) of chitosan. The lower limit of the degree of deacetylation of chitosan may be 70% or more, 75% or more, or 80% or more. The upper limit of the degree of deacetylation of chitosan may be 100% or less, 98% or less, or 95% or less.

[0024] In one embodiment, the polymer chain is composed mainly of chitosan. When the number of units constituting the polymer chain is taken as 100%, the proportion of units represented by (1) or (2) is 50% or more, 70% or more, or 90% or more. In one embodiment, the polymer chain is composed substantially only of chitosan. A polymer chain composed substantially only of chitosan is composed of units represented by (1) or (2), excluding unavoidable impurities.

[0025] The shape of the polymer chain is not particularly limited. In one embodiment, the polymer chain is linear. In another embodiment, the polymer chain has branches. The polymer chain may be a star polymer.

[0026] The length of the polymer chain is not particularly limited. In one embodiment, the lower limit of the number average molecular weight of the polymer chain may be 1,000 or more, 3,000 or more, 5,000 or more, or 10,000 or more. The upper limit of the number average molecular weight of the polymer chain may be 500,000 or less, 300,000 or less, 100,000 or less, 80,000 or less, or 50,000 or less.

[0027] [1.2. Bile Acids] The compounds include bile acids. Bile acids are a group of steroid compounds and their derivatives that are major components of bile. Bile acids are biosynthesized from cholesterol, but they can also be chemically synthesized.

[0028] Examples of bile acids include cholic acid, chenodeoxycholic acid, hyocholic acid, deoxycholic acid, lithocholic acid, hyodeoxycholic acid, and ursodeoxycholic acid. The bile acid may be a salt (sodium salt, potassium salt, etc.). The bile acid may be a conjugated bile acid (taurine-conjugated, glycine-conjugated, etc.). In one embodiment, the bile acid is one or more selected from the group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, and ursodeoxycholic acid. In one embodiment, the bile acid is one or more selected from the group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, salts thereof, and conjugated forms thereof.

[0029] The compound may contain only one type of bile acid, or two or more types of bile acids.

[0030] Bile acids are usually bound to polymer chains. The binding may be a covalent bond or a non-covalent bond. The bile acid and the polymer may be bound directly or via a linker. The linker structure may be, for example, an organic group. The number of carbon atoms in the organic group may be 20 or less, 15 or less, or 10 or less. The organic group may have a heteroatom. Examples of heteroatoms include oxygen atoms, nitrogen atoms, sulfur atoms, phosphorus atoms, silicon atoms, and halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms). The number of heteroatoms contained in the organic group may be 10 or less, 8 or less, or 5 or less.

[0031] The degree to which bile acid is introduced into one polymer chain can be adjusted by the blending ratio of the polymer chain and bile acid used when synthesizing the compound. When the total number of spots in the polymer chain where bile acid can be introduced is taken as 100%, the lower limit of the bile acid introduction rate can be 1% or more, 2.5% or more, 5% or more, 7.5% or more, or 10% or more. The upper limit of the bile acid introduction rate can be 100% or less, 95% or less, 90% or less, or 85% or less.

[0032] [1.3. Overall Properties of the Compound] The compound has the property of not aggregating in the environment surrounding normal cells but aggregating in the environment surrounding tumor cells. From this viewpoint, it is preferable that the particle size of the compound in a neutral environment is significantly different from the particle size of the compound in a weakly acidic environment. In one embodiment, the average particle size of the compound at pH = 6.5 is 10 times or more, 20 times or more, or 30 times or more than the average particle size of the compound at pH = 7.4. In this specification, the average particle size of the compound refers to the volume-based average particle size measured by dynamic light scattering.

[0033] [2. Antitumor Agent] One aspect of the present invention is an antitumor agent containing the compound described above. As described above, the compound according to one aspect of the present invention can selectively damage tumor cells, and therefore has an antitumor effect and can be suitably used as an antitumor agent.

[0034] In the antitumor agent, the contents of the above-mentioned compounds, biocompatible cationic polymers, and bile acids are not particularly limited.The lower limit of the total content of these components, based on 100% by weight of the entire antitumor agent, may be 0.001% by weight or more, 0.005% by weight or more, 0.01% by weight or more, 0.05% by weight or more, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, or 5% by weight or more.The upper limit of the content of these components, based on 100% by weight of the entire antitumor agent, may be 100% by weight or less, 95% by weight or less, 90% by weight or less, 80% by weight or less, 70% by weight or less, 60% by weight or less, 50% by weight or less, 40% by weight or less, 30% by weight or less, 20% by weight or less, or 10% by weight or less.

