CN107365422B - Hydrophilic modification method of polyglycidyl methacrylate or copolymer thereof and modified material - Google Patents

Hydrophilic modification method of polyglycidyl methacrylate or copolymer thereof and modified material Download PDF

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CN107365422B
CN107365422B CN201610309058.3A CN201610309058A CN107365422B CN 107365422 B CN107365422 B CN 107365422B CN 201610309058 A CN201610309058 A CN 201610309058A CN 107365422 B CN107365422 B CN 107365422B
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hydrophilic modification
hydrophilic
modification method
reaction
copolymer
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CN107365422A (en
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马光辉
李强
张坤
赵岚
黄永东
周炜清
吴学星
朱凯
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Institute of Process Engineering of CAS
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/12—Chemical modification
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/08—Epoxidation
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
    • C08F220/32—Esters containing oxygen in addition to the carboxy oxygen containing epoxy radicals
    • C08F220/325—Esters containing oxygen in addition to the carboxy oxygen containing epoxy radicals containing glycidyl radical, e.g. glycidyl (meth)acrylate
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2333/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers
    • C08J2333/04—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters
    • C08J2333/14—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters of esters containing halogen, nitrogen, sulfur, or oxygen atoms in addition to the carboxy oxygen

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  • Medicinal Chemistry (AREA)
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Abstract

A hydrophilic modification method and material of crosslinked polyglycidyl methacrylate or a copolymer thereof are disclosed, wherein the method comprises the following steps: active epoxy groups on the surface of crosslinked polyglycidyl methacrylate or a copolymer thereof are utilized to covalently crosslink natural polysaccharide molecules for multiple times for hydrophilic modification, so that the hydrophilic modification material of polyglycidyl methacrylate or a copolymer thereof is obtained. The method has simple operation and mild reaction conditions, the obtained multi-layer hydrophilic modified group modified polyglycidyl methacrylate or the copolymer thereof has high content of sugar hydroxyl, the coating is stable, the non-specific adsorption of the polymer microspheres to protein is eliminated, and the hydrophilic layer can be directly or further coupled with other ligands or functional groups through derivatization, thereby having great application prospect in the field of biochemical engineering, particularly biochemical separation.

Description

Hydrophilic modification method of polyglycidyl methacrylate or copolymer thereof and modified material
Technical Field
The invention relates to the technical field of polymer material modification, in particular to a hydrophilic modification method of polyglycidyl methacrylate or a copolymer thereof (namely, glycidyl methacrylate copolymer) and a modified material.
Background
There are three main types of substrates as chromatographic packing: 1. natural polysaccharide macromolecules represented by cellulose, dextran and agarose; 2. synthetic polymers such as polystyrene/divinylbenzene (PS/DVB), polyacrylic acid (PAA), and polyglycidyl methacrylate (PGMA); 3. silica gel, hydroxyapatite, glass and other inorganic base materials. The polymer microsphere is used as chromatographic separation medium, and has the advantages of stable chemical property, high mechanical strength, high acid and alkali resistance, capacity of being operated under high pressure, etc. and wide application foreground. However, some characteristics of the polymer itself limit its application in the separation of biological macromolecules. The skeleton structure of the polymer microsphere substrate has extremely strong hydrophobicity, and hydrophilic modification is difficult, which mainly comes from the hydrophobic groups such as residual double bonds and inert benzene rings which are exposed on the skeleton and are not polymerized, and the hydrophobic groups have strong nonspecific adsorption on biomolecules such as protein and enzyme, and are very easy to cause denaturation and inactivation of the biomolecules.
Therefore, in addition to direct application to reverse phase chromatography, polymeric microspheres must be surface modified, masked or eliminated from hydrophobic groups for use in other chromatographic formats.
Cross-linked polyglycidyl methacrylate (PGMA) is a pressure resistant polymer substrate with functional epoxy groups (Wang et al, Preparation of inorganic Poly (glycidyl methacrylate) powders by membrane emulsification-polymerization technology, J Appl Poly Sci.2006,102: 5018-. Compared with the inert skeleton of the crosslinked polystyrene, the epoxy group of the crosslinked polyglycidyl methacrylate material has strong activity and can directly react with a plurality of active groups, such as carboxyl (-COOH), hydroxyl (-OH), isochloroacetic acid (-NCO), amino (-NH)2) Etc.; by taking the active groups as sites, other macromolecular materials or functional ligands can be further introduced to prepare a functionalized layerAnd (5) separating the materials.
The applicant researches hydrophilic modification (CN102617869A) on the surface of a cross-linked polyacrylate material in earlier stage, and bonds a single layer of hydrophilic polysaccharide molecules on the surface of the polyacrylate material in a chemical coupling mode, so that certain hydrophilicity is given to the surface of the material.
Therefore, it is desirable in the art to develop a method that can achieve modification of the hydrophobic groups in the interior and on the surface of the crosslinked polyglycidyl methacrylate or its copolymer material.
Disclosure of Invention
The invention aims to provide a hydrophilic modification method of crosslinked polyglycidyl methacrylate or a copolymer thereof. The method comprises the steps of activating residual vinyl double bonds into epoxy groups through epoxy, eliminating nonspecific adsorption through coupling polysaccharide molecules, and further coupling hydrophilic polysaccharide molecules on the surface coated with a single-layer hydrophilic polysaccharide molecule to form a stable high-density multi-layer hydrophilic polysaccharide molecule chemical crosslinking layer. The surface of the material after hydrophilic modification has abundant sugar hydroxyl groups, and can be further derived into various functional groups for the requirements of different biochemical molecule separation and purification modes.
