Cell-adhesive composition and polymer-coated microparticles

Abstract

[Problem] To provide a cell-adhesive composition containing an oxyethylene chain-containing polymer having excellent biocompatibility and excellent reactivity. [Solution] This cell-adhesive composition contains an oxyethylene chain-containing polymer represented by general formula (1) (in general formula (1), R1 is-(CH2) p-SH,-(CH2) p-N3,-(CH2) p-NH2, or-(CH2) p-COOH, p is an integer of 1-5, R2-R4 are each independently hydrogen or an alkyl group having 1-10 carbon atoms, R5 is an alkyl group having 1-10 carbon atoms, R6 is hydrogen or an alkyl group having 1-5 carbon atoms, R7 is an alkyl group having 1-10 carbon atoms, n is an integer of 5-1000, and n is an integer of 5-1000. M is an integer of 1-10, and q is an integer of 0-5. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a cell-adhesive composition comprising an oxyethylene chain-containing polymer. In addition, the present invention relates to microparticles coated with an oxyethylene chain-containing polymer. Background Art

[0002] Conventionally, vinyl ether polymers have been used as a component of chemicals such as adhesives, coatings, and lubricants. It is known that vinyl ethers generally have electron-donating substituents, and therefore vinyl ether polymers are obtained by cationic polymerization. For the purpose of modifying vinyl ether polymers, polymerization methods for introducing functional groups at the ends have been studied. For example, it has been proposed to introduce acetal groups at the ends of vinyl ether polymers (see Patent Documents 1 and 2).

[0003] In addition, polymers containing oxyethylene chains are materials with excellent biocompatibility. In order to utilize polymers containing oxyethylene chains as biomaterials, it is indispensable to introduce highly reactive functional groups. However, polymers containing oxyethylene chains with highly reactive functional groups introduced at the ends are not known.

[0004] In recent years, as a method for improving the blood retention of drug delivery systems (DDS), polyethylene glycol (PEG) is most widely used. The reason is that PEG exerts an effect (stealth, stealth) of suppressing the adsorption and immune recognition of proteins. However, it is known that PEG suppresses the interaction with cells (such as cancer cells) as targets at the same time due to its high stealth, and therefore the amount of delivery of medicaments to cells is greatly reduced. This is called the dilemma of PEG, which is one of the important issues in DDS.

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: Japanese Patent Application Publication No. 2003-201315

[0008] Patent Document 2: Japanese Patent Application Publication No. 2004-244535 Summary of the invention

[0009] Problems to be solved by the invention

[0010] The inventors of the present application have attempted to develop DDS using poly-2-methoxyethyl vinyl ether (PMOVE), a vinyl ether polymer containing an oxyethylene chain, instead of PEG. PMOVE has excellent biocompatibility like PEG and can be expected to exhibit high stealth properties, but since PMOVE with highly reactive substituents has not been developed, it cannot be fully utilized as DDS.

[0011] Therefore, an object of the present invention is to provide a cell adhesive composition comprising an oxyethylene chain-containing polymer having excellent biocompatibility and excellent reactivity. Another object of the present invention is to provide microparticles having excellent biocompatibility and coated with an oxyethylene chain-containing polymer.

[0012] Means for solving problems

[0013] The inventors of the present application have conducted intensive studies to solve the above problems and have found that the above problems can be solved by using a polymer having an oxyethylene chain having a highly reactive functional group introduced at one end (ω end), thereby completing the present invention.

[0014] That is, according to the present invention, the following inventions are provided.

[0015] [1] A cell adhesive composition comprising an oxyethylene chain-containing polymer represented by the following general formula (1),

[0016] [Chemical formula 1]

[0017]

[0018] (In general formula (1), R 1 -(CH2) p -SH, -(CH2) p -N3, -(CH2) p -NH2, or -(CH2) p -COOH, p is an integer from 1 to 5,

[0019] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 10 carbon atoms,

[0020] R 5 is an alkyl group having 1 to 10 carbon atoms,

[0021] R 6 is hydrogen or an alkyl group having 1 to 5 carbon atoms,

[0022] R 7 is an alkyl group having 1 to 10 carbon atoms,

[0023] n is an integer from 5 to 1000,

[0024] m is an integer from 1 to 10,

[0025] q is an integer from 0 to 5).

[0026] [2] The cell adhesive composition according to [1], wherein in the general formula (1), R 1 -(CH2) p-SH, p is an integer from 1 to 3,

[0027] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms,

[0028] R 5 is an alkyl group having 1 to 4 carbon atoms,

[0029] R 6 is an alkyl group having 1 to 2 carbon atoms,

[0030] R 7 is an alkyl group having 1 to 7 carbon atoms,

[0031] n is an integer from 10 to 500,

[0032] m is an integer from 1 to 5,

[0033] q is an integer from 0 to 2.

[0034] [3] The cell adhesive composition according to [1], wherein in the general formula (1), R 1 -(CH2) p -N3, p is an integer from 1 to 3,

[0035] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms,

[0036] R 5 is an alkyl group having 1 to 4 carbon atoms,

[0037] R 6 is an alkyl group having 1 to 2 carbon atoms,

[0038] R 7 is an alkyl group having 1 to 7 carbon atoms,

[0039] n is an integer from 10 to 500,

[0040] m is an integer from 1 to 5,

[0041] q is an integer from 0 to 2.

[0042] [4] The cell adhesive composition according to [1], wherein in the general formula (1), R 1 -(CH2) p -NH2, p is an integer from 1 to 3,

[0043] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms,

[0044] R5 is an alkyl group having 1 to 4 carbon atoms,

[0045] R 6 is an alkyl group having 1 to 2 carbon atoms,

[0046] R 7 is an alkyl group having 1 to 7 carbon atoms,

[0047] n is an integer from 10 to 500,

[0048] m is an integer from 1 to 5,

[0049] q is an integer from 0 to 2.

[0050] [5] The cell adhesive composition according to [1], wherein in the general formula (1), R 1 -(CH2) p -COOH, p is an integer from 1 to 3,

[0051] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms,

[0052] R 5 is an alkyl group having 1 to 4 carbon atoms,

[0053] R 6 is an alkyl group having 1 to 2 carbon atoms,

[0054] R 7 is an alkyl group having 1 to 7 carbon atoms,

[0055] n is an integer from 10 to 500,

[0056] m is an integer from 1 to 5,

[0057] q is an integer from 0 to 2.

[0058] [6] The cell adhesive composition according to any one of [1] to [5], wherein the number average molecular weight (Mn) of the oxyethylene chain-containing polymer is 500 to 100,000.

[0059] [7] The cell adhesive composition according to any one of [1] to [6], wherein the ratio of the weight average molecular weight (Mw) to the number average molecular weight (Mn) of the oxyethylene chain-containing polymer is 1.0 to 3.0.

