Method for grafting polymyxin on surface of polystyrene

Abstract

The invention provides a method for grafting polymyxin on the surface of polystyrene, which comprises the following steps: by taking chloromethylated polystyrene as a carrier base material, carrying out nucleophilic substitution reaction on the chloromethylated polystyrene and diallylamine, and carrying out zwitterionic reaction on the chloromethylated polystyrene and a zwitterionic reagent in sequence; the polymyxin is grafted on the surface of the polystyrene through graft copolymerization between the polystyrene, a glycidyl-containing zwitterionic monomer and a glycidyl-containing gemini zwitterionic cross-linking agent and amino ring-opening reaction of the polymyxin. According to the technical scheme of the invention, the prepared surface polymyxin polystyrene not only has specific adsorbability to blood endotoxin, but also has excellent hydrophilicity, blood compatibility, anti-blood coagulation function and anti-protein non-specific adhesion characteristic.

Description

Technical Field

[0001] The present invention relates to a method for preparing a medical functional polymer material, and in particular to a method for grafting polymyxin on the surface of polystyrene. After the polymyxin is grafted on the surface of polystyrene according to the present invention, it has excellent hydrophilicity, blood compatibility, anti-coagulation function, and anti-protein nonspecific adhesion properties in addition to specific adsorption of blood endotoxin, and belongs to the field of functional polymer materials. Background Art

[0002] Since Japanese scholars used polystyrene fiber bonded with polymyxin B as an adsorption material to remove endotoxins from the blood through hemoperfusion and used it to treat endotoxemia, it has played an important role in improving the quality of life of patients and prolonging their lives. For this reason, scholars from many countries have been scrambling to carry out multi-faceted research and development for decades, and have achieved some beneficial results: (1) The adsorption material used for hemoperfusion must consist of two parts: a carrier and a ligand bonded to the surface of the carrier. (2) The basic characteristics of the substrate used as a carrier are excellent mechanical properties, chemical structure stability, hydrophilicity, biocompatibility, no blood coagulation phenomenon, no biological toxicity and variability, etc., and the carrier substrate structure contains the active functional groups required for the immobilized ligand. The carrier substrates currently used for blood endotoxin adsorption materials include: cellulose, polyvinyl alcohol, agarose, chitosan, polyamide, polyethersulfone, polyvinylidene fluoride, polystyrene and other polymer materials, and the carrier form has also expanded from polymer fibers to resin microspheres, filter membranes, hydrogels, etc. However, these carrier substrates themselves do not have all the functions or characteristics of good specific adsorption, high adsorption capacity, good biocompatibility, high anti-coagulation, and low non-specific adsorption of proteins in the blood, so the carrier substrates must be coated, deposited, cross-linked, or grafted for modification. (3) People have also found that polymyxin B (PMB) has a specific adsorption effect on endotoxins in the blood. Other cationic antimicrobial peptides with similar functions and effects include nisin, melittin, etc.; there are also some polymers or small molecule compounds, such as polyethyleneimine, polylysine, lysine, histidine, hexamethylenediamine, etc., which are used as ligands, all of which have different degrees of specific affinity for blood endotoxins. In recent years, the scientific optimization of carrier substrates, simplification of surface modification schemes and process steps, high stability of ligand bonding, and excellent comprehensive adsorption functions of related blood endotoxin adsorption materials are still hot topics for collaborative research in the fields of chemistry, materials science, biology, and medicine. Summary of the invention

[0003] According to the performance requirements of polystyrene bonded immobilized polymyxin B adsorption materials used for blood perfusion for treating endotoxemia, the present invention provides a new method for grafting polymyxin on the surface of polystyrene, the polymer chemistry principle of which is that under the action of sodium hydroxide, chloromethylated polystyrene undergoes a nucleophilic substitution reaction with diallylamine in a solvent to obtain diallyl aminated polystyrene; then the diallyl aminated polystyrene undergoes a zwitterionization reaction with a zwitterionizing agent to obtain an unsaturated zwitterionized polystyrene with a highly hydrophilic surface; The unsaturated zwitterionic polystyrene is then subjected to a graft copolymerization reaction with a zwitterionic monomer containing a glycidyl group and a gemini zwitterionic crosslinking agent containing a glycidyl group, and a polyzwitterionic chain and a large number of glycidyl ether units on the side chain of the polystyrene are connected to the surface of the polystyrene to obtain a polyzwitterionic polystyrene containing a glycidyl ether group; and then the glycidyl ether group contained in the polyzwitterionic polystyrene is reacted with the amino group of polymyxin to achieve polymyxin grafting on the surface of the polystyrene, thereby obtaining polymyxinated polystyrene.

[0004] The innovative feature of the present invention is to use existing cheap industrial materials as raw materials, adopt classical chemical reactions, graft polymyxin on the surface of polystyrene, and achieve multiple functional effects: first, the polyzwitterionic chains connected on the surface of the polystyrene material make the polystyrene show high hydrophilicity, high water retention, excellent blood compatibility and tissue compatibility, high anti-fouling function against nonspecific protein adhesion, and anti-coagulation function; secondly, the density of polymyxin introduced on the surface of polystyrene by bonding is adjustable, and the stability of bonded immobilized polymyxin is high, which has positive significance for improving the use of polymyxin-modified polystyrene as a blood perfusion adsorption material for the treatment of endotoxemia.

[0005] Professionals are well aware that polystyrene is a widely used thermoplastic synthetic polymer material with good thermal processing properties, excellent mechanical properties, high chemical structure stability and no biological toxicity. Although polystyrene's intrinsic structure does not have active groups bonded to polymyxin, polystyrene can obtain a variety of active groups bonded to polymyxin through functionalization reactions such as nitration, sulfonation, chloromethylation, and chloroacetylation. In particular, the industrialized macroporous hollow chloromethylated cross-linked polystyrene resin is a reactive polystyrene product with strong rigidity and resistance to a variety of solvents, which is widely available and inexpensive. It has become the preferred substrate for a variety of functional polymer materials. The present invention selects a diallyl amination scheme for macroporous hollow chloromethylated cross-linked polystyrene, based on the following principles: 1. diallyl amination cross-linked polystyrene can be conveniently converted into surface unsaturated zwitterionic polystyrene; 2. the surface unsaturated zwitterionic polystyrene can undergo graft copolymerization reaction with zwitterionic monomers carrying glycidyl groups; 3. the glycidyl groups remaining on the surface of polystyrene after graft copolymerization can undergo a ring-opening reaction with the amino groups of polymyxin under mild conditions, which is the basis for adjustable density of polystyrene grafted polymyxin; 4. the whole process of polystyrene grafted polymyxin according to the present invention does not require drastic chemical processes such as oxidation and reduction, which is of great significance for ensuring the adsorption performance, biological activity and medicinal value of the material after polystyrene grafted polymyxin.

