copolymer

Abstract

This invention provides a copolymer suitable for use in drug delivery technologies. More specifically, it provides a copolymer for use as a drug delivery carrier targeting tumors. This invention relates to a copolymer comprising structural units represented by formulas (A), (B), and (C). [Where R...] 1 R 2 and R 3 Representing hydrogen atoms or C atoms in the same or different ways 1‑3 Alkyl, R 4 Indicate C 1‑3 Alkyl, R 5 Represents hydrogen atom, C 1‑18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6‑18 Aryl, or 5-10 heteroaryl groups that may have substituents, X 1 X 2 and X 3 Representing oxygen atoms, sulfur atoms, or N-R atoms in the same or different ways 7 R 6 R represents a hydrogen atom, leaving group, or linker. 7 Represents a hydrogen atom or C 1‑3 Alkyl group, where m represents an integer from 1 to 100, and n represents an integer from 0 to 3.

Description

Technical Field

[0001] This invention relates to a copolymer that can be used in drug delivery technology. More specifically, this invention relates to a copolymer for use as a drug delivery carrier targeting tumors, a pharmaceutical composition comprising loading the copolymer with physiologically active substances such as anticancer agents, and a pharmaceutical product containing the composition. Background Technology

[0002] In recent years, research on drug delivery systems (DDS) has been actively conducted as a technology for efficiently and safely delivering drugs to disease sites. Among these, the demand for DDS using nanoparticles as drug delivery carriers is increasing, as a technology that utilizes the structural characteristics of disease sites to improve the selectivity of drug aggregation.

[0003] For example, in solid tumor tissue, the structure of newly formed blood vessels (tumor vessels) is immature compared to normal blood vessels, resulting in intercellular gaps of several hundred nm in the vascular endothelium, thus leading to high permeability of substances. It is known that this structural characteristic allows high molecular weight nanoparticles to selectively permeate tumor vessels and accumulate in solid tumor tissue. Furthermore, due to dysfunction of the lymphatic system involved in the expulsion of high molecular weight particles in solid tumor tissue, the permeated nanoparticles are persistently retained within the tissue (Enhanced Permeability and Retention Effect, EPR). Since conventional low molecular weight drugs leak out of blood vessels through membrane permeation, they are non-selectively distributed in the tissue and do not accumulate in solid tumor tissue. Based on the EPR effect methodology, drug delivery using nanoparticles, due to the tissue distribution being governed by the permeability of the intercellular gaps in the vascular endothelial cells, results in enhanced tissue selectivity for drug distribution in solid tumors. Therefore, the EPR effect provides a strong academic basis for developing nanotechnology-based pharmaceuticals (nanomedicines) targeting solid tumors.

[0004] It is generally believed that drug delivery in the EPR effect occurs via the bloodstream, and that extravasation of nanoparticles is passive. Therefore, to maximize the aggregation of nanoparticles in solid tumors, it is crucial to molecularly design the components of the nanoparticles that serve as drug delivery carriers to withstand prolonged blood retention. This necessitates that drug delivery carriers possess the ability to avoid barriers such as nonspecific interactions with blood components; foreign body recognition by the reticuloendothelial system (RES) in the liver, spleen, and lungs; and glomerular filtration in the kidneys. Furthermore, these barriers are known to be overcome through particle size optimization or surface modification using biocompatible polymers. For example, an ideal particle size for drug delivery carriers is approximately 6 nm, greater than the threshold for renal clearance, and less than 200 nm to avoid RES recognition.

[0005] Furthermore, it is known that the particle size of drug delivery carriers also affects tissue penetration at the disease site. For example, a comparative study of the anticancer activity of drug-encapsulated nanoparticles with particle sizes of 30 nm, 50 nm, 70 nm, and 100 nm exhibiting equivalent blood retention showed that the drug-encapsulated nanoparticles with a particle size of 30 nm showed the highest therapeutic effect because they reached deeper into the disease site (Non-Patent Literature 1). Therefore, it can be considered that the ideal particle size for drug delivery carrier nanoparticles targeting solid tumors is as small as possible while avoiding renal clearance.

[0006] The industry has developed the following methods: methods using colloidal dispersions such as liposomes, emulsions, or nanoparticles as drug delivery carrier nanoparticles; methods using biological raw materials such as albumin as drug delivery carrier nanoparticles; methods using natural polymers such as natural polysaccharides as drug delivery carrier nanoparticles; and methods using synthetic polymers as drug delivery carrier nanoparticles. Among these, synthetic polymers are widely used as components of drug delivery carriers because they can be used to prepare nanoparticles with precisely controlled particle size by appropriately selecting monomers and synthetic methods.

[0007] For example, a method has been disclosed for using amphiphilic block copolymers containing hydrophilic and hydrophobic segments as drug delivery carriers. These block copolymers spontaneously associate in an aqueous medium driven by intermolecular hydrophobic interactions, forming core-shell nanoparticles (polymeric microcells). It is known that the hydrophobic segments of these polymeric microcells can encapsulate or bind low-molecular-weight drugs, resulting in drug-encapsulated polymeric microcells exhibiting higher blood stability and selectively accumulating in solid tumors through the EPR effect, thereby achieving higher anticancer activity with solutions containing lower-molecular-weight drugs (Patent Document 1). However, since polymeric microcells are aggregates of several molecules, a particle size of approximately 30 nm is the lower limit for feasible preparation, and controlling the fine size of around 10 nm, which avoids the influence of renal clearance, is more difficult.

[0008] On the other hand, among the nanoparticles formed by synthesizing polymers, those formed by chemical cross-linking, hydrophobic interactions, ionic bonds, etc. within a single chain (hereinafter referred to as single-chain nanoparticles (SCNPs)) are known to be small-diameter nanoparticles with a particle size of less than 20 nm (Non-Patent Document 2). Therefore, although SCNPs are expected to be useful as drug delivery carriers, no technology for precisely controlling their particle size has been found to date.