In order to achieve the purpose, the invention adopts the following technical scheme:
a hydrophilic modification method of polyglycidyl methacrylate or a copolymer thereof comprises the following steps:
(1) under the action of an oxidant, hydrophilic modification is carried out on unpolymerized hydrophobic residual vinyl double bonds in the poly glycidyl methacrylate or the copolymer thereof, so that the hydrophobicity of the material is greatly reduced;
(2) in the presence of an organic solvent, covalently grafting and coupling a hydrophilic modification group to the surface of the material obtained in the step (1) through an active epoxy group to form a single-layer hydrophilic modification group-modified polyglycidyl methacrylate or a copolymer thereof;
(3) and (3) under an aqueous phase environment, covalently grafting and coupling hydrophilic modification groups to the surface of the material obtained in the step (2) by utilizing abundant hydroxyl groups of polysaccharide molecules which are already plated to form a multilayer hydrophilic modification group modified polyglycidyl methacrylate or a copolymer thereof.
The method of the invention pretreats the polyglycidyl methacrylate or the copolymer thereof so that the residual vinyl double bonds of the unpolymerized polymer are also converted into epoxy groups. Then, hydrophilic polysaccharide molecules are plated on the surface of the polymer material in a chemical coupling mode to form a single-layer plating layer of the polysaccharide molecules. The polysaccharide molecules are further coated in a chemical coupling mode by utilizing rich hydroxyl groups of the coated polysaccharide molecules.
The method can realize hydrophilic modification of hydrophobic sites and residual vinyl double bonds in and on the surfaces of the polyglycidyl methacrylate or the copolymer thereof, and the surfaces and pore canal surfaces of the modified polyglycidyl methacrylate or the copolymer thereof are bonded with a plurality of layers of hydrophilic substances, so that the hydrophilicity reaches the standard of natural polysaccharide polymer materials. The modified surface can be further covalently grafted with various functional groups and applied to separation and purification of biochemical molecules.
In the hydrophilic modification method of the present invention, the crosslinking degree of the polyglycidyl methacrylate or the copolymer thereof in step (1) is preferably 0 to 80%, for example, 1%, 5%, 11%, 18%, 25%, 33%, 38%, 44%, 52%, 61%, 70%, 77%, or the like, preferably 20% to 80%, more preferably 40 to 60%.
Preferably, the glycidyl methacrylate copolymer is prepared by combining a glycidyl methacrylate monomer with a crosslinking agent such as one or more of Divinylbenzene monomer (DVB), hexanediol dimethacrylate (EGDMA), Ethylene glycol dimethacrylate (EDMA), N-methylenebis (acrylamide) (N', N-methyl-bis (acrylamide), MBAA, etc., with DVB and EGDMA being the most common, prepared by copolymerization, such as by suspension polymerization, emulsion polymerization, membrane emulsion polymerization, etc.
Preferably, the polyglycidyl methacrylate or the copolymer thereof is polyglycidyl methacrylate microspheres or copolymer microspheres thereof.
Preferably, the divinylbenzene monomer accounts for 20% or more of the total mass of the glycidyl methacrylate and the divinylbenzene monomer, for example, 22%, 28%, 34%, 42%, 47%, 55%, 68%, 74%, 81%, 89%, etc., preferably 20 to 80%, and more preferably 50 to 70%.
Preferably, the oxidant is any one of or a combination of at least two of m-chloroperoxybenzoic acid, 2-chloroperoxybenzoic acid or p-chloroperoxybenzoic acid.
Preferably, the mass ratio of the polyglycidyl methacrylate or the copolymer thereof to the oxidizing agent is 0.1-100:1, for example, 0.4:1, 0.8:1, 1.3:1, 2:1, 2.6:1, 3.5:1, 4.1:1, 4.7:1, 5.5:1, 6.6:1, 7.5:1, 8:1, 8.6:1, 9.2:1, 9.8:1, 15:1, 30:1, 45:1, 50:1, 66:1, 80:1, 95:1, etc., preferably 1-10: 1.
Preferably, the temperature of the oxidation reaction is 0-90 deg.C, such as 1 deg.C, 5 deg.C, 11 deg.C, 20 deg.C, 35 deg.C, 47 deg.C, 56 deg.C, 66 deg.C, 71 deg.C, 78 deg.C, 84 deg.C, preferably 25-50 deg.C.
Preferably, the time of the oxidation reaction is 0.5 to 10h, such as 0.7h, 1.2h, 1.8h, 2.5h, 3.3h, 4.2h, 4.9h, 5.5h, 6.3h, 7.0h, 7.6h, 8.2h, 8.8h, 9.4h, 9.9h, etc., preferably 2 to 5 h.
Preferably, the hydrophilic modification is the oxidation of hydrophobic residual vinyl double bonds to active epoxy groups.
Preferably, the active epoxy group is an oxirane group.
Preferably, in the hydrophilic modification method of the present invention, the hydrophilic modification group donor is any one or a combination of at least two of hydrophilic natural polysaccharide macromolecules, preferably any one or a combination of at least two of hydrophilic natural polysaccharide macromolecules having a weight average molecular weight of 1000-50000, such as 1100, 1500, 2500, 4000, 6000, 15000, 22000, 29000, 33000, 38000, 44000, 49000, and more preferably any one or a combination of at least two of natural glucan molecules having a weight average molecular weight of 1000-50000.
Preferably, the hydrophilic modification group is any one of natural glucan molecules with weight average molecular weight of 2000, natural glucan molecules with weight average molecular weight of 5000, or natural glucan molecules with weight average molecular weight of 10000, or a combination of at least two of the natural glucan molecules.