[0006] Professionals are well aware that zwitterionic polymers refer to polymers that contain positive and negative ionic groups in a structural unit of their polymer chains. The polymer is electrically neutral as a whole, has stronger electrostatic interactions with water molecules, and thus has excellent hydrophilicity. The chemical structure of zwitterionic polymers is similar to that of biological membranes, which gives them better biocompatibility and resistance to protein non-specific adsorption. However, the existing publicly available polymer materials bonded to immobilize polymyxins for endotoxin adsorption materials for blood purification only focus on the endotoxin adsorption, biocompatibility, and anti-coagulation functions of the adsorption materials, and do not focus on the adhesion of some proteins in the blood to the adsorption materials, which is one of the key factors that significantly affect their endotoxin adsorption performance. The present invention utilizes the polyzwitterionic chains bonded to the polystyrene surface to give the polymyxinized polystyrene surface better biocompatibility and resistance to protein non-specific adsorption, which is of great significance for ensuring the blood endotoxin adsorption performance of the polymyxinized polystyrene material.

[0007] As is well known to professionals, polymyxin is a general term for a group of basic polypeptide antibiotics. It was discovered in 1947 that it was produced by Bacillus polymyxa. Its chemical structure is a quasi-cyclic decapeptide sequence, including a heptapeptide ring connected to a tripeptide chain. Three side amino groups are connected to the heptapeptide ring, and two side amino groups are connected to the tripeptide chain (the five side amino groups are the functional groups that bond polymyxin to the polymer material). In addition, the amino acid residue end of the tripeptide chain has a fatty acid tail chain. The different amino acid and fatty acid compositions have different chemical structures, mainly including A, B, C, D and E. Among them, polymyxin B has been used to treat infections caused by various Gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella and Haemophilus, and is a cationic antimicrobial peptide among antibiotics. Another feature of it is that it has a specific high affinity for lipopolysaccharide (that is, endotoxin) released in large quantities after the death of Gram-negative bacteria, and is a preferred ligand for removing endotoxin from the blood by adsorption. At present, the fermentation production technology of polymyxin B has been industrialized, which provides the material conditions for the optimal ligand for the low-cost promotion of polymyxin B in the treatment of endotoxemia.

[0008] The glycidyl group-containing zwitterionic monomer of the present invention has a structure shown in the general formula (I):

[0009]

[0010] Wherein R in the general formula (I) is selected from C1 to C 18 One of the hydrocarbon groups, the Q - Refers to -CH2CH2CH2SO3 - 、-CH2CH(OH)CH2SO3 - 、-CH2CH2SO3 - 、-CH2CH2CH2CH2SO3 - 、-CH2CH2CH2CO2 - 、-CH2CH2CO2 - , or -CH2CO2 - One of them.

[0011] The zwitterionic monomer containing glycidyl group in the general formula (I) can retain the glycidyl group after the free radical polymerization reaction, and the glycidyl group can undergo a ring-opening reaction with a substance containing an NH group in a neutral, weakly alkaline, or medium-strong alkaline aqueous solution system, thereby bonding a polymer or a small molecule compound having an amino group to the surface of the polystyrene material. The reaction conditions are mild, the process control is simple, and the reaction efficiency is high. In particular, it is more meaningful for biologically active substances containing NH (such as polymyxin, nisin, bee venom peptide, human serum albumin, etc.) that are sensitive to medium, temperature, or pH and have biological activity.

[0012] The glycidyl-containing zwitterionic monomer in the general formula (I) is also an amphiphilic compound, and the grafting efficiency of the free radical copolymerization reaction in aqueous solution on the surface of the highly hydrophilic unsaturated zwitterionic polystyrene is high; if the R hydrocarbon group in the general formula (I) is specified, such as preferably allyl, benzyl, C7-C 16 The hydrocarbon group, while highlighting the hydrophilic properties of the zwitterionic monomer containing glycidyl groups, can also demonstrate its efficient biocidal and antibacterial efficacy; this is the scientific basis for the present invention to select the zwitterionic compound containing glycidyl groups described in general formula (I) as the grafting monomer of the present invention.

[0013] The crosslinking agent used for the surface grafting of polystyrene material is a Gemini zwitterionic crosslinking agent containing glycidyl group, having the structure shown in the general formula (II):

[0014]

[0015] Among them, Selected from C1~C 18 Alkylene or One of the following, wherein n is selected from a natural number between 0 and 200; Q - Refers to -CH2CH2CH2SO3 - 、-CH2CH(OH)CH2SO3 - 、-CH2CH2SO3 - 、-CH2CH2CH2CH2SO3 - 、-CH2CH2CH2CO2 - 、-CH2CH2CO2 - 、-CH2CO2 - or -CH2PO3H - One of them.

[0016] It is well known to professionals that the surface grafting polymerization process of polymer materials has an insurmountable defect, which is the homopolymerization of monomer raw materials. For example, the homopolymerization of the glycidyl zwitterionic monomer described in the general formula (I) not only causes ineffective consumption of raw materials, but also brings a necessary cleaning process to the re-functionalization process of the polystyrene membrane material after surface grafting. The glycidyl-containing gemini zwitterionic crosslinking agent of the present invention is an unsaturated gemini betaine containing glycidyl groups, which is used as a crosslinking agent for graft copolymerization on the surface of polystyrene membrane materials, and aims to improve the grafting efficiency of the glycidyl-containing zwitterionic monomer described in the general formula (I) and ensure the utilization rate of monomer raw materials in the grafting process; and at the same time, it is expected that both ends of the polyzwitterionic chain after the graft copolymerization are fixed on the polystyrene surface, showing a flat extension state, which is conducive to combining water molecules to form a hydration layer on the polystyrene surface, and can avoid the curling and accumulation of the other end of the polyzwitterionic chain fixed at one end to block the ultrafiltration pores of the polystyrene, which is of great significance for ensuring the adsorption rate and adsorption efficiency of polymyxin grafted on the polystyrene surface for blood perfusion.

[0017] The blocking agent refers to one of hydroxylamine hydrochloride, ethanolamine, tromethamine, or amino acid. The blocking agent is used to graft polymyxin on the polystyrene surface and then perform grafting and end-capping to eliminate the residual glycidyl ether group, because the latter has chemical reactivity with some proteins in the blood, affecting the protein recovery rate in blood perfusion.

[0018] The amino acid has a structure shown in the general formula (III):

[0019]

[0020] Wherein the general formula (III) Selected from C1~C 18 The alkylene group, wherein W is selected from one of -SO3H, -COOH or -PO3H2.