[0009] Existing technical documents

[0010] Patent documents

[0011] Patent Document 1: Japanese Patent No. 3270592

[0012] Non-patent literature

[0013] Non-patent literature 1: H. Cabral et al., Nat. Nanotechnol. 6 815-823 (2011)

[0014] Non-patent document 2: Jose A. Pomposo, Single-Chain Polymer Nanoparticles: Synthesis, Characterization, Simulations, and Applications (2017) Summary of the Invention

[0015] The problem that the invention aims to solve

[0016] The objective of this invention is to provide a copolymer for a drug delivery carrier targeting tumors. More specifically, the objective of this invention is to provide a copolymer for a drug delivery carrier capable of improving drug retention in the blood and / or tumor aggregation.

[0017] Technical means for solving problems

[0018] During their in-depth research to address the aforementioned problems, the inventors of this invention discovered the characteristic that terpolymers of acrylic acid derivatives can form SCNPs in water. Furthermore, in addition to achieving precise particle size control of SCNPs at a microscale of approximately 10 nm (below 20 nm), they successfully created a polymer for drug delivery carriers with high tumor aggregation. Subsequently, when this polymer was loaded with an anticancer agent and administered to a mouse model of subcutaneous transplantation of colorectal cancer, excellent antitumor effects were confirmed.

[0019] This invention relates to the following inventions.

[0020] [1] A copolymer having structural units shown in formulas (A), (B) and (C).

[0021]

[0022] [In the formula, R] 1 R 2 and R 3 Representing hydrogen atoms or C atoms in the same or different ways 1-3 Alkyl, R 4 C represents 1-3 Alkyl, R 5 Represents hydrogen atom, C 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, X 1 X 2 and X 3 Representing oxygen atoms, sulfur atoms, or NR in the same or different ways 7 R 6 R represents a hydrogen atom, leaving group, or linker. 7 Represents a hydrogen atom or C 1-3 Alkyl group, where m represents an integer from 1 to 100, and n represents an integer from 0 to 3.

[0023] [2] A copolymer formed by polymerization of three monomers represented by the following general formulas (1) to (3):

[0024]

[0025] [In the formula, R] 1 R 2 and R 3 Representing hydrogen atoms or C atoms in the same or different ways 1-3 Alkyl, R 4 C represents 1-3Alkyl, R 5 Represents hydrogen atom, C 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, X 1 X 2 and X 3 Representing oxygen atoms, sulfur atoms, or NR in the same or different ways 7 R 6 R represents a hydrogen atom, leaving group, or linker. 7 Represents a hydrogen atom or C 1-3 Alkyl group, where m represents an integer from 1 to 100, and n represents an integer from 0 to 3.

[0026] [3] The copolymer as described in [1] or [2] above, wherein R 1 It is a hydrogen atom.

[0027] [4] The copolymer as described in any one of [1] to [3] above, wherein R 2 It is a hydrogen atom.

[0028] [5] The copolymer as described in any one of [1] to [4] above, wherein R 3 It is a hydrogen atom.

[0029] [6] The copolymer as described in any one of [1] to [5] above, wherein R 4 It is a methyl group.

[0030] [7] The copolymer as described in any one of [1] to [6] above, wherein R 5 C that can have substituents 6-18 Aryl.

[0031] [8] The copolymer as described in any one of [1] to [7] above, wherein R 5 It is a phenyl group.

[0032] [9] The copolymer as described in any one of [1] to [8] above, wherein R 6 It is a hydrogen atom.

[0033]

[10] The copolymer as described in any one of [1] to [8] above, wherein R 6 The leaving group is given by the following formula (4):

[0034]

[0035]

[11] The copolymer as described in any one of [1] to [8] above, wherein R 6 The connecting base is selected from the following formulas (5) to (7):

[0036]

[0037]

[12] The copolymer as described in any one of [1] to

[11] above, wherein X 1 It is an oxygen atom.

[0038]

[13] The copolymer as described in any one of [1] to

[12] above, wherein X 2 It is an oxygen atom.

[0039]

[14] The copolymer as described in any one of [1] to

[13] above, wherein X 3 It is an oxygen atom.

[0040]

[15] The copolymer as described in any one of [1] to

[14] above, wherein m is an integer from 4 to 22.

[0041]

[16] The copolymer as described in any one of [1] to

[15] above, wherein n is 1.

[0042]

[17] The copolymer as described in any one of [1] to

[16] above, wherein the ratio of structural units (A), (B), and (C) is such that, relative to 1 part by mass of (A), it consists of 0.01 to 100 parts by mass of (B) and 0.1 to 100 parts by mass of (C).

[0043]

[18] The copolymer as described in any one of [2] to

[16] above is a copolymer formed by polymerizing 0.01 to 100 parts by mass of monomer (2) and 0.1 to 100 parts by mass of monomer (3) relative to 1 part by mass of monomer (1).

[0044]

[19] The copolymers described in any one of [1] to

[18] above have a number average molecular weight of 5,000 to 150,000.

[0045]

[20] A single-chain nanoparticle comprising any one of the copolymers described in [1] to

[19] above.

[0046]

[21] A pharmaceutical composition comprising any one of the copolymers described in any one of [1] to

[19] above.

[0047] The effects of the invention

[0048] As can be seen from the examples described later, the SCNP obtained by self-association of the copolymer of the present invention and loading an anticancer agent exhibits a tumor growth inhibition effect in a mouse model bearing cancer, and is therefore suitable as a therapeutic agent for malignant tumors. The SCNP obtained by self-association of the copolymer of the present invention and loading an anticancer agent exhibits a high tumor growth inhibition effect at low dosages, thus providing a malignant tumor therapeutic agent that can balance enhanced pharmacological effects and suppression of side effects. Attached Figure Description

[0049] Figure 1 To represent the copolymer obtained in Example 1, measurements were performed using nuclear magnetic resonance (NMR). 1 The 1H-NMR spectrum.

[0050] Figure 2 This is a graph showing the chromatogram obtained by gel permeation chromatography (GPC) for the copolymer obtained in Example 1.

[0051] Figure 3 The graph shows the particle size distribution (scattering intensity distribution) of the copolymer before encapsulation with DACHPt (Example 69) and the SCNP with encapsulated DACHPt (Example 70) in dynamic light scattering (DLS).