The hydrophilic modification group in step (2) may be the same as or different from the hydrophilic modification group in step (3).
Preferably, in the hydrophilic modification method of the present invention, the method for covalently graft-coupling the hydrophilic modification group in step (2) to the surface of the material obtained in step (1) comprises the following steps: (a) dissolving a donor of a hydrophilic modification group and a catalyst in an organic solvent; (b) and (2) adding the material obtained in the step (1) into the solution obtained in the step (a), stirring, heating for reaction, and washing the obtained single-layer hydrophilic modified group modified polyglycidyl methacrylate or the copolymer thereof after the reaction is finished.
Preferably, the mass ratio of the donor of the hydrophilic modification group in step (2) to the material obtained in step (1) is 0.01-100:1, such as 0.04:1, 0.12:1, 0.2:1, 0.5:1, 0.9:1, 1.3:1, 2:1, 2.6:1, 3.5:1, 4.1:1, 4.7:1, 5.5:1, 6.6:1, 7.5:1, 8:1, 8.6:1, 9.2:1, 9.8:1, 15:1, 30:1, 45:1, 50:1, 66:1, 80:1, 95:1, etc., preferably 0.1-10: 1.
Preferably, the organic solvent is any one of or a combination of at least two of dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone or methanol.
Preferably, the catalyst is an organic base, preferably any one or a combination of at least two of N-methylmorpholine, 4-dimethylaminopyridine or tetramethylethylenediamine.
Preferably, the dissolution is carried out with stirring, preferably for 2 hours or more, more preferably for 4 hours, until complete dissolution to transparency is obtained.
Preferably, the stirring time in step (b) is 0.5h or more, for example, 0.7h, 1.1h, 1.6h, 2.1h, 2.8h, 3.5h, 5.0h, etc., preferably 1 h.
Preferably, the temperature rise is to 0-90 ℃, such as 1 ℃, 5 ℃, 11 ℃, 20 ℃, 35 ℃, 47 ℃, 56 ℃, 66 ℃, 71 ℃, 78 ℃, 84 ℃, preferably 30-60 ℃.
Preferably, the reaction time is 0.5 to 90h, such as 0.7h, 1.1h, 1.6h, 2.1h, 2.8h, 3.5h, 5h, 15h, 23h, 36h, 50h, 60h, 70h, 80h, 85h, etc., preferably 72 h. The color of the reaction solution deepens and becomes dark yellow during the reaction period to 12 hours, and the color does not change until the reaction is finished.
Preferably, the step (b) is followed by the addition of a cross-linking agent to effect a cross-linking and strengthening reaction.
Preferably, the crosslinking and strengthening reaction process is as follows: and (c) dissolving a cross-linking agent and NaOH in water, then adding the material obtained in the step (b), and reacting under stirring to obtain the water-soluble polyurethane. And washing the material obtained after the reaction by using deionized water until a washing solution is neutral, storing the material in 20% ethanol, and storing the material at room temperature for later use.
Preferably, the cross-linking agent is alcohol-based glycidyl ether, preferably any one of ethylene glycol methyl ether glycidyl ether, propylene glycol diglycidyl ether or ethylene glycol diglycidyl ether or a combination of at least two of the same.
Preferably, the mass ratio of the cross-linking agent to NaOH is 1-5:1, e.g. 1.3:1, 2:1, 2.6:1, 3.5:1, 4.1:1, 4.7:1, etc., preferably 3: 1.
Preferably, the reaction temperature is room temperature to 45 degrees C, such as 30 degrees C, 33 degrees C, 35 degrees C, 38 degrees C, 42 degrees C, 44 degrees C, preferably room temperature; the reaction time is 10 hours or more, for example, 12 hours, 16 hours, 21 hours, 24 hours, 27 hours, 30 hours, 35 hours, 41 hours, 50 hours, etc., preferably 12 to 36 hours.
Preferably, in the hydrophilic modification method of the present invention, the method for covalently graft-coupling the water-modifying group in step (3) to the surface of the material obtained in step (2) comprises the following steps: (a) activating the material obtained in the step (2); (b) brominating the activated material of step (a) with excess bromine water and washing; (c) adding the washed material in the step (b) into a donor solution of a hydrophilic modification group for reaction, and then sealing in an alkali metal hydroxide solution for reaction.
Preferably, the mass ratio of the donor of the hydrophilic modification group to the material obtained in step (2) is 0.01-100:1, such as 0.04:1, 0.12:1, 0.2:1, 0.5:1, 0.9:1, 1.3:1, 2:1, 2.6:1, 3.5:1, 4.1:1, 4.7:1, 5.5:1, 6.6:1, 7.5:1, 8:1, 8.6:1, 9.2:1, 9.8:1, 15:1, 30:1, 45:1, 50:1, 66:1, 80:1, 95:1, etc., preferably 1-10: 1.
Preferably, the activation process in step (a) is: adding sodium borohydride, anhydrous sodium sulfate and sodium hydroxide solution into the material obtained in the step (2), and reacting at 30-80 ℃, preferably at 40-60 ℃ for more than 10min, preferably 30min-2 h; then adding allyl glycidyl ether to react for more than 5 hours, preferably 10min-30 hours at 30-80 ℃, preferably 40-60 ℃; and finally washing the reacted microspheres.
Preferably, the mass ratio of the material obtained in the step (2) to the sodium borohydride, the anhydrous sodium sulfate and the sodium hydroxide is 1:0.1-100: 0.1-100.
Preferably, the concentration of the sodium hydroxide solution is 0.1-100g/L, such as 0.3g/L, 0.8g/L, 1.5g/L, 3g/L, 6g/L, 9g/L, 18g/L, 27g/L, 45g/L, 60g/L, 75g/L, 86g/L, 91g/L, 99g/L, and the like.