[0021] The present invention uses amino acids as the blocking agent after polystyrene surface grafting polymyxin, not only because its molecular structure contains amino groups with high chemical activity, but also amino acids have various physical, chemical, biological and other characteristics and functions. Professionals are well aware that more than 20 kinds of natural amino acids are the raw materials for the composition of natural life bodies known to ordinary people, but the number of functional groups carried in the molecular structure of these only natural amino acids is limited, including sulfhydryl, hydroxyl, guanidine, aromatic ring, heteroaromatic ring, carboxyl, amino, etc., which cannot meet the needs of modern chemistry, biological science research and application for giving new functions to materials. At present, through computer-aided design and chemical modification, non-natural amino acids that are artificially given diverse functional groups, also known as synthetic amino acids, have outstanding performance in synthetic material modification and also provide more opportunities for biological research. In addition to the functional groups carried by natural amino acids, these non-natural amino acid molecular structures can also be keto, aldehyde, ester, amide, imide, azide, alkynyl, alkenyl, quaternary ammonium cation, nitro, carboxylate, phosphonate, sulfonate, polyether chain and other functional groups, which correspond to different functional applications. The selection of the amino acid structure in the general formula (III) structure of the present invention is based on the functional requirements of the polystyrene-based adsorption material used for blood perfusion. Not only can one of more than 20 natural amino acids be selected, but also a primary amino-carboxylic acid, a primary amino-sulfonic acid, or a primary amino-phosphonic acid combination of amino acids can be specifically optimized and selected from non-protein amino acids or synthetic amino acids, or preferably one of a secondary amino-carboxylic acid, a secondary amino-sulfonic acid, or a secondary amino-phosphonic acid combination of amino acids, to better improve or enhance the hydrophilicity, biocompatibility, anti-coagulation function and anti-fouling function of the polystyrene material, or to give the polystyrene grafted polymyxin of the present invention a more powerful biomedical function and a wider application.

[0022] The present invention provides a method for grafting polymyxin on the surface of polystyrene, which is achieved by the following steps:

[0023] Step 1: Preparation of surface diallylamine-modified polystyrene

[0024] Weigh chloromethylated polystyrene and put it into the solvent in the reactor. After swelling at room temperature for 2 to 24 hours, add diallylamine and polymerization inhibitor, control the reaction temperature to 50 to 90 ° C, and react for 20 to 24 hours. After the nucleophilic substitution reaction is completed, cool it to room temperature, filter out the polystyrene, and use a molar concentration of 0.2 to 2 mol·L -1 The polystyrene is treated with alkalization by caustic soda aqueous solution, and then washed with clean water until it is neutral. After drying, the surface diallylamine polystyrene is obtained. Reaction formula-1 schematically expresses the process of preparing the surface diallylamine polystyrene using chloromethylated polystyrene and diallylamine as raw materials:

[0025]

[0026] The chloromethylated polystyrene refers to one of chloromethylated cross-linked or non-cross-linked polystyrene macroporous hollow resin spheres, chloromethylated cross-linked or non-cross-linked polystyrene macroporous hollow resin powders, chloromethylated cross-linked or non-cross-linked polystyrene microspheres, chloromethylated cross-linked or non-cross-linked polystyrene filter membranes, chloromethylated cross-linked or non-cross-linked polystyrene fibers, or chloromethylated cross-linked or non-cross-linked polystyrene open-cell foams; wherein the mass percentage of chlorine in the chloromethylated polystyrene is 10 to 30%.

[0027] The solvent refers to one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, 2-methoxyethanol acetate, 2-ethoxyethanol acetate, ethyl acetate, methyl acetate, butyl acetate, toluene, acetone, butanone, anisole, chloroform, chlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide; the amount of the solvent used is 2 to 20 times the mass of the chloromethylated polystyrene.

[0028] The amount of diallyl ammonium used is 1.0 to 2.5 times the molar amount of chlorine contained in the chloromethylated polystyrene.

[0029] The polymerization inhibitor is selected from one or more of hydroquinone, p-methoxyphenol, tert-butyl hydroquinone, 2,6-dibutyl hydroquinone, 2,6-di-tert-butyl-p-cresol, and 2,4,6-tri-tert-butylphenol; the dosage of the polymerization inhibitor is 0.2-12% of the mass of diallylamine.

[0030] The dosage of the caustic soda aqueous solution is 0.5 to 5 times the mass of the chloromethylated polystyrene.

[0031] Step 2: Preparation of surface unsaturated zwitterionic polystyrene

[0032] The surface diallylamine polystyrene prepared in step 1 is put into a solvent in a reactor, and after swelling at room temperature for 2 to 24 hours, a zwitterionizing agent and a polymerization inhibitor are added, the reaction temperature is controlled at 20 to 90° C., and the reaction is carried out for 2 to 24 hours. After the zwitterionization reaction is completed, the temperature is lowered to room temperature, the polystyrene is filtered out, the polystyrene is washed with ethanol, and the surface unsaturated zwitterionized polystyrene is obtained after centrifugal drying; Reaction formula-2 schematically expresses the process of preparing surface unsaturated zwitterionized polystyrene using the surface diallylamine polystyrene and the zwitterionizing agent as raw materials:

[0033]

[0034] The solvent refers to one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, 2-methoxyethanol acetate, 2-ethoxyethanol acetate, ethyl acetate, methyl acetate, butyl acetate, toluene, acetone, butanone, anisole, chloroform, chlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide; the amount of the solvent used is 2 to 20 times the mass of the surface diallylamine polystyrene.

[0035] The zwitterionization agent refers to one of 1,3-propane sultone, sodium 3-chloro-2-hydroxypropane sulfonate, sodium 2-bromoethyl sulfonate, sodium 4-bromobutyl sulfonate, γ-butyrolactone, β-propiolactone, sodium 2-chloroacetate or sodium 2-bromoethylphosphonate, and the amount of the zwitterionization agent used is 1.0 to 1.5 times the molar amount of N atoms contained in the surface diallylamine polystyrene.

[0036] The polymerization inhibitor refers to one or more of hydroquinone, p-methoxyphenol, tert-butyl hydroquinone, 2,6-dibutyl hydroquinone, 2,6-di-tert-butyl-p-cresol, and 2,4,6-tri-tert-butylphenol; the dosage of the polymerization inhibitor is 0.2-12% of the mass of the zwitterionization agent.