[0052] Figure 4 This graph shows the change in relative tumor volume when mice with a mouse colorectal cancer cell line (C26) were administered oxaliplatin solution or SCNP containing DACHPt (Example 70) three times every other day via a subcutaneous back transplantation model. Detailed Implementation

[0053] Unless otherwise specified, the terms used in this specification shall be used in their ordinary sense in the art. The invention will now be described in further detail.

[0054] In this specification, "nanoparticles" refers to structures with a particle size of less than 100 nm.

[0055] In this specification, "single-chain nanoparticle (SCNP)" refers to nanoparticles formed by chemical cross-linking, hydrophobic interactions, and ionic bonding within a single chain. Most SCNPs have a relatively small particle size, below 20 nm.

[0056] In this specification, "initiator" means an initiator for thermal free radical polymerization, such as an azo compound or a peroxide.

[0057] In this specification, "chain transfer agent" refers to a compound that undergoes a chain transfer reaction in free radical polymerization, preferably a compound having a thiocarbonyl group.

[0058] In this specification, "C" 1-3 "Alkyl" refers to an alkyl group with 1 to 3 carbon atoms in a straight or branched chain. Examples include methyl, ethyl, n-propyl, and isopropyl.

[0059] In this specification, "C" 1-18 "Alkyl" refers to alkyl groups with 1 to 18 carbon atoms in a straight or branched chain. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0060] In this specification, "3- to 8-membered cycloalkyl groups that may have substituents" refers to cycloalkyl groups with 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Substituents are not particularly limited and may include, for example, halogen atoms, alkyl groups with 1 to 6 carbon atoms, alkenyl groups with 2 to 6 carbon atoms, alkynyl groups with 2 to 6 carbon atoms, hydroxyl groups, alkoxy groups with 1 to 6 carbon atoms, amino groups, alkylamino groups with 1 to 6 carbon atoms (with or without the same alkyl group), dialkylamino groups with 1 to 6 carbon atoms (with the same or different alkyl groups), thiols, alkylthiols with 1 to 6 carbon atoms, carboxyl groups, alkoxycarbonyl groups with 1 to 6 carbon atoms, and carbamoyl groups.

[0061] In this specification, "C that may have substituents" 6-18 "Aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group, such as phenyl, naphthyl, anthracene, phenanthrene, triphenyl, pyrene, chrysenyl group, and naphthacenyl group. Substituents are not particularly limited and can include, for example, halogen atoms, alkyl groups with 1 to 6 carbon atoms, alkenyl groups with 2 to 6 carbon atoms, alkynyl groups with 2 to 6 carbon atoms, hydroxyl groups, alkoxy groups with 1 to 6 carbon atoms, amino groups, alkylamino groups with 1 to 6 carbon atoms, dialkylamino groups with the same or different alkyl groups, thiols, alkylthio groups with 1 to 6 carbon atoms, carboxyl groups, alkoxycarbonyl groups with 1 to 6 carbon atoms, and carbamoyl groups.

[0062] In this specification, "5-10 member heteroaryl group that may have substituents" means a 5-10 member monocyclic aromatic heterocyclic group or condensed aromatic heterocyclic group whose constituent atoms, in addition to carbon atoms, include 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms. Examples of monocyclic aromatic heterocyclic groups include: furanyl, thiophene, pyrrole, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl. Examples of condensed aromatic heterocyclic groups include: benzofuranyl, benzothiopheneyl, quinoxalinyl, indolyl, isoindolyl, isobenzofuranyl, benzodihydropyranyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, and isoquinolinyl. Substituents are not particularly limited and examples include: halogen atoms, alkyl groups with 1 to 6 carbon atoms, alkenyl groups with 2 to 6 carbon atoms, alkynyl groups with 2 to 6 carbon atoms, hydroxyl groups, alkoxy groups with 1 to 6 carbon atoms, amino groups, alkylamino groups with 1 to 6 carbon atoms, dialkylamino groups with the same or different alkyl groups, thiols, alkylthio groups with 1 to 6 carbon atoms, carboxyl groups, alkoxycarbonyl groups with 1 to 6 carbon atoms, and carbamoyl groups.

[0063] In this specification, examples of "halogen atoms" include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.

[0064] In the copolymer of the present invention, structural unit (A) functions as a unit imparting hydrophilicity, and structural unit (B) functions as a unit imparting hydrophobicity. Furthermore, structural unit (C) functions as a scaffold for binding the active ingredient (drug, physiologically active substance) to the copolymer. Because the copolymer of the present invention possesses these three structural units, it has the characteristic of forming SCNPs in water. The formed SCNPs can achieve precise particle size control at a microscale below 20 nm, thereby functioning as a drug delivery carrier with high tumor aggregation.

[0065] R in structural unit (A) 1 Represents a hydrogen atom or C 1-3 Alkyl groups are preferably hydrogen atoms, methyl, ethyl, n-propyl, or isopropyl, and more preferably hydrogen atoms.

[0066] X 1 Represents oxygen atom, sulfur atom, or NR. 7 Preferably, it is an oxygen atom, a sulfur atom, or NH, and more preferably an oxygen atom.

[0067] m represents an integer from 1 to 100, preferably an integer from 3 to 100. From the perspective of imparting good hydrophilicity, it is preferably 3 to 80, more preferably 4 to 60, and even more preferably 4 to 40, and even more preferably 4 to 22.

[0068] R 4 C represents 1-3 Alkyl, specifically methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl, more preferably methyl.

[0069] R in structural unit (B) 2 Represents a hydrogen atom or C 1-3 Alkyl groups are preferably hydrogen atoms, methyl, ethyl, n-propyl, or isopropyl, and more preferably hydrogen atoms.

[0070] X 2 Represents oxygen atom, sulfur atom, or NR. 7 Preferably, it is an oxygen atom, a sulfur atom, or NH, and more preferably an oxygen atom.

[0071] n represents an integer from 0 to 3, preferably an integer from 1 to 3, and more preferably 1.