Preferably, the ratio of allyl glycidyl ether added to the material obtained in step (2) is 0.01-1000mL/g, e.g., 0.04mL/g, 0.12mL/g, 0.4mL/g, 1.2mL/g, 3mL/g, 9mL/g, 20mL/g, 60mL/g, 120mL/g, 240mL/g, 360mL/g, 500mL/g, 650mL/g, 720mL/g, 800mL/g, 910mL/g, etc.
Preferably, the washing is sequentially washed by water, ethanol, water, acetic acid and water; preferably washing with water for 2-4 times, ethanol for 1-3 times, water for 2-4 times, acetic acid for 1-3 times, and water for 5-20 times; preferably 3 times with 5 times water wash, 2 times with 95% ethanol, 3 times with 2 times water wash, 2 times with 0.2M acetic acid wash 2 times (neutralize the mixture), and finally 10 times with 5 times water.
Preferably, the bromination process in step (b) is: adding sodium acetate and water into the microspheres activated in the step (a), adding bromine water for reaction, adding a proper amount of sodium formate after the reaction is finished until the suspension is colorless, and washing with water.
Preferably, the bromine-added water is added until the color is unchanged.
Preferably, the temperature of the reaction is room temperature; the reaction time is 0.5 to 3 hours, for example, 0.7 hour, 1.1 hour, 1.6 hour, 2.1 hour, 2.8 hour, etc., preferably 1 hour.
Preferably, the number of times of the water washing is 3 or more, preferably 5 to 15 times, and more preferably 10 times.
Preferably, the mass ratio of the hydrophilic modifying group donor in step (c) to the material after washing in step (b) is 0.3 to 1:1, for example 0.4:1, 0.48:1, 0.55:1, 0.6:1, 0.75:1, 0.9:1, etc., preferably 0.5 to 0.7:1, more preferably 0.6: 1.
The dissolution of the donor of the hydrophilic modifying group can be assisted by ultrasound.
Preferably, the temperature for adding the washed material of step (b) into the donor solution of the hydrophilic modification group for reaction is 25-40 ℃, preferably 30 ℃; the reaction time is 0.5h or more, preferably 0.5 to 2h, more preferably 1 h. The reaction is preferably carried out by shaking at a speed of 150 rpm.
Preferably, the NaOH solution contains NaBH4Preferably NaBH4The concentration in the NaOH solution is 2 to 5g/L, more preferably 3 to 4 g/L.
Preferably, the temperature of the reaction after sealing in NaOH solution is 25-40 ℃, preferably 30 ℃; the reaction time is 5 hours or more, preferably 10 to 30 hours, and more preferably 20 hours. The reaction is preferably carried out by shaking at a speed of 150 rpm.
And after the reaction is finished, fully washing a product by deionized water, and draining for later use.
The invention also aims to provide a modified material prepared by the modification method. The surface and pore canal surface of the modified cross-linked poly glycidyl methacrylate or the copolymer thereof are bonded with a plurality of layers of hydrophilic substances, and the hydrophilicity reaches the standard of natural polysaccharide polymer materials. The modified surface can be further covalently grafted with various functional groups and applied to separation and purification of biochemical molecules.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, the hydrophilic modification of the pore channel and the surface of the crosslinked polyglycidyl methacrylate or the copolymer material thereof can be realized by carrying out hydrophilic modification on the hydrophobic sites in the crosslinked polyglycidyl methacrylate or the copolymer material thereof and the hydrophobic residual vinyl double bonds which are not completely polymerized after the polymerization process of the monomers is finished, so that the modified crosslinked polyglycidyl methacrylate or the copolymer material thereof has consistent hydrophilicity with the natural polysaccharide molecular polymer material.
The modified cross-linked polyglycidyl methacrylate or the copolymer thereof has greatly reduced hydrophobicity, and surface hydroxyl groups on the polysaccharide coating can be subjected to substitution reaction with various functional groups, and the surface of the modified cross-linked polyglycidyl methacrylate or the copolymer thereof can be further derivatized into functional groups such as protein A, sulfonic group, amino group and the like, and can be used as a medium for biochemical separation in multiple separation modes. Therefore, the method has good application prospect and advantages in the field of biochemical separation and purification.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings described below are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
FIG. 1 is a schematic diagram of hydrophilized PGMA-Glucan microspheres provided in example IV of the present invention;
FIG. 2 is the scanning electron microscope photographs of the microspheres obtained in example two and example four of the present invention before and after modification, wherein 1a and 1b are the microspheres obtained in example two and example four before modification, respectively, and 2a and 2b are the microspheres obtained in example two and example four after modification, respectively;
FIG. 3 is a drawing showing the nonspecific adsorption of Bovine Serum Albumin (BSA) before and after the modification of the microspheres coated with dextran, a natural polysaccharide obtained in example IV of the present invention.
Detailed Description
For the purpose of facilitating an understanding of the present invention, the present invention will now be described by way of examples. It should be understood by those skilled in the art that the examples are only for the purpose of facilitating understanding of the present invention and should not be construed as specifically limiting the present invention.