[0060] [8] polymer-coated microparticles, which are microparticles coated with a polymer containing oxyethylene chains,

[0061] The aforementioned polymer containing ethylene oxide chains is represented by the following general formula (1):

[0062] [Chemical formula 2]

[0063]

[0064] (In general formula (1), R 1 -(CH2) p -SH, -(CH2) p -N3, -(CH2) p -NH2, or -(CH2) p -COOH, p is an integer from 1 to 5,

[0065] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 10 carbon atoms,

[0066] R 5 is an alkyl group having 1 to 10 carbon atoms,

[0067] R 6 is hydrogen or an alkyl group having 1 to 5 carbon atoms,

[0068] R 7 is an alkyl group having 1 to 10 carbon atoms,

[0069] n is an integer from 5 to 1000,

[0070] m is an integer from 1 to 10,

[0071] q is an integer from 0 to 5).

[0072] [9] The polymer-coated fine particles according to [8], wherein in the general formula (1), R 1 -(CH2) p -SH, p is an integer from 1 to 3,

[0073] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms,

[0074] R 5 is an alkyl group having 1 to 4 carbon atoms,

[0075] R 6 is an alkyl group having 1 to 2 carbon atoms,

[0076] R 7 is an alkyl group having 1 to 7 carbon atoms,

[0077] n is an integer from 10 to 500,

[0078] m is an integer from 1 to 5,

[0079] q is an integer from 0 to 2.

[0080]

[10] The polymer-coated fine particles according to [8], wherein in the general formula (1), R 1 -(CH2) p -N3, p is an integer from 1 to 3,

[0081] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms,

[0082] R 5 is an alkyl group having 1 to 4 carbon atoms,

[0083] R 6 is an alkyl group having 1 to 2 carbon atoms,

[0084] R 7 is an alkyl group having 1 to 7 carbon atoms,

[0085] n is an integer from 10 to 500,

[0086] m is an integer from 1 to 5,

[0087] q is an integer from 0 to 2.

[0088]

[11] The polymer-coated fine particles according to [8], wherein in the general formula (1), R 1 -(CH2) p -NH2, p is an integer from 1 to 3,

[0089] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms,

[0090] R 5 is an alkyl group having 1 to 4 carbon atoms,

[0091] R 6 is an alkyl group having 1 to 2 carbon atoms,

[0092] R 7 is an alkyl group having 1 to 7 carbon atoms,

[0093] n is an integer from 10 to 500,

[0094] m is an integer from 1 to 5,

[0095] q is an integer from 0 to 2.

[0096]

[12] The polymer-coated fine particles according to [8], wherein in the general formula (1), R 1 -(CH2) p -COOH, p is an integer from 1 to 3,

[0097] R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms,

[0098] R 5 is an alkyl group having 1 to 4 carbon atoms,

[0099] R 6 is an alkyl group having 1 to 2 carbon atoms,

[0100] R 7 is an alkyl group having 1 to 7 carbon atoms,

[0101] n is an integer from 10 to 500,

[0102] m is an integer from 1 to 5,

[0103] q is an integer from 0 to 2.

[0104]

[13] The polymer-coated fine particles according to any one of [8] to

[12] , wherein the number average molecular weight (Mn) of the oxyethylene chain-containing polymer is 500 to 100,000.

[0105]

[14] The polymer-coated fine particles according to any one of [8] to

[13] , wherein the ratio of the weight average molecular weight (Mw) to the number average molecular weight (Mn) of the oxyethylene chain-containing polymer is 1.0 to 3.0.

[0106]

[15] The polymer-coated fine particles according to any one of [8] to

[14] , wherein the fine particles are at least one inorganic fine particle selected from the group consisting of gold, platinum, silver, and silica.

[0107]

[16] The polymer-coated fine particles according to any one of [8] to

[15] , wherein the average particle size of the fine particles is from 10 nm to 500 nm.

[0108]

[17] A cell adhesive composition comprising the polymer-coated fine particles according to any one of [8] to

[16] .

[0109] Effects of the Invention

[0110] According to the present invention, a cell adhesive composition comprising a polymer containing an oxyethylene chain having excellent biocompatibility and excellent reactivity or microparticles coated with the polymer can be provided. In addition, according to the present invention, microparticles having excellent biocompatibility and coated with a polymer containing an oxyethylene chain can be provided. The biocompatibility and cell adhesiveness of these cell adhesive compositions and polymer-coated microparticles are excellent, and high stealth can be brought into play, so they can be effectively utilized as DDS. BRIEF DESCRIPTION OF THE DRAWINGS

[0111] [Figure 1 ] is the reaction product (polymer containing ethylene oxide chain) and its precursor measured in Synthesis Example 1 1 H-NMR spectrum.

[0112] [ Figure 2 ] is the reaction product (polymer containing ethylene oxide chain) and its precursor measured in Synthesis Example 2 1 H-NMR spectrum. DETAILED DESCRIPTION

[0113] <Cell Adhesive Composition>

[0114] The cell adhesive composition of the present invention comprises the polymer of the oxyethylene chain stated in detail below. In addition, the cell adhesive composition of the present invention can comprise the polymer coated microparticles stated in detail below. The cell adhesive composition of the present invention can also comprise medicament, other additives except the polymer and the polymer coated microparticles comprising the oxyethylene chain. The biocompatibility of the polymer of the oxyethylene chain stated in detail below is excellent, and the cell adhesiveness is excellent. Therefore, the biocompatibility and the cell adhesiveness of the cell adhesive composition comprising the polymer of the oxyethylene chain are excellent, and high stealth can be brought into play, so it can be effectively utilized as DDS.

[0115] <Polymers containing ethylene oxide chains>

[0116] The polymer containing oxyethylene chains is represented by the following general formula (1).

[0117] [Chemical formula 3]

[0118]

[0119] In the general formula (1), R 1 -(CH2) p -SH, -(CH2) p -N3, -(CH2) p -NH2, or -(CH2) p -COOH.

[0120] p is an integer of 1-5, preferably an integer of 1-3, and more preferably 1 or 2.

[0121] R 2 ~R 4 Each is independently hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 4 carbon atoms, more preferably hydrogen or an alkyl group having 1 to 3 carbon atoms, further preferably hydrogen or an alkyl group having 1 to 2 carbon atoms, and still more preferably hydrogen.

[0122] R 5It is an alkyl group having 1 to 10 carbon atoms, preferably an alkyl group having 1 to 10 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, and further preferably an alkyl group having 1 to 2 carbon atoms.

[0123] R 6 It is hydrogen or an alkyl group having 1 to 5 carbon atoms, preferably an alkyl group having 1 to 2 carbon atoms, and more preferably a methyl group.

[0124] R 7 The alkyl group is an alkyl group having 1 to 10 carbon atoms, preferably an alkyl group having 1 to 7 carbon atoms, and more preferably an alkyl group having 1 to 4 carbon atoms.

[0125] n is an integer of 5 to 1000, preferably an integer of 10 to 500, and more preferably an integer of 20 to 400.