[0072] R 5 Represents hydrogen atom, C 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, preferably C, from the perspective of imparting hydrophobicity to structural unit (B). 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, more preferably C 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, and more preferably C 1-18 Alkyl, 3- to 8-membered cycloalkyl, adamantyl or C 6-18 Aryl. Furthermore, on the other hand, 3- to 8-membered cycloalkyl groups, adamantyl groups, and C4 groups that can have substituents are also preferred. 6-14 The aryl group may be a 6-10 heteroaryl group having substituents. Here, the substituents are preferably one or more selected from halogen atoms, alkyl groups having 1-6 carbon atoms, alkenyl groups having 2-6 carbon atoms, and alkynyl groups having 2-6 carbon atoms.

[0073] R in structural unit (C) 3 Represents a hydrogen atom or C 1-3Alkyl groups are preferably hydrogen atoms, methyl, ethyl, n-propyl, or isopropyl, and more preferably hydrogen atoms.

[0074] X 3 Represents oxygen atom, sulfur atom, or NR. 7 Preferably, it is an oxygen atom, a sulfur atom, or NH, and more preferably an oxygen atom.

[0075] R 6 This refers to a hydrogen atom, a leaving group, or a linking group. The leaving group is a group that can detach when the structural unit (C) is bound to the drug (physiologically active substance), and the linking group is a group that can be used for bridging when the structural unit (C) is bound to the drug (physiologically active substance). Preferably, the C atom may have substituents. 1-18 Alkyl groups, 3- to 8-membered cycloalkyl groups that may have substituents, and C-membered cycloalkyl groups that may have substituents 7-19 Aryl groups. Examples of substituents include: halogen atoms, alkyl groups with 1 to 6 carbon atoms, alkenyl groups with 2 to 6 carbon atoms, alkynyl groups with 2 to 6 carbon atoms, hydroxyl groups, alkoxy groups with 1 to 6 carbon atoms, amino groups, alkylamino groups with 1 to 6 carbon atoms, dialkylamino groups with the same or different alkyl groups, thiols, alkylthiols with 1 to 6 carbon atoms, carboxyl groups, alkoxycarbonyl groups with 1 to 6 carbon atoms, and carbamoyl groups. Among these groups, those having functional groups such as hydroxyl, amino, thiols, or carboxyl groups as substituents are preferred as linking groups.

[0076] As R 6 Preferred examples of the leaving group can be given by, for example, the following formula (4):

[0077]

[0078] As R 6 Preferred examples of the linking group can be given, for example, groups selected from the following formulas (5) to (7):

[0079]

[0080] The copolymer of the present invention is a copolymer having structural units shown in formulas (A), (B), and (C). The copolymer can be a random copolymer or a block copolymer, preferably a random copolymer. The composition ratio of each structural unit in one molecule is preferably such that when (A) is 1 part by mass, (B) is 0.01 to 100 parts by mass and (C) is 0.1 to 100 parts by mass; more preferably, when (A) is 1 part by mass, (B) is 0.05 to 18 parts by mass and (C) is 0.1 to 20 parts by mass; particularly preferably, when (A) is 1 part by mass, (B) is 0.7 to 0.9 parts by mass and (C) is 0.1 to 0.3 parts by mass.

[0081] The degree of polymerization of the copolymers of the present invention is not particularly limited, but is preferably 5,000 to 150,000 in terms of number average molecular weight, and more preferably 8,000 to 150,000.

[0082] In the copolymers of the present invention, as described above, the monomer represented by general formula (1) functions as a unit imparting hydrophilicity, and the monomer represented by general formula (2) functions as a unit imparting hydrophobicity. Furthermore, the monomer represented by general formula (3) functions as a scaffold for binding the drug to the copolymer. Regarding the monomer represented by general formula (2) that functions as a hydrophobic unit, examples include monomers represented by the following formula:

[0083]

[0084]

[0085] In general formula (1), R 1 Represents a hydrogen atom or C 1-3 Alkyl groups are preferably hydrogen atoms, methyl, ethyl, n-propyl, or isopropyl, and more preferably hydrogen atoms.

[0086] In general formula (2), R 2 Represents a hydrogen atom or C 1-3 Alkyl groups are preferably hydrogen atoms, methyl, ethyl, n-propyl, or isopropyl, and more preferably hydrogen atoms.

[0087] In general formula (3), R 3 Represents a hydrogen atom or C 1-3 Alkyl groups are preferably hydrogen atoms, methyl, ethyl, n-propyl, or isopropyl, and more preferably hydrogen atoms.

[0088] In general formula (1), R 4 C represents 1-3 Alkyl, specifically methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl, more preferably methyl.

[0089] In general formula (1), X 1 Represents oxygen atom, sulfur atom, or NR. 7 Preferably, it is an oxygen atom, a sulfur atom, or NH, and more preferably an oxygen atom.

[0090] In general formula (1), m represents an integer from 1 to 100. From the perspective of imparting good hydrophilicity, it is preferably 3 to 80, more preferably 4 to 60, and even more preferably 4 to 40, and even more preferably 4 to 22.

[0091] In general formula (2), R 5 Represents hydrogen atom, C 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents.6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, preferably C, from the perspective of imparting hydrophobicity to structural unit (B). 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, more preferably C 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, and preferably C 1-18 Alkyl, 3- to 8-membered cycloalkyl, adamantyl or C 6-18 Aryl. Furthermore, on the other hand, 3- to 8-membered cycloalkyl groups, adamantyl groups, and C4 groups that can have substituents are also preferred. 6-14 The aryl group may be a 6-10 heteroaryl group having substituents. Here, the substituents are preferably one or more selected from halogen atoms, alkyl groups having 1-6 carbon atoms, alkenyl groups having 2-6 carbon atoms, and alkynyl groups having 2-6 carbon atoms.

[0092] In general formula (2), X 2 Represents oxygen atom, sulfur atom, or NR. 7 Preferably, it is an oxygen atom, a sulfur atom, or NH, and more preferably an oxygen atom.

[0093] In general formula (2), n represents an integer from 0 to 3, preferably from 1 to 3, and more preferably 1.