EXAMPLE 1 preparation and pretreatment of Linear Polyglycidyl methacrylate (PGMA) powder
Since the epoxy group of Glycidyl Methacrylate (GMA) is susceptible to ring-opening reaction at high temperature, the atom transfer radical polymerization of GMA is carried out in this example under low temperature conditions. 6.6mL (50mmol) of GMA monomer, CuBr was added to a polytetrafluoroethylene-lined 100mL reactor255mg (0.25mmol), 78.1mg (0.5mmol) of 2,2' -bipyridine (bpy), 2mL of Azobisisobutyronitrile (AIBN) as an initiator, 15mL of THF, N.sub.2To remove O in the reaction system2The mixture is placed in an oven and reacted for 8 hours at the set temperature (the reaction is stopped by taking out the ice bath and cooling the ice bath). With Tetrahydrofuran (THF) or CH2Cl2Purifying the polymer with methanol or n-hexane as precipitant, and vacuum drying at 45 deg.C for 24 hr to obtain white powder PGMA. As shown in FIG. 1, the residual double bond treatment method comprises swelling 10g of the obtained PGMA powder with 200mL of dichloromethane, mixing overnight at room temperature, adding 15g of m-chloroperoxybenzoic acid, reacting at 25 ℃ for 1.5h, alternately washing with deionized water and ethanol, and drying.
EXAMPLE 2 preparation and pretreatment of Cross-Linked Polyglycidyl methacrylate (PGMA-DVB) microspheres
GMA monomer, cross-linking agent (DVB), diluent, surfactant and initiator (BPO) are added into a beaker according to a certain proportion to prepare an oil phase, and the oil phase is stirred until the BPO is completely dissolved. Mixing a certain amount of stabilizer (PVA) and anhydrous Na2SO4SDS and HQ are dissolved in deionized water to prepare a water phase, and the oil phase is dispersed in the water phase under the condition of stirring (200r/min) to prepare O/W emulsion. After 1h of nitrogen, the temperature was raised to 75 ℃ and polymerization was carried out for 20h under a nitrogen atmosphere. The obtained polymer microspheres were washed with water and ethanol three times, respectively. Unpolymerized substances such as surfactant and diluent in the microspheres are removed by acetone extraction for 24 h. Vacuum drying at room temperature to obtain PGMA microsphere. As shown in figure 1, the residual double bond treatment method, 10g of the microspheres obtained are taken to swell with 130mL of dichloromethane, mixed overnight at room temperature, 10g of m-chloroperoxybenzoic acid is added, after reaction for 1.5h at 25 ℃,and alternately washing and drying the deionized water and the ethanol. The microspheres obtained were examined by scanning electron microscopy as shown in FIG. 2 by 1 (a)/(b).
Example 3 grafting of a monolayer dextran
Injecting 30L of dimethyl sulfoxide (DMSO) into a 50L reaction kettle at normal temperature, starting stirring at 100rpm, then weighing 1kg of glucan powder and 12g of 4-Dimethylaminopyridine (DMAP) powder, putting the glucan powder and the DMAP powder into a large beaker, directly pouring the mixture into the kettle from the beaker, and keeping stirring until the mixture is completely dissolved and transparent for 4 hours; after complete dissolution, 2kg of the dried PGMA microspheres prepared in example 2 were added to the reaction kettle, stirred at room temperature for 1 hour, and then stirred at 100 rpm; the temperature is increased to 37 ℃, the time is counted from the temperature increase, the reaction is kept for 3 days, the color of the reaction solution is deepened and changed into dark yellow during the reaction period to 12 hours, and the color is not changed until the reaction is finished. Discharging, filtering, washing the microspheres after the coating with deionized water. Crosslinking and reinforcing the coating: preparing a water phase: 1kg of NaOH, 3kg of polyethylene glycol diglycidyl ether (PEGDE) and 25L of deionized water, firstly adding water into a 50L reaction kettle, then adding NaOH and PEGDE, and simultaneously stirring at 100rpm until the NaOH and the PEGDE are completely dissolved; adding deionized water to wash the plated microspheres, adding the microspheres through a hand hole, stirring at 100rpm, and reacting for 24 hours at room temperature; discharging, filtering, washing the crosslinked microspheres with deionized water until the washing liquid is neutral, storing in 20% ethanol, and storing at room temperature.
Example 4 grafting of Multi-layered Glucan
1kg of PGMA microspheres coated with a single layer of dextran obtained in example 3 was charged into a 50L reactor, and 7g of sodium borohydride, 0.1kg of anhydrous sodium sulfate, and 6L of 50% sodium hydroxide solution were added and mixed for 1 hour at 50 ℃ and 150rpm on a shaker. Then 1.7L of allyl glycidyl ether was added and reacted on a shaker at 50 ℃ and 150rpm for 20 h. After the reaction had stopped, the medium was washed 3 times with 5 times deionized water, 2 times with 95% ethanol, 3 times with 2 times water, 2 times with 0.2M ethanol for 2 times (neutralization mixture), and finally 10 times with 5 times water. Adding 1kg of activated microspheres into a reaction kettle, adding 70g of sodium acetate, 1.5L of water and bromine water until the color is unchanged, reacting for 1 hour at room temperature, adding a proper amount of sodium formate until the suspension is colorless after the reaction is stopped, and washing for 10 times. 1kg aliveAdding 1L dextran solution (0.6kg dextran dissolved in 1L water, ultrasonic-assisted dissolving), mixing at 30 deg.C and 150rpm for 1 hr, adding 0.4L water and 1L 1.5mol/LNaOH solution (containing 3.6g NaBH)4) After sealing, the mixture was placed in a shaker at 30 ℃ and 150rpm for 20 hours. And after the reaction is finished, fully washing the medium by deionized water, and draining for later use. The microspheres obtained were examined by scanning electron microscopy as shown in FIG. 2 (a)/(b).