[0126] m is an integer of 1-10, preferably an integer of 1-5, and more preferably an integer of 1-3.

[0127] q is an integer of 0-5, preferably an integer of 0-2, and more preferably an integer of 0-1.

[0128] It should be noted that the above-mentioned alkyl group may be linear or branched.

[0129] In the case of polymers containing ethylene oxide chains, by introducing a thiol group, an azido group, an amino group, or a carboxyl group as a highly reactive functional group at a single end (ω end), it is possible to modify substrates, microparticles, etc. while making biocompatibility excellent. Therefore, biocompatibility can be imparted to substrates, microparticles, etc. In addition, these highly reactive functional groups can also be further converted to further improve performances such as reactivity and modifiability.

[0130] Preferred embodiments of the oxyethylene chain-containing polymer represented by the general formula (1) include the following polymers: In the following formula, n is an integer of 5 to 1000, preferably an integer of 10 to 500, and more preferably an integer of 20 to 400.

[0131] [Chemical formula 4]

[0132]

[0133] [Chemical formula 5]

[0134]

[0135] [Chemical formula 6]

[0136]

[0137] [Chemical formula 7]

[0138]

[0139] The number average molecular weight (Mn) of the polymer containing oxyethylene chains is preferably 500 to 100,000. The lower limit of the number average molecular weight (Mn) is more preferably 700 or more, more preferably 1,000 or more, and more preferably 1,500 or more. In addition, the upper limit is more preferably 70,000 or less, more preferably 50,000 or less, more preferably 30,000 or less, particularly preferably 20,000 or less, and most preferably 10,000 or less. If the number average molecular weight (Mn) of the polymer containing oxyethylene chains is within the above range, the biocompatibility is excellent, and it is easy to modify the substrate, microparticles, etc., and it is easy to impart biocompatibility.

[0140] The ratio of the weight average molecular weight (Mw) to the number average molecular weight (Mn) of the polymer containing an oxyethylene chain of the present invention (molecular weight distribution, Mw / Mn) is preferably 1.0 to 3.0, more preferably 1.0 to 2.0, further preferably 1.0 to 1.5, and further preferably 1.0 to 1.3. If the molecular weight distribution (Mw / Mn) of the polymer containing an oxyethylene chain is within the above range, the performance of the polymer can be easily kept uniform.

[0141] In addition, in the present invention, the number average molecular weight (Mn) and the weight average molecular weight (Mw) can be calculated from a standard polystyrene calibration curve using a gel permeation chromatography (GPC) method.

[0142] <Method for producing oxyethylene chain-containing polymer>

[0143] The embodiment of the method for producing a polymer containing an oxyethylene chain is described. First, using vinyl ether as a raw monomer, in the presence of a polymerization initiator, living cationic polymerization is used to synthesize, for example, a polymer containing an oxyethylene chain having a carbonyl group at one end represented by the following general formula (2). At the end of the polymerization, a small amount of water is added, whereby the terminal cation reacts with water to introduce a carbonyl group. Next, the carbonyl group at one end of the polymer containing an oxyethylene chain represented by the following general formula (2) is converted, thereby introducing a reactive functional group (thiol group, azido group, amino group, or carboxyl group).

[0144] [Chemical formula 8]

[0145]

[0146] It should be noted that in the general formula (2), R 2 ~R 7 , n, m, and q are the same as R in the general formula (1) 2 ~R 7 , n, m, and q are the same.

[0147] In general formula (2), R 2 ~R 7 The preferred embodiments of n, m, and q are also the same as those of R in the general formula (1). 2 ~R 7 The preferred aspects of , n, m, and q are the same.

[0148] As the vinyl ether as the raw material monomer, for example, a vinyl ether represented by the following general formula (3) can be used:

[0149] [Chemical formula 9]

[0150]

[0151] In the general formula (3), R 2 ~R 5 , and m and R in the general formula (1) 2 ~R 5 , and m are the same.

[0152] In general formula (2), R 2 ~R 5 The preferred embodiments of , and m are also the same as those of R in the general formula (1). 2 ~R 5 , and m are the same.

[0153] Examples of the vinyl ether represented by the general formula (3) include 2-methoxyethyl vinyl ether (MOVE), 2-ethoxyethyl vinyl ether (EOVE), diethylene glycol monoethyl monovinyl ether (EOEOVE), and triethylene glycol monomethyl vinyl ether (TEGMVE).

[0154] The polymerization initiator used in the polymerization of the polymer of oxyethylene chain is not particularly limited as long as cationic polymerization is actively carried out, and polymerization initiators known in the past can be used.As polymerization initiator, for example, HI / I2 system initiator (for example, Japanese Patent Laid-Open No. 60-228509 publication), polymerization initiator (for example, Japanese Patent No. 3096494 specification, Japanese Patent No. 7-2805 publication, Japanese Patent Laid-Open No. 62-257910 publication, Japanese Patent Laid-Open No. 1-108202 publication and Japanese Patent Laid-Open No. 1-108203 publication) etc., which are preferably used as active cationic polymerization initiators of vinyl ethers, can be preferably used.

[0155] The amount of the polymerization initiator used is preferably 0.001 to 20 mol %, more preferably 0.01 to 10 mol %, particularly preferably 1 mol % or less, based on the total amount of the raw material monomers.

[0156] In addition, the living cationic polymerization reaction is preferably carried out under the condition of the presence of a suitable organic solvent, but it can also be carried out under the condition of the absence of a suitable organic solvent. As the usable organic solvent, for example, aromatic hydrocarbon solvents such as benzene, toluene, and xylene can be cited; aliphatic hydrocarbon solvents such as propane, n-butane, isobutane, n-pentane, isopentane, n-hexane, n-heptane, n-octane, isooctane, decane, hexadecane, and cyclohexane; halogenated hydrocarbon solvents such as dichloromethane, ethylene chloride, and carbon tetrachloride; ether solvents such as ether, dibutyl ether, tetrahydrofuran (THF), dioxane, and ethylene glycol diethyl ether. These organic solvents can be used alone or in combination of two or more as needed. In addition, among these organic solvents, hydrocarbon solvents such as aromatic hydrocarbon solvents and aliphatic hydrocarbon solvents are preferred, preferably toluene, THF, etc.

[0157] The polymerization temperature in the living cationic polymerization reaction varies according to the type of polymerization initiator, monomer, solvent, etc. used, and is usually -80 to 150°C, preferably -50 to 100°C, and particularly preferably -20 to 80°C. In addition, the polymerization time varies according to the polymerization initiator, monomer, solvent, reaction temperature, etc. used, and is usually about 10 minutes to 100 hours. The polymerization reaction can be suitably carried out by any method in a batch type or a continuous type. After the polymerization reaction, in order to remove the unreacted monomer, a purification treatment can be carried out by a known method as needed.