[0037] Step 3: Preparation of polyzwitterionic polystyrene containing glycidyl groups

[0038] The surface unsaturated zwitterionic polystyrene prepared in step 2, the zwitterionic monomer containing glycidyl group of general formula (I), the Gemini zwitterionic crosslinking agent containing glycidyl group of general formula (II), an aqueous initiator, and deionized water are mixed uniformly, poured into a reactor already filled with an organic solvent, stirred and dispersed, and nitrogen-filled for deoxygenation for 30 minutes. The material temperature in the reactor is controlled to 50-90° C., and reverse suspension polymerization is performed for 2-12 hours. The polystyrene is filtered and recovered, and the filtered and recovered polystyrene is washed with water, and centrifuged to obtain polyzwitterionic polystyrene containing glycidyl group. Reaction formula-3 schematically expresses the preparation process of polyzwitterionic polystyrene containing glycidyl group:

[0039]

[0040] The glycidyl-containing zwitterionic monomer has a structure shown in general formula (I):

[0041]

[0042] Wherein R in the general formula (I) is selected from C1 to C 18 One of the hydrocarbon groups, the Q- Refers to -CH2CH2CH2SO3 - 、-CH2CH(OH)CH2SO3 - 、-CH2CH2SO3 - 、-CH2CH2CH2CH2SO3 - 、-CH2CH2CH2CO2 - 、-CH2CH2CO2 - 、-CH2CO2 - or -CH2PO3H - One of them.

[0043] The glycidyl-containing Gemini zwitterionic crosslinking agent has a structure shown in the general formula (II):

[0044]

[0045] Among them, Select C1~C 18 Alkylene or One of the following, wherein n is selected from a natural number between 0 and 200; Q - Refers to -CH2CH2CH2SO3 - 、-CH2CH(OH)CH2SO3 - 、-CH2CH2SO3 - 、-CH2CH2CH2CH2SO3 - 、-CH2CH2CH2CO2 - 、-CH2CH2CO2 - 、-CH2CO2 - or -CH2PO3H - One of them.

[0046] The aqueous initiator refers to one or more of hydrogen peroxide, sodium persulfate, potassium persulfate, ammonium persulfate, azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, 4,4'-azobis(sodium cyanovalerate), or azobisisopropylimidazoline hydrochloride.

[0047] The organic solvent refers to one or more of chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, xylene, chlorobenzene, decahydronaphthalene, anisole, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, kerosene, diesel, paraffin oil, and petroleum ether (boiling range 60-90° C.).

[0048] The mass ratio of the surface unsaturated quaternary ammonium cationized polystyrene / the zwitterionic monomer containing glycidyl groups of the general formula (I) / the gemini zwitterionic crosslinking agent containing glycidyl groups of the general formula (II) / aqueous initiator / deionized water / organic solvent is 1:0.1-3:0.1-3:0.03-0.13:1-10:2-200.

[0049] Step 4: Preparation of surface polymyxin-coated polystyrene

[0050] At room temperature, start stirring and add the polymyxin product to the buffer solution. After the polymyxin product is dissolved, add the polyzwitterionic polystyrene containing glycidyl groups prepared in step 3, control the temperature between 20 and 40°C, stir and react for 20 to 200 hours, then add a sealing agent aqueous solution with a mass percentage concentration of 10 to 30%, continue to heat and stir and react for 4 to 40 hours, filter out the polystyrene, wash with water to neutrality, and centrifuge to obtain surface polymyxin polystyrene. Reaction formula-4 schematically expresses the process of polystyrene surface grafting polymyxin:

[0051]

[0052] The mass ratio of the polyzwitterionic polystyrene containing glycidyl groups / polymyxin product / buffer solution is 1-10:0.1-5:1-50.

[0053] The buffer solution refers to one of a boric acid / borax buffer solution, a boric acid / potassium chloride / sodium hydroxide buffer solution, a sodium dihydrogen phosphate / sodium hydroxide buffer solution, a borax / sodium hydroxide buffer solution, a sodium bicarbonate / sodium carbonate buffer solution, or a sodium carbonate / sodium hydroxide buffer solution with a pH value between 7.0 and 10.0;

[0054] The polymyxin product refers to one of polymyxin A, polymyxin B, polymyxin C, polymyxin D, polymyxin E, a mixture of polymyxin A + polymyxin B + polymyxin C + polymyxin D + polymyxin E mixed in any mass ratio, polymyxin B sulfate, or polymyxin E sodium methanesulfonate.

[0055] The amount of the blocking agent aqueous solution is 0.3 to 3 times the mass of the polyzwitterionic polystyrene containing glycidyl groups; wherein the blocking agent is one of ethanolamine, tromethamine, or amino acid.

[0056] The amino acid has a structure shown in the general formula (III):

[0057]

[0058] Wherein the general formula (III) Selected from C1~C 18 The alkylene group, wherein W is selected from one of -SO3H, -COOH or -PO3H2.

[0059] The beneficial effects of the present invention are:

[0060] ① The technical solution of the present invention realizes the cross-linking of the polyamphoteric cationic graft chain and presents a woven net structure, which is closely attached to the surface of the polystyrene material in a flat unfolded state, and is bonded to the surface of the polystyrene material through multi-point covalent bonds of the woven net structure, so the polyamphoteric cationic graft chain is very firmly bonded to the surface of the polystyrene material. At the same time, the ring-opening reaction of the glycidyl ether unit on the outer layer of the polystyrene material surface is utilized, and the graft-bonded polymyxin has high stability and the graft density can be adjusted, which is of great significance for ensuring the safety of use in medical treatment.

[0061] ② By adopting the technical scheme described in the present invention, the effect of the cross-linked mesh structure of the polyamphoteric cationic grafted chain coating the polystyrene material is achieved, and a high-coverage hydration layer is formed on the surface of the polystyrene by combining water molecules, which is beneficial for its rapid miscibility with blood and easy contact adsorption with medium and small water molecules in the blood on the surface of the polystyrene, and also has the function of preventing nonspecific adsorption of proteins in the blood, which is beneficial to protein recovery during blood perfusion.

[0062] ③ The technical solution of the present invention is adopted to realize the multi-layer structure characteristics of polystyrene material as the inner core layer + the woven mesh structure of polyamphoteric cationic grafted chain as the middle layer + grafted polymyxin as the outermost layer, which is of great significance for fully demonstrating the efficiency of polymyxin grafted on the surface of polystyrene material in adsorbing endotoxin in blood and quickly completing equilibrium adsorption in a short time. DETAILED DESCRIPTION

[0063] The following examples further illustrate the method for grafting polymyxin onto the surface of polystyrene provided by the present invention, the purpose of which is to provide a better understanding of the content of the present invention.

[0064] Example 1 Preparation of polystyrene resin spheres grafted with polymyxin B (1)

[0065] Step 1: Weigh 20 grams of chloromethylated cross-linked polystyrene hollow macroporous resin balls (Nankai University Chemical Plant, commonly known as chlorine balls, particle size 0.45-0.65 mm, cross-linking degree 4.7%, Cl content 17.34%) and mix them into 160 ml of N, N-dimethylformamide in a reactor and soak them for 20 hours to fully swell. Then add 15.5 grams of N, N-diallylamine and 0.85 grams of hydroquinone to the reactor. After nitrogen deoxygenation for 30 minutes, control the temperature of the materials in the reactor to 40-50°C, stir and react for 6 hours, and then increase the reaction temperature to 80- 90 ℃, stirring and reacting for 6 hours, lowering the temperature of the materials in the reactor to room temperature, filtering and recovering the polystyrene resin balls, soaking them in a caustic soda aqueous solution with a mass percentage concentration of 20%, filtering and recovering the polystyrene resin balls, and then washing the polystyrene resin balls with water until neutral, centrifuging and drying at a constant speed of 2000±200 rpm for 5 minutes to obtain 35.4 g of diallyl aminated polystyrene resin balls. The water content of the diallyl aminated polystyrene resin balls obtained by thermogravimetric analysis was 18.71%, and the chloromethyl conversion rate was calculated by the weight gain method to be 93.4%.