Example 5 Hydroxygroup determination of Hydrophilically modified microspheres
Weighing 0.5g of dried glucan, and placing the glucan in a 100mL single-mouth reaction bottle; preparing 50mL of acetic anhydride (density 1.08)/pyridine (density 0.9827g/mL) reaction solution according to a ratio of 1:20, accurately measuring 30mL of reaction solution by using a pipette, and adding the reaction solution into an upper reaction bottle; adding a dry condenser pipe, sealing by using a balloon, starting to heat until the reaction solution starts to flow back after condensed water is opened, and carrying out reflux reaction for 2 hours; after the reaction is finished, cooling the reaction system to room temperature, leaching the condenser tube with 20mL of deionized water, ensuring that leached water completely flows into the reaction bottle, oscillating for reacting for 30min, and titrating with 0.1M NaOH solution to obtain the alkali consumption volume of V1. Titration of the blank solution: 10mL of the acetic anhydride/pyridine reaction solution with the ratio of 1:20 is taken, 20mL of deionized water is added, after oscillation reaction is carried out for 30min, 0.1M NaOH solution is used for titration, and the volume amount of the consumed alkali is V2. The hydroxyl content on the surface of the hydrophilic modified microsphere obtained in example 4 is calculated to be 500mmol/g, and the calculation formula is as follows:
[ (3V2-V1) × C ]/M ═ microsphere hydroxyl content (mmol/g)
Wherein C is the concentration of the alkali liquor, and M is the mass of the microspheres.
Example 6 measurement of nonspecific adsorption Properties of hydrophilically modified microspheres
The size of four stainless steel chromatographic columns of the same type is 4.6 × 50mm, and the filler is respectively the hydrophilic modified microspheres obtained in example 2, the hydrophilic modified microspheres obtained in example 4, the modified microspheres obtained in example three in CN102617869A, and the commercial product GE Sepharose 4FF with better effect at present. The test protein was Bovine Serum Albumin (BSA) (66KDa PI ═ 4.6) and was dissolved in PB buffer at pH 7.0 (0.22 μm filter membrane was used for sample preparation).
Whether or not adsorption was observed in a 50mM buffer pH 7.0PB was determined by Shimadzu liquid LC-20A. Mobile phase: phase a 50mM pH 7.0PB buffer; b phase 1M NaOH aqueous solution (mobile phases need to be filtered by a 0.22um filter membrane); the flow rate is 1.0 mL/min; 100% A phase loading. Sample introduction amount: 200 μ L. Recording the peak area and retention time of the BSA sample, and taking 5 times for the sample; after elution of each sample, the sample was washed with 5mL of 100% phase B, then with 10mL of 100% phase A, and then loaded again. And (3) determining the peak area of the connector under the same sample feeding amount, feeding three times, recording the respective peak areas, then calculating the average value of the three times, recording as A0, determining the recovery rate as 100%, comparing the peak areas of the above samples with the peak areas, and calculating the recovery rate and the nonspecific adsorption amount.
Through detection, as shown in fig. 3, the nonspecific adsorption of the PGMA microspheres before and after modification is 80% and 0.2%, respectively; nonspecific adsorption of GE Sepharose 4FF was 0.1%; the nonspecific adsorption of the modified microspheres of example three in CN102617869A was 16%. Therefore, the modified microspheres of the invention realize complete hydrophilic modification.
The applicant states that the present invention is illustrated by the above examples to show the detailed process equipment and process flow of the present invention, but the present invention is not limited to the above detailed process equipment and process flow, i.e. it does not mean that the present invention must rely on the above detailed process equipment and process flow to be implemented. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims (82)

1. A hydrophilic modification method of polyglycidyl methacrylate or a copolymer thereof comprises the following steps:
(1) under the action of an oxidant, carrying out hydrophilic modification on unpolymerized hydrophobic residual vinyl double bonds in the polyglycidyl methacrylate or the copolymer thereof;
(2) in the presence of an organic solvent, covalently grafting and coupling a hydrophilic modification group to the surface of the material obtained in the step (1) through an active epoxy group to form a single-layer hydrophilic modification group-modified polyglycidyl methacrylate or a copolymer thereof;
(3) covalently grafting and coupling a hydrophilic modification group to the surface of the material obtained in the step (2) in an aqueous phase environment to form a multilayer hydrophilic modification group modified polyglycidyl methacrylate or a copolymer thereof;
the hydrophilic modification is to oxidize hydrophobic residual vinyl double bonds into active epoxy groups;
the donor of the hydrophilic modification group is any one or the combination of at least two of hydrophilic natural polysaccharide macromolecules.
2. The hydrophilic modification method according to claim 1, wherein the degree of crosslinking of the polyglycidyl methacrylate or the copolymer thereof in step (1) is 0 to 80%.
3. The hydrophilic modification method according to claim 1, wherein the degree of crosslinking of the polyglycidyl methacrylate or the copolymer thereof in step (1) is 20% to 80%.
4. The hydrophilic modification method according to claim 1, wherein the degree of crosslinking of the polyglycidyl methacrylate or the copolymer thereof in step (1) is 40 to 60%.
5. The hydrophilic modification method according to claim 1, wherein the glycidyl methacrylate copolymer is prepared by copolymerizing a glycidyl methacrylate monomer with a crosslinking agent.
6. The hydrophilic modification method according to claim 5, wherein the crosslinking agent is any one or a combination of at least two of a divinylbenzene monomer, a hexanediol dimethacrylate monomer, an ethylene glycol dimethacrylate monomer, or an N, N-methylenebis (acrylamide) monomer.
7. The hydrophilic modification method according to claim 5, wherein the crosslinking agent accounts for 20% or more of the total mass of the glycidyl methacrylate and the crosslinking agent.