[0158] Below, an example of the polymerization reaction of a polymer containing an oxyethylene chain (PMOVE) using 2-methoxyethyl vinyl ether (MOVE) as a raw material monomer is shown. First, MOVE is used in the presence of a polymerization initiator to synthesize PMOVE having a carbonyl group at one end using the following reaction formula (I). A small amount of water is added at the end of the polymerization, whereby the terminal cation reacts with water to introduce a carbonyl group. The polymerization reaction conditions of the following reaction formula (I) can be referred to J.Polym.Sci., Part A:Polym.Chem.2005,43,468-472. It should be noted that in the following reaction formulas (I) to (V), n in PMOVE is an integer of 5 to 1000, similarly to the general formula (1), preferably an integer of 10 to 500, and more preferably an integer of 20 to 400.

[0159] [Chemical formula 10]

[0160]

[0161] Hereinafter, the synthesis method (reaction formula) of PMOVE is described according to the type of reactive functional group. The catalyst, polymerization initiator, and solvent in the following series of reactions can be appropriately selected with reference to the known methods. In addition, polymerization reaction conditions such as polymerization temperature and polymerization time can be appropriately set.

[0162] When the reactive functional group is a thiol group, the carbonyl group at one end of the PMOVE obtained above is changed as shown in the following reaction formula (II), and a PMOVE having a thiol group at one end can be synthesized. The polymerization reaction conditions of the following reaction formula (II) can be referred to Journal of Colloid and Interface Science 428 (2014) 276-285. It should be noted that in the following reaction formula (II), EtOH represents ethanol, MsCl represents methanesulfonyl chloride, TEA represents triethylamine, KSAc represents potassium thioacetate, DMSO represents dimethyl sulfoxide, MeOH represents methanol, and NaOH represents sodium hydroxide.

[0163] [Chemical formula 11]

[0164]

[0165] When the reactive functional group is an azido group, the carbonyl group at one end of the PMOVE obtained above is changed as shown in the following reaction formula (III), and a PMOVE having an azido group at one end can be synthesized. The polymerization reaction conditions of the following reaction formula (III) can be referred to Med Chem Res (2016) 25: 824-833. It should be noted that in the following reaction formula (III), NaN3 is sodium azide, and the other abbreviations are the same as those in the above reaction formula (II).

[0166] [Chemical formula 12]

[0167]

[0168] When the reactive functional group is an amino group, the carbonyl group at one end of the PMOVE obtained above is changed as shown in the following reaction formula (IV), and a PMOVE having an amino group at one end can be synthesized. The polymerization reaction conditions of the following reaction formula (IV) can be referred to Med Chem Res (2016) 25: 824-833. It should be noted that in the following reaction formula (IV), PPh3 is triphenylphosphine, and the other abbreviations are the same as those in the above reaction formula (II).

[0169] [Chemical formula 13]

[0170]

[0171] When the reactive functional group is a carboxyl group, the carbonyl group at one end of the PMOVE obtained above is modified as shown in the following reaction formula (IV) to synthesize a PMOVE having a carboxyl group at one end. It should be noted that in the following reaction formula (V), NaClO2 represents sodium chlorite, and NaH2PO4 represents sodium dihydrogen phosphate.

[0172] [Chemical formula 14]

[0173]

[0174] <Pharmacy>

[0175] The cell adhesive composition of the present invention may also include a previously known medicament. By combining the polymer containing an oxyethylene chain with the medicament, the biocompatibility and cell adhesiveness of the medicament can be improved, and the medicament can be effectively utilized as DDS. As the medicament, there is no particular limitation, and examples thereof include nucleic acid drugs, anticancer agents, and anti-inflammatory agents.

[0176] Examples of nucleic acid drugs include siRNA, plasmid DNA, and mRNA.

[0177] Examples of the anticancer agent include BCG, actinomycin D, asparaginase, acetoglucuronolactone, anastrozole, allopurinol, anthracyclines, bicalutamide, antiandrogens, idarubicin, ifosfamide, imatinib, irinotecan, interferon, α-interferon, interleukin-2, ubenimex, exemestane, estramustine, estrogen, etoposide, enocitabine, epirubicin, oxaliplatin, octreotide, carpecitabine, carboquinone, carboplatin, carmofur, cladribine, and clarithromycin. , Versicolor polysaccharide, ketoconazole, gefitinib, gemcitabine, gemtuzumab, goserelin, cyclophosphamide, cisplatin, schizophyllan, cytarabine, cyproheptadine, statins, cetuximab, sobuzoxan, tamoxifen, daunorubicin, dacarbazine, actinomycin, thiotepa, tegafur, tegafur-uracil, tegafur-gimeracil-oteracil potassium potassium), dexamethasone, topotecan, trastuzumab, triptorelin, tretinoin, toremifene, doxifluridine, doxorubicin, docetaxel, nimustine, neocarcinomatidylserine, nedaplatin, paclitaxel, hydroxyurea, hydroxycarbamide, bicalutamide, vinorelbine, vincristine, vindesine, vinblastine, picibanil, pirarubicin The invention relates to anticancer agents such as leuprorelin, fadrozole, fluorouracil, flutamide, fludarabine, busulfan, bleomycin, prednisone, procarbazine, progestin, peplomycin, pentostatin, porfimer sodium, mitomycin, mitoxantrone, mitotane, mesna, methotrexate, medroxyprogesterone, mercaptopurine, melphalan, ranimustine, rituximab, leuprorelin, retinoic acid, lentinan, leucovorin, etc. These anticancer agents may be used alone or in combination of two or more.

[0178] Examples of the anti-inflammatory agent include steroidal anti-inflammatory agents and non-steroidal anti-inflammatory agents.

[0179] Examples of the steroidal anti-inflammatory agent include adrenocortical steroidal anti-inflammatory agents such as dexamethasone, triamcinolone acetonide, beclomethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone diacetate, cortisone, cortisol, paramethasone, triamcinolone, diflucortolone, difluprednate, diflorasone, flumethasone, fluocinonide, fluocinolone acetonide, alclomethasone, fludrocortisone, and the like, or salts thereof. More specifically, dexamethasone, triamcinolone acetonide, beclomethasone dipropionate, hydrocortisone succinate, methylprednisolone succinate, dexamethasone acetate, hydrocortisone acetate, prednisolone acetate, dexamethasone metasulfobenzoate, triamcinolone diacetate, prednisolone butyrate, butylacetate), dexamethasone phosphate, hydrocortisone phosphate, prednisolone phosphate, betamethasone phosphate, prednisolone succinate, cortisone acetate, paramethasone acetate, methylprednisolone acetate, triamcinolone, hydrocortisone, prednisolone, betamethasone, prednisolone valerate, diflucortolone valerate, dexamethasone valerate, betamethasone valerate, difluprednate acetate, diflorasone acetate, difluprednate, betamethasone dipropionate, flumethasone pivalate, fluocinolone acetonide, fluocinolone acetate, alclomethasone propionate, beclomethasone propionate, clobetasone butyrate, hydrocortisone butyrate, hydrocortisone butyrate propionate, fludrocortisone butyrate, dexamethasone palmitate, methylprednisolone, etc.