[0066] Step 2: Wash 35.4 g of diallylamine polystyrene resin balls obtained in step 1 with ethanol for 2 to 3 times, vacuum dry and then add 160 ml of N,N-dimethylformamide into a reactor and soak for 20 hours to fully swell. Add 13.6 g of 1,3-propanesultone and 0.85 g of 2,6-di-tert-butyl-p-cresol into the reactor, fill with nitrogen and deoxygenate for 30 minutes, control the temperature of the material in the reactor to 60 to 70 ° C, stir and react for 16 hours, reduce the temperature of the material in the reactor The polystyrene resin balls are filtered and recovered, and the filtered and recovered polystyrene resin balls are washed with ethanol. After centrifugation at a constant speed of 2000±200 rpm for 5 minutes, 96.6 g of surface unsaturated zwitterion polystyrene resin balls (1) are obtained. The surface unsaturated zwitterion polystyrene resin balls (1) obtained by thermogravimetric analysis contain 50.56% volatile matter. The yield of the surface unsaturated zwitterion polystyrene resin balls (1) calculated by weight gain method is 98.2%.

[0067] Step 3: Weigh 30 g of deionized water, 10 g of 3-(N-glycidyl-N,N-diallylammonium)-1-propanesulfonate, 5 g of 1,4-di(N-glycidyl-N-allyl-N-(3-sulfopropyl)ammonium)butane, 1.8 g of azobisisobutylamidine hydrochloride, and 96.6 g of surface unsaturated zwitterionic polystyrene resin balls obtained in step 2, mix them together, pour them into a polymerization reactor filled with 250 ml of chlorobenzene, and fill with nitrogen to remove the residue. The polystyrene resin balls were washed with ethanol and water respectively, and then centrifuged and dried at a constant speed of 2000±200 rpm for 5 minutes to obtain 127.2 g of polyzwitterionic polystyrene resin balls (1) containing glycidyl groups.

[0068] The hydrochloric acid acetone method of GB1677-81 was used to determine that the epoxy mass percentage of the polyzwitterionic polystyrene resin sphere (1) containing glycidyl groups was 3.874% (theoretical value is 4.216%), and the grafting rate was calculated to be 91.9%; according to the thermogravimetric analysis, the water content was 60.13%, and the grafting rate of the polyzwitterionic polystyrene resin sphere (1) containing glycidyl groups was calculated to be 92.6% by using the mass increase method. The calculation results of the two grafting rate detection methods are basically close, indicating that the preparation of the polyzwitterionic polystyrene resin sphere (1) containing glycidyl groups is successful.

[0069] Step 4: weigh 12 g of a boric acid / borax buffer solution with a pH value of 7.5 into a reactor, add 3.2 g of polymyxin B sulfate under stirring at room temperature, and after the polymyxin B sulfate is dissolved, add 12.4 g of the polyquaternary ammonium cationized polystyrene resin beads (1) containing glycidyl groups obtained in step 3, stir evenly, and detect the pH value of the material in the reactor ≥ 7.0, control the temperature of the material in the reactor to 35-37° C., and react by stirring for 24 hours. Filter out the polystyrene resin beads and then put them into 12 g of a 38% ethanolamine aqueous solution, control the temperature to 35-37° C., and continue stirring and reacting for 4 hours. Filter out the polystyrene resin beads, wash with deionized water until the washing water is neutral, and centrifuge at a constant speed of 2000±200 rpm for 5 minutes to obtain polystyrene resin beads with polymyxin B (1) grafted on the surface.

[0070] Thermogravimetric analysis of the samples revealed that the water content of the polymyxin B (1) grafted on the surface of the polystyrene resin sphere was 60.9%. The ninhydrin colorimetric method was used to measure the changes before and after the addition of polymyxin B sulfate to the boric acid / borax buffer solution and the reaction of the polyzwitterionic polystyrene resin sphere (1) containing glycidyl groups, and the grafting amount of polymyxin B (1) grafted on the surface of the polystyrene resin sphere was calculated to be 263.5 mg / g, and the utilization rate of polymyxin B sulfate was also calculated to be 94.7%.

[0071] Example 2 Polystyrene film resin ball surface grafted with polymyxin B (2)

[0072] According to the preparation method and operation steps of Example 1:

[0073] The "13.6 g of 1,3-propane sultone" in step 2 of Example 1 was replaced with "20.3 g of sodium 3-chloro-2-hydroxypropane sulfonate" to obtain surface unsaturated zwitterionic polystyrene resin spheres (2). The surface unsaturated zwitterionic polystyrene resin spheres (2) obtained by thermogravimetric analysis contained 53.18% of volatile matter, and the yield of the surface unsaturated zwitterionic polystyrene resin spheres (2) was 76.3% calculated by the weight gain method. This indicates that when 1,3-propane sultone was replaced with sodium 3-chloro-2-hydroxypropane sulfonate, the utilization rate of sodium 3-chloro-2-hydroxypropane sulfonate was not high, probably because the solubility of sodium 3-chloro-2-hydroxypropane sulfonate in DMF was not high.

[0074] The "3-(N-glycidyl-N,N-diallyl-ammonium)-1-propanesulfonate 10 g, 1,4-di(N-glycidyl-N-allyl-N-(3-sulfopropyl)ammonium)butane 5 g" in step 3 of Example 1 were replaced with "3-(N-glycidyl-N,N-diallyl-ammonium)-1-propanesulfonate 0 g, 1,4-di(N-glycidyl-N-allyl-N-(3-sulfopropyl)ammonium)butane 15 g" to obtain polyquaternary ammonium cationized polystyrene resin spheres (2) containing glycidyl groups. Thermogravimetric analysis showed that the water content was 57.72%, and the grafting rate of the polyzwitterionic polystyrene resin spheres (2) containing glycidyl groups was calculated by weight gain method to be as high as 100%. When all zwitterionic monomers are replaced with gemini zwitterionic crosslinking agents containing glycidyl ether groups, the grafting rate of the polyzwitterionic polystyrene resin spheres (2) containing glycidyl groups reaches 100%, indicating that the efficiency of the graft copolymerization reaction on the surface of the polymer material is determined by the crosslinking agent.