8. The hydrophilic modification method according to claim 5, wherein the crosslinking agent is 20 to 80% by mass of the total mass of the glycidyl methacrylate and the crosslinking agent.
9. The hydrophilic modification method according to claim 5, wherein the crosslinking agent is 50 to 70% by mass of the total mass of the glycidyl methacrylate and the crosslinking agent.
10. The hydrophilic modification method according to claim 1, wherein the polyglycidyl methacrylate or the copolymer thereof is polyglycidyl methacrylate microspheres or glycidyl methacrylate copolymer microspheres.
11. The hydrophilic modification method according to claim 1, wherein the oxidizing agent is any one of meta-chloroperoxybenzoic acid, 2-chloroperoxybenzoic acid, or para-chloroperoxybenzoic acid, or a combination of at least two of them.
12. The hydrophilic modification method according to claim 1, wherein the mass ratio of the polyglycidyl methacrylate or the copolymer thereof to the oxidizing agent is 0.1 to 100: 1.
13. The hydrophilic modification method according to claim 1, wherein the mass ratio of the polyglycidyl methacrylate or the copolymer thereof to the oxidizing agent is 1-10: 1.
14. The hydrophilic modification method according to claim 1, wherein the temperature of the oxidation reaction is 0 to 90 ℃.
15. The hydrophilic modification method according to claim 1, wherein the temperature of the oxidation reaction is 25 to 50 ℃.
16. The hydrophilic modification method according to claim 1, wherein the time of the oxidation reaction is 0.5 to 10 hours.
17. The hydrophilic modification method according to claim 1, wherein the oxidation reaction time is 2 to 5 hours.
18. The hydrophilic modification method according to claim 1, wherein the active epoxy group is an oxirane group.
19. The hydrophilic modification method according to claim 1, wherein the donor of the hydrophilic modification group is any one or a combination of at least two of hydrophilic natural polysaccharide macromolecules having a weight average molecular weight of 1000-50000.
20. The hydrophilic modification method according to claim 1, wherein the donor of the hydrophilic modification group is any one or a combination of at least two of natural glucan molecules having a weight average molecular weight of 1000-50000.
21. The hydrophilic modification method according to claim 1, wherein the donor of the hydrophilic modification group is any one of natural glucan molecules having a weight average molecular weight of 2000, natural glucan molecules having a weight average molecular weight of 5000, or natural glucan molecules having a weight average molecular weight of 10000, or a combination of at least two of them.
22. The hydrophilic modification method according to claim 1, wherein the method for covalently graft-coupling the hydrophilic modification group to the surface of the material obtained in step (1) in step (2) comprises the following steps: (a) dissolving a donor of a hydrophilic modification group and a catalyst in an organic solvent; (b) and (2) adding the material obtained in the step (1) into the solution obtained in the step (a), stirring, heating for reaction, and washing the obtained single-layer hydrophilic modified group modified polyglycidyl methacrylate or the copolymer thereof after the reaction is finished.
23. The method of claim 22, wherein the mass ratio of the hydrophilic modification group donor in step (2) to the material obtained in step (1) is 0.01-100: 1.
24. The method of claim 22, wherein the mass ratio of the hydrophilic modification group donor in step (2) to the material obtained in step (1) is 0.1-10: 1.
25. The hydrophilic modification method according to claim 22, wherein the organic solvent is any one of or a combination of at least two of dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, or methanol.
26. The hydrophilic modification method of claim 22, wherein the catalyst is an organic base.
27. The hydrophilic modification method of claim 22, wherein the catalyst is any one of N-methylmorpholine, 4-dimethylaminopyridine, or tetramethylethylenediamine, or a combination of at least two of these.
28. The hydrophilic modification method of claim 22, wherein the dissolving is performed under agitation.
29. The method of claim 28, wherein the dissolving is performed for 2 hours or more.
30. The hydrophilic modification method according to claim 28, wherein the dissolving is performed for 4 hours to completely dissolve to be transparent.
31. The method of claim 22, wherein the stirring time in step (b) is 0.5h or more.
32. The hydrophilic modification method of claim 22, wherein the stirring time in step (b) is 1 hour.
33. The hydrophilic modification method according to claim 22, wherein the temperature is raised to 0 to 90 ℃.
34. The hydrophilic modification method according to claim 22, wherein the temperature is raised to 30 to 60 ℃.
35. The hydrophilic modification method according to claim 22, wherein the reaction time is 0.5 to 90 hours.
36. The hydrophilic modification method according to claim 22, wherein the reaction time is 72 hours.
37. The method of claim 22, wherein the step (b) is followed by the step of adding a cross-linking agent to effect the cross-linking and strengthening reaction.
38. The hydrophilic modification method according to claim 37, wherein the cross-linking and strengthening reaction process is as follows: and (c) dissolving a cross-linking agent and NaOH in water, then adding the material obtained in the step (b), and reacting under stirring to obtain the water-soluble polyurethane.
39. The method of claim 38, wherein the cross-linking agent is an alcohol-based glycidyl ether.
40. The method of claim 38, wherein the cross-linking agent is any one of ethylene glycol methyl ether glycidyl ether, propylene glycol diglycidyl ether, or ethylene glycol diglycidyl ether, or a combination of at least two thereof.
41. The method of claim 38, wherein the cross-linking agent to NaOH mass ratio is 1-5: 1.
42. The method of claim 38, wherein the cross-linking agent to NaOH mass ratio is 3: 1.
43. The hydrophilic modification method according to claim 38, wherein the reaction temperature is from room temperature to 45 ℃; the reaction time is more than 10 h.
