阅读说明：本技术 一种含双硫键的双亲性无规共聚物、制备方法及其应用 (Amphiphilic random copolymer containing disulfide bond, preparation method and application thereof ) 是由 曾碧榕 王潇 戴李宗 朱继红 吴海洋 沈洪 周瑞瑞 陈国荣 罗伟昂 于 2019-08-05 设计创作，主要内容包括：本发明公开了一种含双硫键的双亲性无规共聚物、制备方法及应用。首先合成分别含有二硫键、醛基的单体,利用各单体间的双键加成反应通过RAFT聚合合成了双亲性共聚物。本发明制备的双亲性无规共聚物既因二硫键的存在表现出对纳米晶良好的螯合性,又因亲疏水单体存在表现出的双亲性,故而具有较好的生物相容性,在生物医学应用方面表现出潜在的应用。(The invention discloses an amphiphilic random copolymer containing disulfide bonds, a preparation method and application thereof. Firstly, monomers respectively containing disulfide bonds and aldehyde groups are synthesized, and an amphiphilic copolymer is synthesized by RAFT polymerization by utilizing double bond addition reaction among the monomers. The amphiphilic random copolymer prepared by the invention shows good chelation on the nanocrystal due to the existence of disulfide bonds and also shows amphiphilicity due to the existence of hydrophilic and hydrophobic monomers, so that the amphiphilic random copolymer has better biocompatibility and shows potential application in the aspect of biomedical application.)

1. An amphiphilic random copolymer containing disulfide bonds, wherein said amphiphilic random copolymer, designated as P (MAPEG-co-MALA-co-MAHA), has the following structural formula:

wherein n is the polymerization degree of hydrophilic monomer polyethylene glycol methacrylate, m is the polymerization degree of methacrylate polymerizable monomer containing disulfide bond, l is the polymerization degree of methacrylate polymerizable monomer containing aldehyde group, and n is m and l is 5-20: 20-25.

2. A method for preparing an amphiphilic random copolymer containing disulfide bonds, which is characterized by comprising the following steps:

1) preparing a methacrylate polymerizable monomer containing a disulfide bond, namely MALA, by using lipoic acid and hydroxyethyl methacrylate as raw materials;

2) preparing methacrylate polymerizable monomers containing aldehyde groups by using methacryloyl chloride and p-hydroxybenzaldehyde as raw materials, and marking the monomers as MAHA;

3) polyethylene glycol methacrylate is used as a hydrophilic monomer, MAHA is used as a hydrophobic monomer, and MALA is used as a functional monomer to carry out RAFT polymerization, so that an amphiphilic random copolymer containing disulfide bonds is obtained and is marked as P (MAPEG-co-MALA-co-MAHA).

3. The method for preparing an amphiphilic random copolymer containing a disulfide bond according to claim 2, wherein step 1) comprises the steps of:

firstly, lipoic acid and hydroxyethyl methacrylate are taken, solvent dichloromethane is added, and magnetic stirring is carried out under ice bath until the lipoic acid and the hydroxyethyl methacrylate are completely dissolved;

secondly, adding a water absorbent and an esterifying agent into the solution obtained in the step I, and reacting at room temperature for 12-24 hours;

thirdly, after the reaction is finished, obtaining light yellow transparent liquid, namely MALA, through extraction, rotary evaporation and vacuum drying;

wherein the dosage ratio of the lipoic acid, the hydroxyethyl methacrylate to the dichloromethane is 1 mol: 1 mol: 3-4L.

4. The method for producing an amphiphilic random copolymer containing a disulfide bond according to claim 3, wherein: the water absorbent is one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and dicyclohexylcarbodiimide; the esterifying agent is 4-dimethylamino pyridine.

5. The method for preparing an amphiphilic random copolymer containing a disulfide bond according to claim 2, wherein the step 2) comprises the steps of:

taking p-hydroxybenzaldehyde and triethylamine, adding dichloromethane serving as a solvent, and stirring and dissolving in ice bath;

dissolving methacryloyl chloride, then dropwise adding the dissolved methacryloyl chloride into the solution obtained in the step I, sealing and stirring, moving to an ice bath device, and stirring at room temperature to react for 12-24 hours;

after the reaction is finished, extracting and drying by a drying agent to obtain a hydrophobic monomer MAHA;

wherein the dosage ratio of the p-hydroxybenzaldehyde, the triethylamine, the methacryloyl chloride and the dichloromethane is 5-6 mol: 5-6 mol: 5-6 mol: 10-11L.

6. The method for producing an amphiphilic random copolymer containing a disulfide bond according to claim 5, wherein: in the step 2) -step II, the methacryloyl chloride is dissolved in dichloromethane, wherein the dosage ratio of the methacryloyl chloride to the dichloromethane is 8-9 mol: 3L.