[0075] The rest of the method and steps of Example 1 were followed to obtain polystyrene resin spheres grafted with polymyxin B (2). Thermogravimetric analysis of the sample showed that the water content of the polystyrene resin spheres grafted with polymyxin B (2) was 59.71%. The ninhydrin colorimetric method was used to measure the changes before and after the reaction of adding polymyxin B sulfate and polyzwitterionic polystyrene resin spheres (2) containing glycidyl groups to the boric acid / borax buffer solution. The grafting amount of polymyxin B (2) grafted on the surface of the polystyrene resin spheres was calculated to be 220.1 mg / g, and the utilization rate of polymyxin B sulfate was calculated to be 86.2%.

[0076] Example 3 Polystyrene film resin ball surface grafted with polymyxin B (3)

[0077] According to the preparation method and operation steps of Example 1:

[0078] The "3-(N-glycidyl-N,N-diallyl ammonium)-1-propanesulfonate 10 g, 1,4-di(N-glycidyl-N-allyl-N-(3-sulfopropyl)ammonium)butane 5 g" in step 3 of Example 1 were replaced with "3-(N-glycidyl-N-benzyl-N-allyl ammonium)-1-propanesulfonate 10 g, 1,4-di(N-glycidyl-N-allyl-N-(3-sulfopropyl)ammonium)butane 5 g" to obtain polyquaternary ammonium cationized polystyrene resin beads (3) containing glycidyl groups. Thermogravimetric analysis showed that the water content was 53.2%, and the grafting rate of polyzwitterionic polystyrene resin beads (3) containing glycidyl groups was 96.2% calculated by weight gain method.

[0079] The rest of the method and steps of Example 1 were followed to obtain polystyrene resin spheres grafted with polymyxin B (3). Thermogravimetric analysis of the samples revealed that the water content of the polystyrene resin spheres grafted with polymyxin B (3) was 59.32%. The ninhydrin colorimetric method was used to determine the changes before and after the reaction of adding polymyxin B sulfate and the polyzwitterionized polystyrene resin spheres (2) containing glycidyl groups to the boric acid / borax buffer solution. The grafting amount of polymyxin B (2) grafted on the surface of the polystyrene resin spheres was calculated to be 217.5 mg / g, and the utilization rate of polymyxin B sulfate was calculated to be 87.1%.

[0080] Example 4 Polystyrene film resin ball surface grafted with polymyxin B (4)

[0081] According to the preparation method and operation steps of Example 1:

[0082] The "13.6 g of 1,3-propane sultone" in step 2 of Example 1 was replaced with "18.5 g of γ-butyrolactone" to prepare surface unsaturated zwitterionic polystyrene resin spheres (3). The surface unsaturated zwitterionic polystyrene resin spheres (3) obtained by thermogravimetric analysis contained 55.43% of volatile matter. The yield of the surface unsaturated zwitterionic polystyrene resin spheres (3) calculated by the weight gain method was 88.7%.

[0083] The "3-(N-glycidyl-N,N-diallylammonium)-1-propanesulfonate 10 g, 1,4-di(N-glycidyl-N-allyl-N-(3-sulfopropyl)ammonium)butane 5 g" in step 3 of Example 1 were replaced with "3-(N-glycidyl-N,N-diallylammonium)-1-butyrate 10 g, 1,4-di(N-glycidyl-N-allyl-N-(3-carboxypropyl)ammonium)butane 5 g" to obtain polyquaternary ammonium cationized polystyrene resin beads (3) containing glycidyl groups. Thermogravimetric analysis showed that the water content was 53.2%, and the grafting rate of the polyzwitterionic polystyrene resin beads (3) containing glycidyl groups was calculated to be 96.2% by weight gain method.

[0084] The rest of the method and steps of Example 1 were followed to obtain polystyrene resin spheres with grafted polymyxin B (4). Thermogravimetric analysis of the sample showed that the water content of the polystyrene resin spheres with grafted polymyxin B (4) was 55.33%. The ninhydrin colorimetric method was used to measure the changes before and after the reaction of adding polymyxin B sulfate and the polyzwitterionized polystyrene resin spheres (3) containing glycidyl groups to the boric acid / borax buffer solution. The grafting amount of polymyxin B (4) grafted on the surface of the polystyrene resin spheres was calculated to be 301.3 mg / g, and the utilization rate of polymyxin B sulfate was calculated to be 96.5%.

[0085] Example 5 Polystyrene film resin ball surface grafted with polymyxin B (5)

[0086] According to the preparation method and operation steps of Example 1:

[0087] The "13.6 g of 1,3-propane sultone" in step 2 of Example 1 was replaced with "18.5 g of γ-butyrolactone" to prepare surface unsaturated zwitterionic polystyrene resin spheres (3). The surface unsaturated zwitterionic polystyrene resin spheres (3) obtained by thermogravimetric analysis contained 45.43% of volatile matter. The yield of the surface unsaturated zwitterionic polystyrene resin spheres (3) calculated by the weight gain method was 88.7%.

[0088] The "3-(N-glycidyl-N,N-diallylammonium)-1-propanesulfonate 10 g, 1,4-di(N-glycidyl-N-allyl-N-(3-sulfopropyl)ammonium)butane 5 g" in step 3 of Example 1 were replaced with "3-(N-glycidyl-N,N-diallylammonium)-1-butyrate 10 g, 1,4-di(N-glycidyl-N-allyl-N-(3-carboxypropyl)ammonium)butane 5 g" to obtain polyquaternary ammonium cationized polystyrene resin beads (3) containing glycidyl groups. Thermogravimetric analysis showed that the water content was 61.32%, and the grafting rate of the polyzwitterionic polystyrene resin beads (3) containing glycidyl groups was calculated to be 96.2% by weight gain method.

[0089] The "12 g mass percentage concentration of 38% ethanolamine aqueous solution" in step 4 was replaced with "15 g mass percentage concentration of 20% glycine aqueous solution with a pH value of 11.0" to obtain polystyrene resin sphere surface grafted polymyxin B (5). Thermogravimetric analysis of the sample showed that the water content of polystyrene resin sphere surface grafted polymyxin B (5) was 61.08%. The ninhydrin colorimetric method was used to determine the changes before and after the reaction of adding polymyxin B sulfate and glycidyl-containing polyzwitterionic polystyrene resin sphere (3) to the boric acid / borax buffer solution, and the grafting amount of polymyxin B (5) grafted on the surface of the polystyrene resin sphere was calculated to be 298.5 mg / g, and the utilization rate of polymyxin B sulfate was calculated to be 92.3%.