44. The hydrophilic modification method according to claim 43, wherein the reaction temperature is room temperature.
45. The hydrophilic modification method according to claim 43, wherein the reaction time is 12-36 h.
46. The hydrophilic modification method according to claim 1, wherein the method for covalently graft-coupling the water-modifying group to the surface of the material obtained in step (2) in step (3) comprises the following steps: (a) activating the material obtained in the step (2); (b) brominating the activated material of step (a) with excess bromine water and washing; (c) adding the washed material in the step (b) into a donor solution of a hydrophilic modification group for reaction, and then sealing in an alkali metal hydroxide solution for reaction.
47. The method of claim 46, wherein the mass ratio of the hydrophilic modification group donor in step (3) to the material obtained in step (2) is 0.01-100: 1.
48. The method of claim 46, wherein the mass ratio of the hydrophilic modification group donor in step (3) to the material obtained in step (2) is 0.1-10: 1.
49. The hydrophilic modification method according to claim 46, wherein the activation process in step (a) is: adding sodium borohydride, anhydrous sodium sulfate and sodium hydroxide solution into the material obtained in the step (2) to react for more than 10min at the temperature of 30-80 ℃; then adding allyl glycidyl ether to react for more than 5 hours at the temperature of 30-80 ℃; and finally washing the reacted microspheres.
50. The hydrophilic modification method of claim 49, wherein sodium borohydride, anhydrous sodium sulfate and sodium hydroxide solution are added to the material obtained in step (2) and reacted at 40-60 ℃.
51. The hydrophilic modification method of claim 49, wherein sodium borohydride, anhydrous sodium sulfate and sodium hydroxide solution are added into the material obtained in step (2) to react for 30min-2 h.
52. The method of claim 49, wherein the allyl glycidyl ether is added to react at 40-60 ℃.
53. The method of claim 49, wherein the allyl glycidyl ether is added to react for 10min to 30 h.
54. The hydrophilic modification method according to claim 49, wherein the mass ratio of the material obtained in step (2) to the sodium borohydride, the anhydrous sodium sulfate and the sodium hydroxide is 1:0.1-100:0.1-100: 0.1-100.
55. The hydrophilic modification method according to claim 49, wherein the concentration of the sodium hydroxide solution is 0.1 to 100 g/L.
56. The hydrophilic modification method according to claim 49, wherein the ratio of the allyl glycidyl ether added to the material obtained in step (2) is 0.01 to 1000 mL/g.
57. The method of claim 49, wherein the washing step is performed with water, ethanol, water, acetic acid, and water.
58. The method of claim 49, wherein the washing is sequentially with water 2-4 times, ethanol 1-3 times, and water 5-20 times.
59. The method of claim 49, wherein the washing is performed 3 times with 5 times water, 2 times with 95% ethanol, 3 times with 2 times water, 2 times with 0.2M acetic acid, and 10 times with 5 times water.
60. The hydrophilic modification method of claim 49, wherein the bromination in step (b) is: adding sodium acetate and water into the microspheres activated in the step (a), adding bromine water for reaction, adding a proper amount of sodium formate after the reaction is finished until the suspension is colorless, and washing with water.
61. The method of claim 60, wherein the bromine-added water is added until the color is unchanged.
62. The hydrophilic modification method according to claim 60, wherein the reaction temperature is room temperature; the reaction time is 0.5-3 h.
63. The hydrophilic modification method according to claim 62, wherein the reaction time is 1 hour.
64. The method of claim 60, wherein the number of times of washing with water is 3 or more.
65. The method of claim 60, wherein the number of water washes is from 5 to 15.
66. The method of claim 60, wherein the number of water washes is 10.
67. The method of claim 46, wherein the step (c) of providing the hydrophilic modifying group comprises washing the material in step (b) in a mass ratio of 0.3 to 1: 1.
68. The method of claim 46, wherein the step (c) of providing the hydrophilic modifying group comprises washing the material in step (b) in a mass ratio of 0.5 to 0.7: 1.
69. The method of claim 46, wherein the hydrophilic modification group donor in step (c) is present in a mass ratio of 0.6:1 of the washed materials of step (b).
70. The hydrophilic modification method according to claim 46, wherein the temperature of the reaction of the washed material of step (b) added to the donor solution of the hydrophilic modification group is 25 to 40 ℃; the reaction time is more than 0.5 h.
71. The method of claim 70, wherein the temperature of the step (b) of adding the washed material to the solution of the hydrophilic modifying group donor is 30 ℃.
72. The method of claim 70, wherein the time for adding the washed material of step (b) into the donor solution of the hydrophilic modification group is 0.5-2 h.
73. The method of claim 70, wherein the time for adding the washed material of step (b) into the donor solution of the hydrophilic modification group for reaction is 30 ℃.
74. The method of claim 46, wherein the alkali metal hydroxide solution in step (c) is NaOH solution.
75. The hydrophilic modification method of claim 46, wherein the alkali metal hydroxide solution comprises NaBH4。
76. The hydrophilic modification of claim 75, wherein NaBH is added to the reaction mixture4The concentration in the alkali metal hydroxide solution is 2-5 g/L.
77. The hydrophilic modification of claim 75, wherein NaBH is added to the reaction mixture4The concentration in the alkali metal hydroxide solution is 3-4 g/L.
78. The hydrophilic modification method of claim 46, wherein the temperature of the post-sealing reaction is 25-40 ℃; the reaction time is more than 5 h.
79. The method of claim 78, wherein the temperature of the post-sealing reaction is 30 ℃.
80. The method of claim 78, wherein the reaction time after sealing is 10-30 h.
81. The method of claim 78, wherein the reaction time after sealing is 20 hours.
82. A modified material obtained by the modification method according to any one of claims 1 to 81.
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