[0180] Examples of nonsteroidal anti-inflammatory drugs include NSAIDs and COX-2 inhibitors. More specifically, examples include acetylsalicylic acid, alclofenac, alminoprofen, benoxaprofen, butibufen, buclonic acid, carprofen, celecoxib, clidenac, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, fentiazic, flufenamic acid, and fenamic acid. acid), flufenasol, flurbiprofen, furofenic acid, ibufenac, ibuprofen, indomethacin, indoprofen, isoxacic acid, isoxicam, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, miprofen, naproxen, oxaprozin, oxyphenylbutazone, oxpinac, parecoxib, phenylbutazone, piramistalast, piroxicam, pirprofen, pranoprofen, rofecoxib, sudoxicam, sulindac, suprofen, tenclofenac, tiaprofenic acid, tolfenamic acid, tolmetin, tramadol, valdecoxib, zomepirac, etc., or salts thereof.

[0181] <Polymer-coated microparticles>

[0182] The polymer-coated microparticles of the present invention are microparticles coated with the above-mentioned PMOVE. Such polymer-coated microparticles have excellent biocompatibility and cell adhesion and can exhibit high stealth properties, and thus can be effectively used as DDS.

[0183] As the microparticles coated by the above-mentioned PMOVE, any of inorganic microparticles and organic microparticles can be used. As inorganic microparticles, there are no particular limitations, and examples thereof include gold, platinum, silver, and silicon dioxide. In addition, as organic microparticles, there are no particular limitations, and examples thereof include polystyrene, polymethyl acrylate, polymethyl methacrylate, polyacrylamide, and copolymers thereof.

[0184] The average particle size of the microparticles coated by the above-mentioned PMOVE is not particularly limited, and is preferably 10 nm to 500 nm, more preferably 50 nm to 300 nm, further preferably 70 nm to 200 nm, and further preferably 100 nm to 150 nm. If the average particle size of the microparticles is within the above range, it is easy to be effectively used as DDS.

[0185] In addition, the average particle size of fine particles can be measured by a dynamic light scattering method.

[0186] Example

[0187] Next, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples and the like.

[0188] It should be noted that in the synthesis examples, the structure of the polymer is based on 1 The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of the polymer were obtained from the molecular weight analysis results (in terms of polystyrene) of GPC. The analytical equipment and measurement conditions for each measurement are shown below.

[0189] (NMR measurement conditions)

[0190] Device: Made by JEOL, Model: ECS-400

[0191] Solvent: deuterated chloroform

[0192] ·Measurement temperature: 25℃

[0193] (GPC measurement conditions)

[0194] ·Device: Made by Tosoh Corporation, "HLC-8320GPC"

[0195] Detector: RI detector

[0196] Mobile phase: tetrahydrofuran

[0197] Flow rate: 1mL / min

[0198] ·Chromatographic column: 3 pieces of "Shodex LF-804" manufactured by Showa Denko K.K.

[0199] Column temperature: 40°C

[0200] [Synthesis example 1]

[0201] Synthesis of a polymer containing an oxyethylene chain having a thiol group at one end (PMOVE-SH) (reaction formula (I) + (II)

[0202] 2-Methoxyethyl vinyl ether (MOVE) was used as a raw material monomer, and as shown in the above reaction formula (I), PMOVE (PMOVE-CHO) having a carbonyl group at one end was obtained. Specifically, 5.8 mL of MOVE as a raw material monomer, 147 μL of MOEA, an acetic acid adduct of MOVE as a polymerization initiator, 90 mL of toluene, 1.6 mL of THF, 108 μL of 2,6-di-tert-butylpyridine, 2.2 mL of ethyl aluminum sesquichloride (25% toluene solution), and 1.0 mL of tin (IV) chloride (1.0 M heptane solution) were added to carry out a polymerization reaction. At the end of the polymerization, 1.0 mL of water was added to introduce a carbonyl group at one end. The solvent was removed with an evaporator, and after being dissolved in ethanol again, it was purified using a 0.45 μm syringe filter. The solvent was removed again to obtain PMOVE-CHO.

[0203] In addition, in this specification, a polymer having a functional group at one end is referred to as "polymer name-functional group name".

[0204] Next, as shown in the above reaction formula (II), the carbonyl group at one end of PMOVE is changed to a thiol group. Specifically, first add 1.0 g of PMOVE-CHO, 0.3 g of sodium borohydride, and 20 mL of ethanol and stir overnight. Dissolve it in water and dialysis and purify it with a dialysis membrane of MWCO=3,500 to obtain PMOVE-OH. Next, add 500 mg of PMOVE-OH, 12 mL of CH2Cl2, 63 μL of TEA, and 23 μL of MsCl, react at 0°C for 0.5 hours under an argon atmosphere, and further react at room temperature for 3.5 hours. Wash with water and saturated brine, and remove the solvent with an evaporator to obtain PMOVE-Ms. Next, add 500 mg of PMOVE-Ms, 12 mL of dehydrated DMSO, and 57 mg of KSAc, and react at 40°C for 18 hours under an argon atmosphere. After quenching with 1.0 M hydrochloric acid, remove the solvent. Dissolve it in water again and purify it by dialyzing with a dialysis membrane of MWCO=3,500 to obtain PMOVE-SAc. Finally, add 500 mg of PMOVE-SAc and 12 mL of dehydrated methanol and bubble with argon. Add 20 mg of NaOH and 46 mg of dithiothreitol to it and react for 1 hour. After quenching with 1.0 M hydrochloric acid, use a dialysis membrane of MWCO=3,500 to purify it by dialyzing in a refrigerator at 4°C to obtain PMOVE-SH.

[0205] The obtained reaction product (PMOVE-SH) and its precursor (PMOVE-SAc) were subjected to the above conditions. 1 H-NMR measurement, we get Figure 1 shown 1 H-NMR spectrum. Figure 1 The upper figure is the spectrum of the precursor. Figure 1 The lower figure is the spectrum of the reaction product. As a result of the spectrum analysis, in the spectrum of the precursor, a peak from the methylene group (CH2) adjacent to the thioacetyl group (SCOCH3) can be confirmed ( Figure 1 ※1) in the upper figure of is located at 2.90 ppm, but in the spectrum of the reaction product, a peak derived from a methylene group adjacent to a thiol group can be confirmed ( Figure 1 ※3) in the lower figure of the figure shifted to 2.60 ppm. In addition, in the spectrum of the precursor, it can be confirmed that the peak derived from the thioacetyl group ( Figure 1 ※2) in the upper figure of the figure is located at 2.30 ppm, but the peak derived from the thioacetyl group disappears in the spectrum of the reaction product. Based on these results, it was confirmed that a thiol group was introduced into one end of PMOVE. In addition, compared with the integral value of the peak derived from the methyl group at the α end (※A), the introduction rate of the thiol group into one end was about 100%.