[0090] Example 6 Polystyrene film resin ball surface grafted with polymyxin B (6)

[0091] According to the preparation method and operation steps of Example 1:

[0092] The "13.6 g of 1,3-propane sultone" in step 2 of Example 1 was replaced with "18.5 g of γ-butyrolactone" to prepare surface unsaturated zwitterionic polystyrene resin spheres (3). The surface unsaturated zwitterionic polystyrene resin spheres (3) obtained by thermogravimetric analysis contained 45.43% of volatile matter. The yield of the surface unsaturated zwitterionic polystyrene resin spheres (3) calculated by the weight gain method was 88.7%.

[0093] The "3-(N-glycidyl-N,N-diallylammonium)-1-propanesulfonate 10 g, 1,4-di(N-glycidyl-N-allyl-N-(3-sulfopropyl)ammonium)butane 5 g" in step 3 of Example 1 were replaced with "3-(N-glycidyl-N-dodecyl-N-allylammonium)-1-butyrate 13.5 g, 1,4-di(N-glycidyl-N-allyl-N-(3-carboxypropyl)ammonium)butane 5 g" to obtain polyquaternary ammonium cationic polystyrene resin beads (4) containing glycidyl groups. Thermogravimetric analysis showed that the water content was 61.10%, and the grafting rate of polyzwitterionic polystyrene resin beads (4) containing glycidyl groups was calculated by weight gain method to be 95.6%.

[0094] The "12 g mass percentage concentration of 38% ethanolamine aqueous solution" in step 4 was replaced with "15 g mass percentage concentration of 20% glycine aqueous solution with a pH value of 11.0" to obtain polystyrene resin sphere surface grafted polymyxin B (6). Thermogravimetric analysis of the sample showed that the water content of polystyrene film resin sphere surface grafted polymyxin B (6) was 60.37%. The ninhydrin colorimetric method was used to determine the changes before and after the reaction of adding polymyxin B sulfate and glycidyl-containing polyzwitterionic polystyrene resin sphere (4) to the boric acid / borax buffer solution, and the grafting amount of polymyxin B (6) grafted on the surface of the polystyrene film resin sphere was calculated to be 302.3 mg / g, and the utilization rate of polymyxin B sulfate was calculated to be 94.3%.

[0095] Example 7 Polystyrene film resin sphere surface grafted with polymyxin B (7)

[0096] According to the preparation method and operation steps of Example 1:

[0097] The "13.6 g of 1,3-propane sultone" in step 2 of Example 1 was replaced with "18.5 g of sodium chloroacetate" to prepare surface unsaturated zwitterionic polystyrene resin spheres (4). The surface unsaturated zwitterionic polystyrene resin spheres (4) obtained by thermogravimetric analysis contained 43.76% of volatile matter. The yield of the surface unsaturated zwitterionic polystyrene resin spheres (4) calculated by weight gain method was 80.6%.

[0098] The "3-(N-glycidyl-N,N-diallylammonium)-1-propanesulfonate 10 g, 1,4-di(N-glycidyl-N-allyl-N-(3-sulfopropyl)ammonium)butane 5 g" in step 3 of Example 1 were replaced with "3-(N-glycidyl-N-dodecyl-N-allylammonium)-1-butyrate 13.5 g, 1,4-di(N-glycidyl-N-allyl-N-(3-carboxypropyl)ammonium)butane 5 g" to obtain polyquaternary ammonium cationized polystyrene resin beads (5) containing glycidyl groups. Thermogravimetric analysis showed that the water content was 61.35%, and the grafting rate of polyzwitterionic polystyrene resin beads (5) containing glycidyl groups was calculated by weight gain method to be 90.9%.

[0099] The "12 g mass percentage concentration of 38% ethanolamine aqueous solution" in step 4 was replaced with "20 g mass percentage concentration of 20% lysine aqueous solution with a pH value of 10.0" to obtain polystyrene resin sphere surface grafted polymyxin B (7). Thermogravimetric analysis of the sample showed that the water content of polystyrene film resin sphere surface grafted polymyxin B (7) was 60.73%. The ninhydrin colorimetric method was used to measure the changes before and after the reaction of adding polymyxin B sulfate and glycidyl-containing polyzwitterionic polystyrene resin sphere (5) to the boric acid / borax buffer solution, and the grafting amount of polymyxin B (7) grafted on the surface of the polystyrene film resin sphere was calculated to be 296.4 mg / g, and the utilization rate of polymyxin B sulfate was calculated to be 92.9%.

[0100] It can be seen from the examples of the present invention that the present invention maintains more than 3 times the theoretical amount of polymyxin B and adopts a high-concentration polymyxin B reaction system in order to reduce the five amino groups of a single polymyxin molecule sharing the adjacent glycidyl groups on the surface of the polyzwitterionized polystyrene resin sphere containing glycidyl groups, affecting the grafting quantity and grafting efficiency of polymyxin B. The results show that the technical solution of the present invention achieves the intention of high-efficiency grafting of polymyxin B on the surface of polystyrene film resin spheres. In addition, from the results of polymyxin B grafted on the surface of polystyrene film resin spheres in Examples 1 to 7, the use of the blocking agent aqueous solution with increased alkalinity is not conducive to improving the grafting efficiency of polymyxin B grafted on the surface of polystyrene film resin spheres.