[0035] In one embodiment, the lower limit of the content of the above-mentioned compound contained in the antitumor agent may be 0.001% by weight or more, 0.005% by weight or more, 0.01% by weight or more, 0.05% by weight or more, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, or 5% by weight or more, based on 100% by weight of the entire antitumor agent. The upper limit of the content of the above-mentioned compound contained in the antitumor agent may be 100% by weight or less, 95% by weight or less, 90% by weight or less, 80% by weight or less, 70% by weight or less, 60% by weight or less, 50% by weight or less, 40% by weight or less, 30% by weight or less, 20% by weight or less, or 10% by weight or less, based on 100% by weight of the entire antitumor agent.

[0036] The antitumor agent may contain pharmaceutically acceptable ingredients other than the active ingredient, such as a buffer, a pH adjuster, an isotonicity agent, a preservative, an excipient, a carrier, a diluent, a solvent, a solubilizer, a stabilizer, an antioxidant, a high-molecular-weight polymer, a filler, a binder, a surfactant, and a stabilizer.

[0037] The administration route of the antitumor agent according to one embodiment of the present invention is not particularly limited, and examples of the administration route include parenteral administration, intradermal administration, intramuscular administration, intraperitoneal administration, intravenous administration, subcutaneous administration, intranasal administration, epidural administration, oral administration, sublingual administration, intranasal administration, intracerebral administration, intravaginal administration, transdermal administration, rectal administration, inhalation, and topical administration.

[0038] The tumor to which the antitumor agent is administered is not particularly limited. In this specification, tumors include carcinomas and sarcomas. Specific examples of tumors include rhabdomyosarcoma, breast cancer, lymphoma, squamous cell carcinoma (oral squamous cell carcinoma, laryngeal squamous cell carcinoma, etc.), ovarian cancer, melanoma, neuroblastoma, lung cancer (pulmonary adenocarcinoma, etc.), pancreatic cancer, liver cancer (hepatocellular carcinoma, etc.), thyroid cancer (medullary thyroid carcinoma, etc.), lung cancer (non-small cell lung cancer, etc.), colon cancer, gastric cancer, and leukemia.

[0039] Example 1: Synthesis of CS-UDCA Chitosan modified with ursodeoxycholic acid (CS-UDCA) was synthesized by the following procedure (see the upper panel of Figure 3). 1. In a dimethyl sulfoxide solution, in the presence of pyridine, toluenesulfonate of chitosan (number-average molecular weight: 20,000, degree of deacetylation: 82%) and sodium salt of mesylated ursodeoxycholic acid were reacted. The reaction temperature was 100°C, and the reaction time was 3 days. 2. The sodium salt of CS-UDCA was obtained, in which some of the hydroxyl or amino groups of chitosan were substituted with ursodeoxycholic acid.

[0040] １ The degree of substitution with ursodeoxycholic acid in the resulting CS-UDCA was measured by H-NMR. Specifically, based on the peak areas of a', b', c', and d' shown in the lower panel of Figure 3, the value of c'÷3×(a'+b'+d') was defined as the degree of substitution (see Figure 3).

[0041] When synthesis was performed by changing the ratio of materials, it was found that the degree of substitution with ursodeoxycholic acid in the product increased depending on the amount of mesylated ursodeoxycholic acid added (see Table 1 and the lower panel of Figure 3).

[0042] Example 2 pH-Dependent Aggregation of CS-UDCA It was confirmed that the CS-UDCA synthesized in Example 1 aggregates depending on the pH.

[0043] ​[Example 2.1: Measurement of zeta potential] The zeta potential was measured for chitosan (CS-UDCA71) having a substitution degree with UDCA of 71% synthesized in Example 1. The concentration of CS-UDCA71 in the measurement sample was 0.1 mg / mL.

[0044] (Results) The results are shown in Figure 4. As can be seen from the figure, the zeta potential of CS-UDCA71 was lower than -20 mV at pH = 7.4, and closer to electroneutrality than -20 mV at pH = 6.5. This suggests that CS-UDCA71 can be stably dispersed at around pH = 7.4 (the environment surrounding normal cells), but loses stability and may aggregate at around pH = 6.5 (the environment surrounding tumor cells).