[0094] In general formula (3), R 6 This represents a hydrogen atom, a leaving group, or a linking group. Preferably, these leaving groups or linking groups are C atoms that can have substituents. 1-18 Alkyl groups, 3- to 8-membered cycloalkyl groups that may have substituents, and C-membered cycloalkyl groups that may have substituents 7-19 Aryl groups. Examples of substituents include: halogen atoms, alkyl groups with 1 to 6 carbon atoms, alkenyl groups with 2 to 6 carbon atoms, alkynyl groups with 2 to 6 carbon atoms, hydroxyl groups, alkoxy groups with 1 to 6 carbon atoms, amino groups, alkylamino groups with 1 to 6 carbon atoms, dialkylamino groups with the same or different alkyl groups, thiols, alkylthiols with 1 to 6 carbon atoms, carboxyl groups, alkoxycarbonyl groups with 1 to 6 carbon atoms, and carbamoyl groups. Among these groups, those having functional groups such as hydroxyl, amino, thiols, or carboxyl groups as substituents are preferred as linking groups.

[0095] As R 6 Preferred examples of the leaving group can be given by, for example, the following formula (4):

[0096]

[0097] As R 6 Preferred examples of the linking group can be given, for example, groups selected from the following formulas (5) to (7):

[0098]

[0099] In general formula (3), X 3 Represents oxygen atom, sulfur atom, or NR. 7 Preferably, it is an oxygen atom, a sulfur atom, or NH, and more preferably an oxygen atom.

[0100] The copolymer of the present invention is a copolymer formed by copolymerizing the three monomers shown in general formulas (1) to (3). The copolymerization can be random copolymerization or block copolymerization, and is preferably formed by random copolymerization. Regarding the mixing ratio of the three monomers, when the mass part of monomer (1) is set to 1, it is preferable to polymerize 0.01 to 100 mass parts of monomer (2) and 0.1 to 100 mass parts of monomer (3), more preferably to polymerize 0.05 to 18 mass parts of monomer (2) and 0.1 to 20 mass parts of monomer (3), and particularly preferably to polymerize 0.7 to 0.9 mass parts of monomer (2) and 0.1 to 0.3 mass parts of monomer (3).

[0101] Furthermore, the copolymers of the present invention also include "solvents" coordinated with various solvents. In this specification, examples of "solvents" include, for instance, hydrates or ethanol compounds. The solvent can be coordinated with the copolymers of the present invention in any amount.

[0102] In this specification, "pharmaceutical composition" means a copolymer of the present invention on which an effective ingredient (drug, physiologically active substance) is supported for the diagnosis, prevention, or treatment of a disease through electrostatic interactions, hydrogen bonds, hydrophobic interactions, or covalent bonds. As a form of support, when the copolymer forms nanoparticles, examples include a form in which the drug is present on the surface of the particles, a form in which the drug is encapsulated within the nanoparticles, or a combination thereof.

[0103] The copolymers of the present invention can be manufactured by various known methods. There are no particular limitations on the manufacturing method; for example, they can be manufactured according to the basic polymer synthesis methods described below.

[0104]

[0105] In the formula, R' represents a hydrogen atom or C. 1-3 Alkyl, R" indicates the above R 4 R 5 Or R 6 The base shown

[0106] This reaction describes the step of reacting monomer (I) with a chain transfer agent (II) and an initiator to produce polymer (III). This reaction can be carried out in the absence of solvent, or in solvents such as methanol, ethanol, 1-propanol, 2-propanol, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; and solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, ethyl acetate, etc., preferably using aromatic hydrocarbons such as toluene, xylene, etc. as solvents. As chain transfer agents, the following can be used: 2-(dodecylthiocarbonocarbonylthio)-2-methylpropionic acid (DDMAT), cyanomethyldodecyltrithiocarbonate (CDTTC), 2-cyano-2-propyldodecyl trithiocarbonate (CPDTTC), and 4-cyano-4-[(dodecylsulfanyl-thiocarbonyl)sulfanyl]pentanoic acid (CDSPA), with DDMAT being preferred.

[0107] When using a chain transfer agent for polymerization, the copolymers of the present invention have a structure in which the chain transfer agent is partially or completely incorporated. In cases where the copolymer contains a chain transfer agent, this structure can be removed by appropriate methods. As initiators, azo-based polymerization initiators such as 2,2'-azobis-isobutyronitrile (AIBN), 1,1'-azobis(cyclohexanecarbonitrile) (ACHN), 2,2'-azobis(2-methylbutyronitrile) (AMBN), and 2,2'-azobis-2,4-dimethylvaleronitrile (ADVN) can be used, with AIBN being preferred. The reaction temperature is 0–300°C, preferably 0–150°C, more preferably room temperature to 100°C, and the reaction time is 1 minute to 48 hours, preferably 5 minutes to 24 hours. In this reaction, random copolymers can be produced by reacting with monomers (I) of different structures in coexistence.

[0108] The copolymers of the present invention can be purified using methods of separation and purification of polymers commonly known in the field of polymer chemistry. Specifically, examples include: extraction, recrystallization, salting out using ammonium sulfate or sodium sulfate, centrifugation, dialysis, ultrafiltration, adsorption chromatography, ion exchange chromatography, hydrophobic chromatography, normal phase chromatography, reverse phase chromatography, gel filtration, gel permeation chromatography, affinity chromatography, electrophoresis, countercurrent partitioning, etc.; or combinations of these methods.

[0109] The copolymers of the present invention can be used as carriers for delivering various physiologically active substances (pharmaceuticals). For example, pharmaceutical compositions obtained by loading (encapsulating) tumor therapeutic agents in the copolymers of the present invention have been shown to inhibit tumor growth in the test examples described later, and therefore can be used, for example, as preventive and / or therapeutic agents for various cancers such as colorectal cancer, duodenal cancer, gastric cancer, pancreatic cancer, liver cancer, lung cancer, uterine cancer, and ovarian cancer. Furthermore, due to their high tumor aggregation capacity, they can be used as diagnostic agents and contrast agents for tumors.

[0110] When the copolymer of the present invention is used as a drug delivery carrier, the dosage and frequency of administration can be appropriately selected by taking into account the administration method, the patient's age, weight, the nature or severity of the symptoms to be treated, etc. The dosage and frequency of administration should not be limited. When the polymer containing the drug is injected intravenously, for each adult (60 kg), for example, a dosage of 0.12 mg to 12,000,000 mg is preferred in a single administration, more preferably 1.2 mg to 1200,000 mg, and particularly preferably 12 to 120,000 mg.