[0206] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of PMOVE-SH obtained above were measured, and the results were Mn=5,000 and Mw / Mn=1.05.

[0207] [Synthesis example 2]

[0208] Synthesis of a polymer containing an oxyethylene chain having an azide group at one end (PMOVE-N3) (Reaction formula (I) + (III))

[0209] PMOVE-CHO was obtained by the same operation as in Synthesis Example 1. Then, as shown in the above reaction formula (III), the carbonyl group at one end of PMOVE was changed to an azido group. Specifically, 500 mg of PMOVE-Ms, 12 mL of dehydrated DMSO, and 39 mg of NaN3 were added, and the reaction was carried out at 70°C for 18 hours under an argon atmosphere. After quenching with water, the solvent was removed. It was dissolved in water again and purified by dialyzing with a dialysis membrane with MWCO=3,500 to obtain PMOVE-N3.

[0210] The reaction product (PMOVE-N3) and its precursor (PMOVE-Ms) obtained above were subjected to the above conditions. 1 H-NMR measurement, we get Figure 2 shown 1 H-NMR spectrum. Figure 2 The upper figure is the spectrum of the precursor. Figure 2 The lower figure is the spectrum of the reaction product. As a result of the spectrum analysis, in the spectrum of the precursor, it is possible to confirm the peak of the methyl group (CH3) in the methylsulfonyl group (CH3SO2) ( Figure 2 ※4) in the upper figure of the reaction product is located at 3.24ppm, but in the spectrum of the reaction product, the peak derived from the methyl group in the methylsulfonyl group disappears. In addition, in the spectrum of the reaction product, the peak derived from the ethylene group (CH2CH2) adjacent to the azido group can be confirmed ( Figure 2 ※5, 6) in the lower figure of is located at 3.40 to 3.50 ppm. Based on these results, it was confirmed that an azido group was introduced at one end of PMOVE. In addition, the integral value of the peak (※A) from the methyl group at the α end was calculated, and the result showed that the introduction rate of the methylsulfonyl group to one end of the precursor was about 100%.

[0211] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of PMOVE-N3 obtained above were measured, and the results were Mn=5,000 and Mw / Mn=1.05.

[0212] [Synthesis example 3]

[0213] Synthesis of a polymer containing an oxyethylene chain having an amino group at one end (PMOVE-NH2) (reaction formula (I) + (IV))

[0214] PMOVE-CHO was obtained by the same operation as in Synthesis Example 1. Then, as shown in the above reaction formula (IV), the carbonyl group at one end of PMOVE was changed to an amino group. Specifically, 500 mg of PMOVE-N3, 525 mg of PPh3, 8.7 mL of MeOH, and 3.3 mL of water were added, refluxed at 90°C, and reacted for 5 hours. After quenching with 1.0 M hydrochloric acid, the solvent was removed. It was dissolved in water again and purified by dialyzing with a dialysis membrane with MWCO=3,500 to obtain PMOVE-NH2.

[0215] The PMOVE-NH2 obtained above was quantitatively analyzed by GPC (RI detector: RI-2031 Plus (manufactured by JASCO Corporation), GPC pump: PU-1580 (manufactured by JASCO Corporation, mobile phase: 2 mM NaCl aqueous solution) using a cation exchange column (SP-5PW). The result showed that the introduction rate of the amino group to one terminal was about 100%. In addition, based on this result, it is estimated that the introduction rate of the azide group to one terminal in the polymer having an azide group at one terminal of Synthesis Example 2, which is a precursor of the polymer having an amino group at one terminal of Synthesis Example 3, is about 100%.

[0216] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of PMOVE-NH2 obtained above were measured, and the results were Mn=5,000 and Mw / Mn=1.05.

[0217] [Synthesis Example 4]

[0218] Synthesis of a polymer containing an oxyethylene chain having a carboxyl group at one end (PMOVE-COOH) (reaction formula (I) + (V))

[0219] PMOVE-CHO was obtained by the same operation as in Synthesis Example 1. Next, as shown in the above reaction formula (V), the carbonyl group at one end of PMOVE was changed to a carboxyl group. Specifically, 500 mg of PMOVE-CHO, 5.5 mL of ethanol, and 0.2 mL of 2-methyl-2-butene were added, stirred thoroughly and cooled to 0°C. Next, 34 mg of NaClO2, 36 mg of NaH2PO4, and 0.9 mL of water were added to another flask and stirred thoroughly. The aqueous solution was added dropwise to the ethanol solution, stirred for 5 minutes, and further reacted at room temperature for 15 hours. After quenching with saturated brine, it was dialyzed and purified using a dialysis membrane with MWCO=3,500 to obtain PMOVE-COOH.

[0220] use 1 The PMOVE-COOH obtained above was measured by H-NMR, and as a result, it was confirmed that a carboxyl group was introduced at one terminal. In addition, the introduction rate of the carboxyl group at one terminal was about 100%.

[0221] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of PMOVE-COOH obtained above were measured, and the results were Mn=5,000 and Mw / Mn=1.05.

[0222] [Synthesis Example 5]

[0223] Synthesis of a polymer containing an oxyethylene chain having a thiol group at one end (PMOVE-SH) (reaction formula (I) + (II)

[0224] PMOVE-SH was obtained in the same manner as in Synthesis Example 1 except that 3.5 mL of MOVE, 230 μL of MOEA, 138 mL of toluene, 2.4 mL of THF, 162 μL of 2,6-di-tert-butylpyridine, 3.3 mL of ethylaluminum sesquichloride (25% toluene solution), and 1.5 mL of tin (IV) chloride (1.0 M heptane solution) were added.

[0225] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of PMOVE-SH obtained above were measured, and the results were Mn=2,000 and Mw / Mn=1.06.

[0226] [Synthesis example 6]

[0227] Synthesis of a polymer containing an oxyethylene chain having a thiol group at one end (PEOVE-SH) (Reaction formula (I) + (II)

[0228] PEOVE-SH was obtained in the same manner as in Example 1 except that 6.5 mL of 2-ethoxyethyl vinyl ether (EOVE) as a raw material monomer and 203 μL of EOEA, which is an acetic acid adduct of EOVE, as an initiator were added.

[0229] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of the PEOVE-SH obtained above were measured, and the results were Mn=5,000 and Mw / Mn=1.08.

[0230] [Synthesis Example 7]

[0231] Synthesis of a polymer containing an oxyethylene chain having a thiol group at one end (PEOEOVE-SH) (Reaction formula (I) + (II)

[0232] PEOEOVE-SH was obtained in the same manner as in Synthesis Example 1 except that 8.7 mL of 2-(2-ethoxy)ethoxyethyl vinyl ether (EOEOVE) as a raw material monomer and 333 μL of EOEOEA, which is an acetic acid adduct of EOEOVE, as an initiator were added.