[0045] [Example 2.2: Measurement of particle size] The particle size distribution of chitosan (CS-UDCA71) with a substitution degree of 71% with UDCA synthesized in Example 1 was measured. The particle size was measured by dynamic light scattering. The concentration of CS-UDCA71 in the measurement sample was 3 mg / mL. The pH of the measurement environment was pH 7.4 or pH 6.5.

[0046] (Results) The results are shown in Figure 5. As shown in the figure, the volume-based average particle size at pH = 7.4 was 9 nm, and the volume-based average particle size at pH = 6.5 was 575 nm. As can be seen from these results, CS-UDCA71 actually forms aggregates in a weakly acidic environment.

[0047] Example 3: Tumor cell injury by CS-UDCA The cytotoxicity of CS-UDCA71 was investigated using the following procedure. 1. CS-UDCA71 was added to a pancreatic cancer cell line (MiaPaCa-2) in culture and incubated for 24 hours. The concentration of CS-UDCA71 was 500 μg / mL. The pH of the medium was set to 7.4 or 6.5. 2. Cell viability was measured using the WST-8 assay.

[0048] (Results) The results are shown in Figure 6. As can be seen from the figure, the cytotoxicity of CS-UDCA71 is significantly enhanced at pH 6.5 (p<0.01). In other words, CS-UDCA71 damages tumor cells in a pH-dependent manner. Since the microenvironment surrounding tumor cells is known to be weakly acidic, this suggests that CS-UDCA71 can specifically damage tumor cells.

[0049] Example 4: Tumor Cell Damage by CS-DCA Example 4.1: Synthesis of CS-DCA Chitosan modified with deoxycholic acid (CS-DCA) was synthesized according to the following procedure. 1. In a dimethyl sulfoxide solution, in the presence of pyridine, a toluenesulfonate salt of chitosan (number-average molecular weight: 20,000, degree of deacetylation: 82%) and mesylated deoxycholic acid were reacted. The reaction temperature was 100°C, and the reaction time was 3 days. 2. A sodium salt of CS-DCA was obtained, in which some of the hydroxyl or amino groups of chitosan were substituted with deoxycholic acid.

[0050] １ According to H-NMR measurement, the degree of substitution of CS-DCA with deoxycholic acid was 71%.

[0051] Example 4.2: Tumor Cell Damage by CS-DCA The cytotoxicity of CS-DCA was examined. The cytotoxicity of 4-PEG-DCA50-AETMA50, described in Non-Patent Document 1, was also examined. 4-PEG-DCA50-AETMA50 is a compound in which two deoxycholic acid groups and two (2-aminoethyl)trimethylammonium groups are introduced to the termini of a four-armed star-shaped polyvinyl alcohol. The specific procedures are as follows: 1. CS-DCA or 4-PEG-DCA50-AETMA50 was added to a colon cancer cell line (HT-29) in culture and incubated. The concentration of CS-DCA was 0.4 μg / mL. The concentration of 4-PEG-DCA50-AETMA50 was 1000 μg / mL. The pH of the medium was set to 6.5. 2. Cell viability was measured by WST-8 assay.

[0052] ​(Results) The results are shown in Figure 7. As can be seen from the figure, CS-DCA was injuring tumor cells 4 hours after the start of incubation. On the other hand, 4-PEG-DCA50-AETMA50 finally began to injuring tumor cells 18 hours after the start of incubation. In other words, CS-DCA injuring tumor cells at a significantly lower concentration than 4-PEG-DCA50-AETMA50 and in a shorter time than 4-PEG-DCA50-AETMA50. These results suggest that CS-DCA has excellent antitumor activity.

[0053] Example 5: Tumor cell damage by CS-S-DCA Example 5.1: Synthesis of CS-S-DCA Chitosan modified with deoxycholic acid via a linker derived from succinic anhydride (CS-S-DCA) was synthesized by the following procedure (see Figure 8). Unlike the CS-DCA synthesized in Example 4.1, in CS-S-DCA, the amino group of chitosan and deoxycholic acid are not directly bonded, but rather via a linker (-CO-CH ２ -CH ２ The bond is via a -CO-O-). 1. Chitosan and succinic anhydride were reacted in the presence of 1 wt% acetic acid. The reaction time was 8 hours. This resulted in compound S-CS, in which a linker derived from succinic anhydride was introduced to some of the amino groups of chitosan. 2. In an acetate buffer solution, S-CS and the sodium salt of deoxycholic acid were reacted in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide. The reaction time was 24 hours. This resulted in compound CS-S-DCA, in which deoxycholic acid was introduced to the carboxy group at the tip of the linker.