[0111] The pharmaceutical compositions of the present invention can be manufactured by mixing the copolymers of the present invention with a drug. Preferably, the single-chain nanoparticles are manufactured by mixing the copolymers of the present invention with a drug, or the drug is mixed in after manufacturing the single-chain nanoparticles of the copolymers of the present invention. The single-chain nanoparticles can be manufactured by known methods.

[0112] In the pharmaceutical composition of the present invention, the drug can be supported on the copolymer through electrostatic interactions, hydrogen bonds, hydrophobic interactions, or covalent bonds, etc.

[0113] Examples of drugs used for various cancers include: pemetrexed sodium, mitomycin C, bleomycin hydrochloride, aclarubicin hydrochloride, amrubicin hydrochloride, epirubicin hydrochloride, doxorubicin hydrochloride, pirarubicin hydrochloride, irinotecan hydrochloride, etoposide, docetaxel, toponotecan hydrochloride, paclitaxel, vinorelbine tartrate, vinblastine sulfate, oxaliplatin, carfilzomib, carboplatin, cisplatin, tesimolimus, trabectedin, fulvestrant, bortezomib, mitoxantrone hydrochloride, miplatin, emtansine, SN-38, monomethylaurestatin E, monomethylaurestatin F, and asteroidin. When these drugs are formulated into the pharmaceutical compositions of the present invention, the drugs only need to be supported on the copolymer as free entities.

[0114] The route of administration of the pharmaceutical composition of the present invention is preferably the most effective for treatment. Administration can be performed using non-oral formulations such as oral, injectable, or transdermal formulations. For example, intra-arterial, intravenous, subcutaneous, intramuscular, and intraperitoneal injections are preferred, with intra-arterial and intravenous injections being more preferred. The frequency of administration is not limited; examples include, on average, once to several times per week.

[0115] Various formulations suitable for different routes of administration may appropriately select excipients, expanders, binders, wetting agents, disintegrants, lubricants, surfactants, dispersants, buffers, preservatives, solubilizers, preservatives, taste and odor modifiers, analgesics, stabilizers, and isotonic agents, and manufacture them according to conventional methods.

[0116] Pharmaceutical additives that can be included in the above-mentioned formulations are pharmaceutically acceptable and are not particularly limited. Examples of such additives include: purified water, water for injection, distilled water for injection, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyethylene polymers, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin wax, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, and lactose. The additives used can be appropriately selected according to the various formulations, used alone or in combination.

[0117] In addition, injectable preparations can also be formulated as non-aqueous diluents (such as polyethylene glycol, vegetable oils like olive oil, and alcohols like ethanol), suspensions, or emulsions. Aseptic preparation of injectable preparations can be achieved through filtration sterilization using filters, formulation of sterilizing agents, etc. Furthermore, injectable preparations can be formulated into a form ready for immediate use. That is, a sterile solid composition can be prepared using methods such as freeze-drying, and then dissolved in water for injection, distilled water for injection, or other solvents before use.

[0118] Example

[0119] The present invention will be further described in detail below through embodiments. These embodiments are provided for illustration only and do not limit the implementation of the present invention.

[0120] [Example 1] Preparation of poly[(benzyl acrylate)-co-(poly(ethylene glycol) methyl ether acrylate)-co-(1-ethoxyethyl acrylate)]

[0121] (1) Synthesis of 1-ethoxyethyl acrylate (EEA)

[0122] Under argon atmosphere, 28.725 mL of ethyl vinyl ether was weighed and 50 mg of phosphoric acid was added while cooling in an ice bath. Then, 17.15 mL of acrylic acid was added, and the mixture was stirred at room temperature for 48 hours. Hydrotalcite (3 g) was added, and the mixture was stirred for another 2 hours to terminate the reaction. After filtration through diatomaceous earth, unreacted ethyl vinyl ether was removed by evaporation. Phenothiazine, a polymerization inhibitor, was added to reach 500 ppm, and the mixture was purified by distillation under reduced pressure with calcium hydride (distillation temperature 28-32 °C). The resulting 1-ethoxyethyl acrylate was aliquoted into glass vials and stored at -30 °C.

[0123] 13 C NMR (400MHz, CDCl3), δ, ppm: 15.29(-OCH2CH3), 21.16(-COOCH(CH3)), 64.98(-OCH2-), 96.73(-COOCH(CH3)), 128.84(CH2CH-), 131.43(CH2CH-), 166.00(-COO).

[0124] (2) Synthesis of poly[(benzyl acrylate)-co-(poly(ethylene glycol) methyl ether acrylate)-co-(1-ethoxyethyl acrylate)]

[0125] 100 mg of 2-(dodecylthiothiocarbonylthio)-2-methylpropionic acid (DDMAT) was weighed and dissolved in 17.3 mL of toluene to prepare a DDMAT / toluene stock solution (5.78 mg / mL based on DDMAT concentration). Similarly, 22 mg of 2,2'-azobis(2-methylpropionitrile) (AIBN) was weighed and dissolved in 17.3 mL of toluene to prepare an AIBN / toluene stock solution (1.27 mg / mL based on AIBN concentration). Additionally, 1.296 g of poly(ethylene glycol) methyl ether acrylate (mPEGA, with an average n of 9 repetitions of ethylene glycol), 0.394 g of benzyl acrylate (BnA), 0.039 g of 1-ethoxyethyl acrylate, 1.73 mL of DDMAT / toluene stock solution, and 1.73 mL of AIBN / toluene stock solution were added, and polymerization was carried out in an oil bath at 70 °C. After 90 minutes, the polymerization was terminated, and the reaction solution was dialyzed with methanol or by reprecipitation to recover the copolymer. Since the obtained copolymer was essentially a viscous substance, for the reprecipitation method, the reaction solution was added dropwise to a centrifuge tube containing a poor solvent (hexane / ethyl acetate = 7 / 3 [v / v]), and the recovery operation was repeated three times by centrifugation (2,000 × g, 5 min). Finally, vacuum drying was performed to obtain 1.223 g of poly[(benzyl acrylate)-co-(poly(ethylene glycol) methyl ether acrylate)-co-(1-ethoxyethyl acrylate)].