Claims

1. A method for grafting polymyxin onto the surface of polystyrene, characterized in that The following preparation steps are adopted: Step 1: Preparation of surface diallylamine-modified polystyrene Weigh chloromethylated polystyrene and put it into the solvent in the reactor. After swelling at room temperature for 2 to 24 hours, add diallylamine and polymerization inhibitor, control the reaction temperature to 50 to 90 ° C, and react for 20 to 24 hours. After the nucleophilic substitution reaction is completed, cool it to room temperature, filter out the polystyrene, and use a molar concentration of 0.2 to 2 mol·L -1 The polystyrene was treated with a caustic soda aqueous solution, and then washed with clean water until it was neutral, and dried to obtain surface diallylamine-modified polystyrene; The amount of diallylamine used is 1.0 to 2.5 times the molar amount of chlorine contained in the chloromethylated polystyrene, the amount of the solvent used is 2 to 20 times the mass of the chloromethylated polystyrene, the amount of the inhibitor used is 0.2 to 12% of the mass of diallylamine, and the amount of the caustic soda aqueous solution used is 0.5 to 5 times the mass of the chloromethylated polystyrene; The chloromethylated polystyrene refers to one of chloromethylated cross-linked or non-cross-linked polystyrene macroporous hollow resin spheres, chloromethylated cross-linked or non-cross-linked polystyrene macroporous hollow resin powders, chloromethylated cross-linked or non-cross-linked polystyrene microspheres, chloromethylated cross-linked or non-cross-linked polystyrene filter membranes, chloromethylated cross-linked or non-cross-linked polystyrene fibers, or chloromethylated cross-linked or non-cross-linked polystyrene open-cell foams; wherein the mass percentage of chlorine in the chloromethylated polystyrene is 10 to 30%; Step 2: Preparation of surface unsaturated zwitterionic polystyrene The surface diallylamine polystyrene obtained in step 1 is put into a solvent in a reactor, and after swelling at room temperature for 2 to 24 hours, a zwitterionizing agent and a polymerization inhibitor are added, the reaction temperature is controlled at 20 to 90° C., and the reaction is carried out for 2 to 24 hours. After the zwitterionization reaction is completed, the temperature is lowered to room temperature, the polystyrene is filtered out, the polystyrene is washed with ethanol, and the polystyrene is centrifuged to obtain surface unsaturated zwitterionized polystyrene; The amount of the zwitterionization agent is 1.0 to 1.5 times the molar amount of N atoms contained in the surface diallylamine polystyrene, the amount of the solvent is 2 to 20 times the mass of the surface diallylamine polystyrene, and the amount of the polymerization inhibitor is 0.2 to 12% of the mass of the zwitterionization agent; The zwitterionizing agent refers to one of 1,3-propane sultone, sodium 3-chloro-2-hydroxypropane sulfonate, sodium 2-bromoethyl sulfonate, sodium 4-bromobutyl sulfonate, γ-butyrolactone, β-propiolactone, or sodium 2-chloroacetate; Step 3: Preparation of polyzwitterionic polystyrene containing glycidyl groups The surface unsaturated zwitterionic polystyrene prepared in step 2, the zwitterionic monomer containing glycidyl group of general formula (I), the Gemini zwitterionic crosslinking agent containing glycidyl group of general formula (II), an aqueous initiator, and deionized water are uniformly mixed together, poured into a reaction kettle already filled with an organic solvent, stirred and dispersed, and nitrogen-filled and deoxygenated for 30 minutes, the temperature of the materials in the reaction kettle is controlled to 50-90° C., and reverse suspension polymerization is performed for 2-12 hours, and the polystyrene is filtered and recovered, and the filtered and recovered polystyrene is washed with water, and centrifuged and dried to obtain polyzwitterionic polystyrene containing glycidyl group; The mass ratio of the surface unsaturated quaternary ammonium cationized polystyrene / the glycidyl group-containing zwitterionic monomer of the general formula (I) / the glycidyl group-containing gemini zwitterionic crosslinking agent of the general formula (II) / aqueous initiator / deionized water / organic solvent is 1:0.1-3:0.1-3:0.03-0.13:1-10:2-200; The glycidyl-containing zwitterionic monomer has a structure shown in general formula (I): Wherein R in the general formula (I) is selected from C1 to C 18 One of the hydrocarbon groups, the Q - Refers to -CH2CH2CH2SO3 - 、-CH2CH(OH)CH2SO3 - 、-CH2CH2SO3 - 、-CH2CH2CH2CH2SO3 - 、-CH2CH2CH2CO2 - 、-CH2CH2CO2 - 、-CH2CO2 - or -CH2PO3H - One of; The glycidyl-containing Gemini zwitterionic crosslinking agent has a structure shown in the general formula (II): Wherein - in the general formula (II) is selected from C1 to C 18 Alkylene or One of the following, wherein n is selected from a natural number between 0 and 200; Q - Refers to -CH2CH2CH2SO3 - 、-CH2CH(OH)CH2SO3 - 、-CH2CH2SO3 - 、-CH2CH2CH2CH2SO3 - 、-CH2CH2CH2CO2 - 、-CH2CH2CO2 - 、-CH2CO2 - or -CH2PO3H - One of; Step 4: Grafting polymyxin on polystyrene surface Under room temperature, stirring is started and a polymyxin product is added to the buffer solution. After the polymyxin product is dissolved, the polyzwitterionic polystyrene containing glycidyl groups prepared in step 3 is added, the temperature is controlled between 20 and 40° C., and the reaction is stirred for 20 to 200 hours. The polystyrene is filtered out, and then the polystyrene is added to a blocking agent aqueous solution with a mass percentage concentration of 10 to 30%. The temperature is controlled between 20 and 40° C., and the reaction is continued with stirring for 4 to 40 hours. The polystyrene is filtered out, washed with water until neutral, and centrifuged to obtain polystyrene surface grafted polymyxin; The mass ratio of the polyzwitterionic polystyrene containing glycidyl groups / polymyxin product / buffer solution is 1-10:0.1-5:1-50; The polymyxin product refers to one of polymyxin A, polymyxin B, polymyxin C, polymyxin D, polymyxin E, a mixture of polymyxin A + polymyxin B + polymyxin C + polymyxin D + polymyxin E mixed in any mass ratio, polymyxin B sulfate, or polymyxin E sodium methanesulfonate; The blocking agent is one of ethanolamine, tromethamine, or amino acid, and the amount of the blocking agent aqueous solution is 0.3 to 3 times the mass of the polyzwitterionic polystyrene containing glycidyl groups.

2. A method for grafting polymyxin onto the surface of polystyrene according to claim 1, characterized in that The solvent refers to one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, 2-methoxyethanol acetate, 2-ethoxyethanol acetate, ethyl acetate, methyl acetate, butyl acetate, toluene, acetone, butanone, anisole, chloroform, chlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

3. A method for grafting polymyxin onto the surface of polystyrene according to claim 1, characterized in that The polymerization inhibitor refers to one or more of hydroquinone, p-methoxyphenol, tert-butylhydroquinone, 2,6-dibutylhydroquinone, 2,6-di-tert-butyl-p-cresol, and 2,4,6-tri-tert-butylphenol.

4. A method for grafting polymyxin onto the surface of polystyrene according to claim 1, characterized in that The aqueous initiator refers to one or more of hydrogen peroxide, sodium persulfate, potassium persulfate, ammonium persulfate, azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, 4,4'-azobis(sodium cyanovalerate), or azobisisopropylimidazoline hydrochloride.

5. A method for grafting polymyxin onto the surface of polystyrene according to claim 1, characterized in that The organic solvent refers to one or more of chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, xylene, chlorobenzene, decahydronaphthalene, anisole, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, kerosene, diesel, paraffin oil, and petroleum ether (boiling range 60-90° C.).

6. A method for grafting polymyxin onto the surface of polystyrene according to claim 1, characterized in that The buffer solution refers to one of a boric acid / borax buffer solution, a boric acid / potassium chloride / sodium hydroxide buffer solution, a sodium dihydrogen phosphate / sodium hydroxide buffer solution, a borax / sodium hydroxide buffer solution, a sodium bicarbonate / sodium carbonate buffer solution, or a sodium carbonate / sodium hydroxide buffer solution with a pH value between 7.0 and 10.

0.

7. A method for grafting polymyxin onto the surface of polystyrene according to claim 1, characterized in that The amino acid has a structure shown in general formula (III): Wherein the general formula (III) Selected from C1~C 18 The W is selected from one of -SO3H, -COOH or -PO3H2.

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