[0054] Example 5.2: Tumor Cell Damage by CS-S-DCA The cytotoxicity of CS-S-DCA against various tumor cells was investigated using the following procedure. 1. CS-S-DCA was added to a pancreatic cancer cell line (MiaPaCa-2), a colon cancer cell line (HT-29), or a lung cancer cell line (A549) in culture and incubated. The concentration of CS-S-DCA was varied. The medium pH was set to 7.4 or 6.5. As a control, a similar experiment was also performed using a normal dermal fibroblast cell line (NHDF). 2. Cell viability was measured using the WST-8 assay. 3. The IC value of CS-S-DCA for each cell type was calculated from a graph plotting CS-S-DCA concentration on the horizontal axis and cell viability on the vertical axis. ５０ It was decided that:

[0055] (Results) The results are shown in FIG.

[0056] As can be seen from Fig. 9 and Table 2, the IC of CS-S-DCA ５０ The IC of CS-S-DCA tended to decrease in an environment of pH 6.5. ５０ The values ​​for tumor cells tended to be smaller than those for normal cells. Since the microenvironment surrounding tumor cells is known to be weakly acidic, the above results taken together suggest that CS-S-DCA can specifically damage various tumor cells.

[0057] [Reference Example: Tumor Cell Damage Caused by Various Bile Acids] The cytotoxicity of deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), cholic acid (CA), and ursodeoxycholic acid (UDCA) against tumor cells (MiaPaCa-2) was measured. The experimental method was as previously reported (Biomacromolecules, 2023, 24, 2369-2379).

[0058] (Results) The results are shown in Figure 10. The upper panel shows the IC at pH 6.3 or 7.4. ５０ The bottom panel shows the IC at pH 7.4. ５０ IC at pH 6.3 ５０As can be seen from the figure, the IC ５０ IC at pH 6.3 ５０ In other words, IC in a neutral environment ５０ IC in a weakly acidic environment ５０ The IC due to the decrease in pH was higher. ５０ The degree of increase was highest for UDCA, followed by CDCA.

[0059] These experimental results suggest that bile acids aggregate in a weakly acidic environment, damaging cells. In this experiment, bile acids were not conjugated to polymer chains. However, even if the two were conjugated, bile acid aggregation would occur in the same way, and similar results would be obtained. This suggests that various bile acids can be used in the compound according to one embodiment of the present invention.

[0060] Example 6: In vivo tumor treatment with CS-S-DCA CS-S-DCA was synthesized using the same procedure as in Example 5. The degree of substitution with DCA was 26%. The ability of this CS-S-DCA26 to damage tumors in vivo was examined. The specific procedures were as follows: 1. A549 cells (lung tumor cells) were subcutaneously transplanted into female BALB / c nude mice. 2. When the tumor volume reached approximately 50 mm ３ When the mice reached 100 μg / mL, they were randomly divided into two groups. 3. The treatment group received CS-S50-DCA26 (900 μg / mL), while the control group received PBS via intratumoral injection. The single dose was 100 μL, administered three times a week for a 7-week administration period. 4. Changes in tumor volume and body weight were monitored throughout the treatment period.

[0061] (Results) The results are shown in Figures 11 and 12. Figure 11 is a graph showing the change in tumor volume over time. As can be seen from the figure, in the control group, ３ From 1250mm ３ In contrast, the tumor growth rate in the treatment group was significantly reduced, with the final volume reaching 770 mm ３Figure 12 is a graph showing the change in mouse weight over time. As can be seen from the graph, there was no significant difference in mouse weight between the treatment group and the control group.

[0062] As can be seen from these results, the tumor therapeutic effect of CS-S-DCA26 was exerted without accompanying weight loss. In other words, CS-S-DCA26 exhibits tumor therapeutic activity while possessing sufficiently high biocompatibility. This suggests that an antitumor agent according to one embodiment of the present invention may be used as a promising and well-tolerated treatment strategy.

[0063] The present invention can be used as an antitumor agent, etc.

Claims

1. A compound comprising a bile acid attached to a polymer chain, wherein the polymer chain is a biocompatible cationic polymer.

2. The compound according to claim 1, wherein the bile acid is one or more selected from the group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, salts thereof, and conjugated forms thereof.

3. The compound according to claim 1, wherein the polymer chain of said compound is based on chitosan.

4. An antitumor agent comprising the compound according to any one of claims 1 to 3.

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