[0126] The obtained copolymer was analyzed using NMR, and the results were based on... 1 H-NMR spectra, for the degree of polymerization and number-average molecular weight (Mn) of each monomer. n,NMR Analysis revealed that the degree of polymerization of mPEGA (n=9) was 102, that of BnA was 94, and that of EEA was 9. n,NMR The value was 65,900. Furthermore, the molecular weight dispersion (M...) of the resulting copolymer was assessed using GPC. w / M n The result was 1.53.

[0127]

[0128] [Measuring apparatus and conditions, etc.]

[0129] (1) 1 H-NMR measurement

[0130] Device: JNM-ECX400 (400MHz) / NEC

[0131] Solvent: Dimethyl sulfoxide-d6 / Kanto Chemical containing 0.03% tetramethylsilane

[0132] Sample concentration: 20 mg / mL

[0133] Measurement temperature: 25℃

[0134] Total number of times: 256

[0135] result: Figure 1

[0136] (2) GPC determination

[0137] Apparatus: HPLC-Prominence system / Shimadzu Corporation

[0138] Detector: RID-10A Refractive Index Detector / Shimadzu Corporation

[0139] Column: TSKgelα-2500 column / Tosoh Corporation

[0140] (Column size 7.8mm × 300mm, particle size 7μm)

[0141] Excluding the limiting molecular weight of 5×10 3 )

[0142] TSKgelα-4000 column / Tosoh Corporation

[0143] (Column dimensions 7.8mm × 300mm, particle size 10μm)

[0144] Excluding the limiting molecular weight of 4×10 5 )

[0145] TSKgel Protective Tube Column / Tosoh Corporation

[0146] Mobile phase: N,N-dimethylformamide (DMF) containing 10 mmol / L lithium bromide.

[0147] Temperature: 40℃

[0148] Flow rate: 0.5 mL / min

[0149] Sample concentration: 6 mg / mL

[0150] Standard substance: Poly(methyl methacrylate) standard ReadyCal kit, M p 800-2,200,000Da / SIGMA

[0151] result: Figure 2

[0152] [Table 1]

[0153]

[0154] [Examples 2-68]

[0155] By appropriately modifying the types, amounts, reaction temperatures, and polymerization times of the monomers (mPEGA, BnA, EEA) used in Example 1, polymers with different composition ratios and average molecular weights as shown in the table below were manufactured using the same method as in Example 1.

[0156] [Table 2]

[0157]

[0158]

[0159]

[0160] [Table 3]

[0161]

[0162]

[0163] [Example 69]

[0164] Manufacturing of poly[(benzyl acrylate)-co-(poly(ethylene glycol) methyl ether acrylate)-co-(acrylic acid)]

[0165] The poly[(benzyl acrylate)-co-(poly(ethylene glycol) methyl ether acrylate)-co-(1-ethoxyethyl acrylate)] obtained in Example 1 was treated with 0.5N HCl at room temperature to remove the ethoxyethyl group, yielding 1.176 g of a terpolymer with carboxyl groups. The Z-mean particle size and polydispersity index of the obtained terpolymer in water were determined by dynamic light scattering (DLS), and the result was 8.5 nm (polydispersity index 0.14).

[0166] [Measuring apparatus and conditions, etc.]

[0167] (1) DLS measurement

[0168] Device: Zetasizer NanoZS / Malvern Instruments Ltd.

[0169] Measurement temperature: 25℃

[0170] Sample concentration: 10 mg / mL

[0171] result: Figure 3

[0172]

[0173] [Example 70]

[0174] Method for manufacturing SCNP containing (1,2-diaminocyclohexane)platinum(II)

[0175] 65.28 mg of the Cl(H2O) form of (1,2-diaminocyclohexane)platin(II) (hereinafter referred to as DACHPt) (DACHPt·Cl·H2O) was dissolved in 20 mL of purified water and stirred at 70 °C for 2 hours. 287.4 mg of the terpolymer obtained in Example 69 was added to 5 mL of this solution and stirred at 50 °C for one night. After stirring, the reaction solution was purified by dialysis with purified water as the external solution to obtain 5 mL of SCNP containing DACHPt. The Pt content of the purified SCNP containing DACHPt was determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES), and the result was 720 μg / mL (1.14 mg / mL as DACHPt). In addition, 200 μL of SCNPs encapsulated with DACHPt was freeze-dried. After calculating the concentration of the solid component, the Pt binding amount per polymer was calculated by taking the ratio of the solid component to the Pt content, and the result was 3.4 mol / mol. Furthermore, the Z-mean particle size and polydispersity index of the obtained SCNPs encapsulated with DACHPt were determined by dynamic light scattering (DLS), and the result was 8.7 nm (polydispersity index 0.14). The particle sizes of SCNPs before and after encapsulation with DACHPt are shown in the figure. Figure 3 The particle size of SCNP remained almost unchanged before and after encapsulation with DACHPt. The results are summarized in the table below.

[0176] [Measuring apparatus and conditions, etc.]

[0177] (1) ICP-AES determination

[0178] Device: Sequential high-frequency plasma light emission device ICPE-9000 / Shimadzu Corporation

[0179] Pretreatment apparatus: Microwave sample pretreatment apparatus ETHOS EASY / Milestone General KK

[0180] Measurement wavelength: 342nm

[0181] Standard solution: Gadolinium standard solution (Gd1000) for ICP analysis / Fujifilm and photopurifier (2) DLS determination

[0182] Device: Zetasizer NanoZS / Malvern Instruments Ltd.

[0183] Measurement temperature: 25℃

[0184] Sample concentration: 10 mg / mL

[0185] result: Figure 3

[0186] [Table 4]

[0187]

[0188] [Comparative Example 1]

[0189] Preparation of oxaliplatin solution

[0190] Add 1 mL of 50 mg ELPLAT intravenous infusion solution (Yakritos Corporation) to 5.58 mL of 5.9% (w / v) glucose solution to prepare a 5% (w / v) glucose solution containing 760 μg of oxaliplatin.