[0233] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of the PEOEOVE-SH obtained above were measured, and the results were Mn=5,000 and Mw / Mn=1.06.

[0234] [Synthesis example 8]

[0235] Synthesis of a polymer containing an oxyethylene chain having a thiol group at one end (PTEGMVE-SH) (Reaction formula (I) + (II)

[0236] PTEGMVE-SH was obtained in the same manner as in Synthesis Example 1 except that 9.6 mL of triethylene glycol monomethyl vinyl ether (TEGMVE) as a raw material monomer and 450 μL of TEGMEA, which is an acetic acid adduct of TEGMVE, as an initiator were added.

[0237] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of the PTEGMVE-SH obtained above were measured, and the results were Mn=5,000 and Mw / Mn=1.08.

[0238] [Synthesis Example 9]

[0239] Synthesis of a polymer containing an oxyethylene chain having a carbonyl group at one end (PMOVE-CHO) (Reaction formula (I))

[0240] PMOVE-CHO was obtained in the same manner as in Synthesis Example 1.

[0241] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of the PMOVE-CHO obtained above were measured, and the results were Mn=5,000 and Mw / Mn=1.05.

[0242] [Synthesis Example 10]

[0243] Synthesis of poly(n-butyl vinyl ether) having a thiol group at one end (PNBVE-SH)

[0244] PNBVE-SH was obtained in the same manner as in Synthesis Example 1 except that n-butyl vinyl ether (NBVE) was used as the raw material monomer instead of 2-methoxyethyl vinyl ether (MOVE).

[0245] The number average molecular weight (Mn) and molecular weight distribution (Mw / Mn) of the PNBVE-SH obtained above were measured, and the results were Mn=5,000 and Mw / Mn=1.10.

[0246] [Example 1]

[0247] Gold microparticles coated with PMOVE (PMOVE-coated gold microparticles) were obtained by modifying gold microparticles having an average particle diameter of 150 nm using PMOVE-SH obtained in Synthesis Example 1. Specifically, the following test was performed.

[0248] Test method:

[0249] The dispersion of 150 nm gold microparticles modified with citric acid was concentrated by centrifugation and then dispersed in 90 μL of water. 2 10 μL of PMOVE-SH prepared in the manner of 10 μL was reacted at 60°C for 1 hour. After the reaction, the mixture was concentrated by centrifugation and the supernatant was removed. Then, the mixture was washed several times with water containing 0.25 mM sodium citrate and 0.05 v / v% Tween 20.

[0250] The average particle size of the PMOVE-coated gold microparticles obtained in the above experiment was measured by dynamic light scattering using a particle size measuring device (Zetasizer Nano ZS, manufactured by Malvern Panalytical). The average particle size increased to 175.6 nm. Based on this result, it is speculated that PMOVE can be modified on the surface of gold microparticles.

[0251] [Example 2]

[0252] Gold fine particles coated with PMOVE (PMOVE-coated gold fine particles) were obtained in the same manner as in Example 1 except that PMOVE-SH obtained in Synthesis Example 5 was used.

[0253] The average particle size of the obtained PMOVE-coated gold microparticles increased to 161.0 nm. Based on this result, it is estimated that PMOVE can be modified on the surface of the gold microparticles.

[0254] [Example 3]

[0255] Gold fine particles coated with PEOVE (PEOVE-coated gold fine particles) were obtained in the same manner as in Example 1 except that PEOVE-SH obtained in Synthesis Example 6 was used.

[0256] The average particle size of the obtained PEOVE-coated gold microparticles increased to 166.4 nm. Based on this result, it is estimated that PEOVE can be modified on the surface of gold microparticles.

[0257] [Example 4]

[0258] Gold fine particles coated with PEOEOVE (PEOEOVE-coated gold fine particles) were obtained in the same manner as in Example 1 except that PEOEOVE-SH obtained in Synthesis Example 7 was used.

[0259] The average particle size of the obtained PEOEOVE-coated gold microparticles increased to 166.9 nm. Based on this result, it is estimated that PEOEOVE can be modified on the surface of gold microparticles.

[0260] [Example 5]

[0261] Gold fine particles coated with PTEGMVE (PTEGMVE-coated gold fine particles) were obtained in the same manner as in Example 1 except that PTEGMVE-SH obtained in Synthesis Example 8 was used.

[0262] The average particle size of the obtained PTEGMVE-coated gold microparticles increased to 164.9 nm. Based on this result, it is estimated that PTEGMVE can be modified on the surface of the gold microparticles.

[0263] [Comparative Example 1]

[0264] An attempt was made to modify gold microparticles according to the above-mentioned test method using PMOVE-CHO obtained in Synthesis Example 9. However, since the polymer had low reactivity with gold microparticles, it did not bond to the terminal and could not modify the gold microparticles.

[0265] [Comparative Example 2]

[0266] An attempt was made to modify gold microparticles according to the above-mentioned test method using PNBVE-SH obtained in Synthesis Example 10. However, since the polymer is hydrophobic, it agglomerated and could not modify the gold microparticles.

[0267] [Comparative Example 3]

[0268] Using PEG-SH (Mn=5000, Mw / Mn=1.02, manufactured by NOF Corporation), the same operation as in Example 1 was carried out to obtain gold microparticles coated with PEG (PEG-coated gold microparticles).

[0269] [Cytotoxicity test]

[0270] The cell adhesive composition comprising the PMOVE-coated gold microparticles obtained in Examples 1 to 5 and the cell adhesive composition comprising the PEG-coated gold microparticles obtained in Comparative Example 3 were subjected to the following cytotoxicity test.

[0271] Test method:

[0272] Human cervical cancer cells Hela-luc suspended in DEME medium were inoculated in a 96-well plate at 5,000 cells / well and cultured for 24 hours. Then, various polymer-coated gold microparticles obtained in Examples 1 to 5 and Comparative Example 3 were added at a concentration of 0.05 mg / mL. After 24 hours, 10 μL of Cell Counting Kit-8 (Dojindo Chemical Research Institute) was added and allowed to stand for 2 hours. Then, the absorption wavelength of 450 nm was measured using an absorbance measuring device (manufactured by Tecan Japan Co., Ltd., model: Spark20M Multimode Microplate Reader) to calculate the cell survival rate.

[0273] The results of the above tests showed that the cell adhesive compositions of Examples 1 to 5 and Comparative Example 3 showed no toxicity to cells and were excellent in biocompatibility.

[0274] [Cell Adhesion Assay]

[0275] The cell adhesive composition comprising the PMOVE-coated gold microparticles obtained in Examples 1 to 5 and the cell adhesive composition comprising the PEG-coated gold microparticles obtained in Comparative Example 3 were subjected to the following cell adhesion test.