[0191] [Experimental Example] Pharmacological Efficacy Test

[0192] A cancer-bearing model was obtained by subcutaneously transplanting mouse colorectal cancer cell line C26 (American Center for Type Culture Collection) into female nude mice (BALB / c-nu nu / nu, 7 weeks old; Charles River Japan strain). This cancer-bearing model was then used in drug efficacy tests.

[0193] Mouse colon cancer cell line C26, which had been subcultured in a CO2 incubator, was suspended in liquid culture medium (Dulbecco's Modified Eagle's Medium-high glucose, Sigma-Aldrich) at a concentration of 1 × 10⁶ cells per mouse. 6 The tumor was injected subcutaneously into the back of nude mice at a dose of 100 μL. After approximately one week of feeding, the average tumor volume had grown to approximately 30 mm. 3 Then, drug administration began. SCNPs encapsulated with DACHPt (SCNPs encapsulated with DACHPt prepared using the copolymer of Example 70) were administered intravenously into the tail vein (3 times every other day), and the antitumor effect was evaluated based on tumor volume (4-5 animals per group). As a comparison, oxaliplatin solution (Comparative Example 1) was used and administered in the same manner. Regarding the dosage of each formulation, in the case of oxaliplatin solution, the highest dosable dose was 8 mg / kg (3.9 mg / kg converted to Pt), and in the case of SCNPs encapsulated with DACHPt, it was 3 mg / kg converted to Pt.

[0194] The changes in tumor volume over time are shown in Figure 4In the case of SCNPs encapsulated with DACHPt, the T / C ratio was 0.4 after 14 days of administration [T / C: tumor volume ratio of the drug-treated group (T) to the control group (C)]. In the case of oxaliplatin solution (Comparative Example 1), the T / C ratio was 1.1 after 14 days of administration. Furthermore, after 14 days of administration, it was confirmed that SCNPs encapsulated with DACHPt significantly inhibited tumor growth compared to the control group (student's t-test). These results indicate that SCNPs encapsulated with DACHPt have superior antitumor effects compared to oxaliplatin solution.

Claims

1. A random copolymer, characterized in that: It is composed of structural units shown in equations (A), (B), and (C). The ratio of structural units (A), (B), and (C) is such that, relative to 1 part by mass of (A), they consist of 0.01 to 100 parts by mass of (B) and 0.1 to 100 parts by mass of (C). In the formula, R 1 R 2 and R 3 Representing hydrogen atoms or C atoms in the same or different ways 1-3 Alkyl, R 4 C represents 1-3 Alkyl, R 5 Represents hydrogen atom, C 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, X 1 X 2 and X 3 Representing oxygen atoms, sulfur atoms, or NR in the same or different ways 7 R 6 Represents a hydrogen atom, leaving group, or linker group, which is a group that can be used for bridging when the structural unit (C) binds to the drug; R 7 Represents a hydrogen atom or C 1-3 Alkyl group, where m represents an integer from 1 to 100 and n represents an integer from 0 to 3.

2. A random copolymer, characterized in that: It is a copolymer formed by polymerizing three monomers represented by the following general formulas (1) to (3), wherein 0.01 to 100 parts by mass of monomer (2) and 0.1 to 100 parts by mass of monomer (3) are polymerized relative to 1 part by mass of monomer (1). In the formula, R 1 R 2 and R 3 Representing hydrogen atoms or C atoms in the same or different ways 1-3 Alkyl, R 4 C represents 1-3 Alkyl, R 5 Represents hydrogen atom, C 1-18 Alkyl groups, 3-8 membered cycloalkyl groups that may have substituents, adamantyl groups, and C4 groups that may have substituents. 6-18 Aryl, or 5-10 heteroaryl groups that may have substituents, X 1 X 2 and X 3 Representing oxygen atoms, sulfur atoms, or NR in the same or different ways 7 R 6 Represents a hydrogen atom, leaving group, or linker, which is a group that can be used for bridging when a structural unit derived from monomer (3) is bound to a drug, R 7 Represents a hydrogen atom or C 1-3 Alkyl group, where m represents an integer from 1 to 100 and n represents an integer from 0 to 3.

3. The random copolymer as described in claim 1 or 2, characterized in that: R 1 It is a hydrogen atom.

4. The random copolymer as described in claim 1 or 2, characterized in that: R 2 It is a hydrogen atom.

5. The random copolymer as described in claim 1 or 2, characterized in that: R 3 It is a hydrogen atom.

6. The random copolymer as described in claim 1 or 2, characterized in that: R 4 It is a methyl group.

7. The random copolymer as described in claim 1 or 2, characterized in that: R 5 C that can have substituents 6-18 Aryl.

8. The random copolymer as described in claim 1 or 2, characterized in that: R 5 It is a phenyl group.

9. The random copolymer as described in claim 1 or 2, characterized in that: R 6 It is a hydrogen atom.

10. The random copolymer according to claim 1 or 2, characterized in that: R 6 The leaving group is given by formula (4).

11. The random copolymer according to claim 1 or 2, characterized in that: R 6 The connecting bases are given by equations (5) to (7).

12. The random copolymer as described in claim 1 or 2, characterized in that: X 1 It is an oxygen atom.

13. The random copolymer as described in claim 1 or 2, characterized in that: X 2 It is an oxygen atom.

14. The random copolymer according to claim 1 or 2, characterized in that: X 3 It is an oxygen atom.

15. The random copolymer as described in claim 1 or 2, characterized in that: m is an integer from 4 to 22.

16. The random copolymer as described in claim 1 or 2, characterized in that: n is 1.

17. The random copolymer according to claim 1 or 2, characterized in that: The number average molecular weight is 5,000 to 150,000.

18. A single-chain nanoparticle, characterized in that: It comprises any one of the random copolymers according to claims 1 to 17.

19. A pharmaceutical composition, characterized in that: It includes any one of the random copolymers according to claims 1 to 17, and a drug that can be supported on the random copolymer through electrostatic interaction, hydrogen bonding, hydrophobic interaction or covalent bonding.

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