[0276] Test method:

[0277] Human cervical cancer cells Hela-luc suspended in DEME medium were inoculated in a 12-well plate at 50,000 cells / well and cultured for 24 hours. Then, various polymer-coated gold particles obtained in Examples 1 to 5 and Comparative Example 3 were added at 0.05 mg / mL. After 24 hours, the culture medium was removed and thoroughly washed with PBS. The cells and the gold particles adhered to the cells were dissolved with nitric acid, and the gold concentration was quantified using an ICP emission spectrometer (manufactured by Thermo Fisher Scientific, model: iCAP PROseries ICP-OES).

[0278] The results of the above tests showed that the cell adhesive compositions of Examples 1 to 5 were found to adhere to cells and were excellent in cell adhesiveness. On the other hand, the cell adhesive composition of Comparative Example 3 was not found to adhere to cells and was poor in cell adhesiveness.

Claims

1. A cell adhesive composition comprising an oxyethylene chain-containing polymer represented by the following general formula (1), [Chemical formula 1] In the general formula (1), R 1 -(CH2) p -SH, -(CH2) p -N3, -(CH2) p -NH2, or -(CH2) p -COOH, p is an integer from 1 to 5, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 10 carbon atoms, R 5 is an alkyl group having 1 to 10 carbon atoms, R 6 is hydrogen or an alkyl group having 1 to 5 carbon atoms, R 7 is an alkyl group having 1 to 10 carbon atoms, n is an integer from 5 to 1000, m is an integer from 1 to 10, q is an integer from 0 to 5.

2. The cell adhesive composition according to claim 1, wherein In the general formula (1), R 1 -(CH2) p -SH, p is an integer from 1 to 3, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, R 5 is an alkyl group having 1 to 4 carbon atoms, R 6 is an alkyl group having 1 to 2 carbon atoms, R 7 is an alkyl group having 1 to 7 carbon atoms, n is an integer from 10 to 500, m is an integer from 1 to 5, q is an integer from 0 to 2.

3. The cell adhesive composition according to claim 1, wherein In the general formula (1), R 1 -(CH2) p -N3, p is an integer from 1 to 3, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, R 5 is an alkyl group having 1 to 4 carbon atoms, R 6 is an alkyl group having 1 to 2 carbon atoms, R 7 is an alkyl group having 1 to 7 carbon atoms, n is an integer from 10 to 500, m is an integer from 1 to 5, q is an integer from 0 to 2.

4. The cell adhesive composition according to claim 1, wherein In the general formula (1), R 1 -(CH2) p -NH2, p is an integer from 1 to 3, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, R 5 is an alkyl group having 1 to 4 carbon atoms, R 6 is an alkyl group having 1 to 2 carbon atoms, R 7 is an alkyl group having 1 to 7 carbon atoms, n is an integer from 10 to 500, m is an integer from 1 to 5, q is an integer from 0 to 2.

5. The cell adhesive composition according to claim 1, wherein In the general formula (1), R 1 -(CH2) p -COOH, p is an integer from 1 to 3, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, R 5 is an alkyl group having 1 to 4 carbon atoms, R 6 is an alkyl group having 1 to 2 carbon atoms, R 7 is an alkyl group having 1 to 7 carbon atoms, n is an integer from 10 to 500, m is an integer from 1 to 5, q is an integer from 0 to 2.

6. The cell adhesive composition according to any one of claims 1 to 5, wherein The number average molecular weight (Mn) of the polymer containing ethylene oxide chains is 500 to 100,000.

7. The cell adhesive composition according to any one of claims 1 to 5, wherein The ratio of the weight average molecular weight (Mw) to the number average molecular weight (Mn) of the oxyethylene chain-containing polymer is 1.0 to 3.

0.

8. Polymer-coated microparticles, which are microparticles coated with a polymer containing oxyethylene chains, The polymer containing ethylene oxide chains is represented by the following general formula (1): [Chemical formula 2] In the general formula (1), R 1 -(CH2) p -SH, -(CH2) p -N3, -(CH2) p -NH2, or -(CH2) p -COOH, p is an integer from 1 to 5, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 10 carbon atoms, R 5 is an alkyl group having 1 to 10 carbon atoms, R 6 is hydrogen or an alkyl group having 1 to 5 carbon atoms, R 7 is an alkyl group having 1 to 10 carbon atoms, n is an integer from 5 to 1000, m is an integer from 1 to 10, q is an integer from 0 to 5.

9. The polymer-coated fine particles according to claim 8, wherein In the general formula (1), R 1 -(CH2) p -SH, p is an integer from 1 to 3, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, R 5 is an alkyl group having 1 to 4 carbon atoms, R 6 is an alkyl group having 1 to 2 carbon atoms, R 7 is an alkyl group having 1 to 7 carbon atoms, n is an integer from 10 to 500, m is an integer from 1 to 5, q is an integer from 0 to 2.

10. The polymer-coated fine particles according to claim 8, wherein In the general formula (1), R 1 -(CH2) p -N3, p is an integer from 1 to 3, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, R 5 is an alkyl group having 1 to 4 carbon atoms, R 6 is an alkyl group having 1 to 2 carbon atoms, R 7 is an alkyl group having 1 to 7 carbon atoms, n is an integer from 10 to 500, m is an integer from 1 to 5, q is an integer from 0 to 2.

11. The polymer-coated fine particles according to claim 8, wherein In the general formula (1), R 1 -(CH2) p -NH2, p is an integer from 1 to 3, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, R 5 is an alkyl group having 1 to 4 carbon atoms, R 6 is an alkyl group having 1 to 2 carbon atoms, R 7 is an alkyl group having 1 to 7 carbon atoms, n is an integer from 10 to 500, m is an integer from 1 to 5, q is an integer from 0 to 2.

12. The polymer-coated fine particles according to claim 8, wherein In the general formula (1), R 1 -(CH2) p -COOH, p is an integer from 1 to 3, R 2 ~R 4 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, R 5 is an alkyl group having 1 to 4 carbon atoms, R 6 is an alkyl group having 1 to 2 carbon atoms, R 7 is an alkyl group having 1 to 7 carbon atoms, n is an integer from 10 to 500, m is an integer from 1 to 5, q is an integer from 0 to 2.

13. The polymer-coated fine particles according to any one of claims 8 to 12, wherein The number average molecular weight (Mn) of the oxyethylene chain-containing polymer is 500 to 100,000.

14. The polymer-coated fine particles according to any one of claims 8 to 12, wherein The ratio of the weight average molecular weight (Mw) to the number average molecular weight (Mn) of the oxyethylene chain-containing polymer is 1.0 to 3.

0.

15. The polymer-coated fine particles according to any one of claims 8 to 12, wherein The fine particles are at least one inorganic fine particle selected from the group consisting of gold, platinum, silver, and silicon dioxide.

16. The polymer-coated fine particles according to any one of claims 8 to 12, wherein The average particle size of the microparticles is greater than or equal to 10 nm and less than or equal to 500 nm. 17 . A cell adhesive composition comprising the polymer-coated fine particles according to claim 8 .

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