7. The method for producing an amphiphilic random copolymer containing a disulfide bond according to claim 5, wherein: in the step 2) -step three, the drying agent is anhydrous magnesium sulfate.

8. The method for preparing an amphiphilic random copolymer containing a disulfide bond according to claim 2, wherein step 3) comprises the steps of:

firstly, adding a chain transfer agent and an initiator into polyethylene glycol maleate monoester, MALA and MAHA, dissolving in tetrahydrofuran, performing freezing-air extraction-unfreezing circulation by using liquid nitrogen and an air extractor, and polymerizing for 24-60 hours at 65 ℃ under the protection of inert gas;

secondly, adding a precipitator to precipitate a sample, and drying in vacuum to obtain light red solid powder, namely amphiphilic copolymer, which is marked as P (MAPEG-co-MALA-co-MAHA);

wherein the dosage ratio of the maleic acid polyethylene glycol monoester, the MALA, the MAHA, the tetrahydrofuran, the chain transfer agent and the initiator is 5-25 mol: 20-25 mol: 20-25 mol: 3-5L: 1 mol: 0.2 mol.

9. The method for producing an amphiphilic random copolymer containing a disulfide bond according to claim 8, wherein: the chain transfer agent is isopropyl phenyl dithiobenzoate, the chain initiator is azobisisobutyronitrile, and the precipitator is one of anhydrous ether and n-hexane.

10. Use of the amphiphilic random copolymer containing disulfide bonds according to claim 1 for the preparation of water-soluble nanocrystals.

Technical Field

The invention belongs to the field of polymer materials, and particularly relates to an amphiphilic copolymer containing disulfide bonds, a preparation method and application thereof.

Background

In recent years, nanocrystalline materials have great application potential in imaging, sensing, diagnosis and other biological aspects, and water-soluble nanocrystals are one of the most widely studied nanocrystalline materials. At present, a two-step synthesis method of synthesizing high-quality oil-soluble nanocrystals and then phase-transferring the oil-soluble nanocrystals to a water phase is the most effective method for preparing water-soluble nanocrystals. The phase transfer process is realized by adopting a ligand exchange method, and the organic ligand is replaced by a sulfhydryl reagent by utilizing the strong complexation acting force between elements on the specific surface of the nanocrystal, such as Zn, Cd and the like, and sulfhydryl groups, so that the nanocrystal and the sulfhydryl acid are complexed. Ligand exchange is generally carried out by adopting a monothiol ligand, wherein the monothiol ligand refers to ligand exchange of only one sulfhydryl group of a ligand molecule with an original ligand on the surface of a nanocrystal, but the water-soluble nanocrystal prepared by the method has poor stability and the performance of the water-soluble nanocrystal is greatly weakened compared with that of the nanocrystal in an organic phase.

Compared with a single sulfydryl ligand, the coordination effect between the disulfide bond ligand and the nanocrystal is stronger, and a plurality of sulfydryl groups can be simultaneously coordinated to the surface of the nanocrystal, so that the stability and the dispersibility of the nanocrystal in an aqueous medium are obviously improved. Based on the purpose, the amphiphilic polymer containing disulfide bonds has wide application prospect.

Disclosure of Invention

The invention aims to overcome the defects of the prior art, provides an amphiphilic random copolymer containing disulfide bonds, a preparation method and application thereof, and solves the problem of amphiphilic property of a nanocrystalline material in the background technology.

One of the technical schemes adopted by the invention for solving the technical problems is as follows: a disulfide bond-containing amphiphilic random copolymer P (MAPEG-co-MALA-co-MAHA) is provided, and the structural formula is as follows:

in the amphiphilic polymer P (MAPEG-co-MALA-co-MAHA), n is the polymerization degree of hydrophilic monomer polyethylene glycol Methacrylate (MAPEG), m is the polymerization degree of functional monomer MALA, l is the polymerization degree of hydrophobic monomer MAHA, and n, m and l are 5-20: 20-25.

The second technical scheme adopted by the invention for solving the technical problems is as follows: a method for preparing an amphiphilic random copolymer containing disulfide bonds is provided, which comprises the following steps:

1) lipoic acid and hydroxyethyl methacrylate (HEMA) are taken as raw materials to prepare a methacrylate polymerizable monomer containing a disulfide bond, which is marked as MALA;

firstly, lipoic acid and hydroxyethyl methacrylate are taken, solvent dichloromethane is added, and magnetic stirring is carried out under ice bath until the lipoic acid and the hydroxyethyl methacrylate are completely dissolved;

secondly, adding a water absorbent and an esterifying agent into the solution obtained in the step I, and reacting at room temperature for 12-24 hours;

thirdly, after the reaction is finished, obtaining light yellow transparent liquid, namely MALA, through extraction, rotary evaporation and vacuum drying;

wherein the dosage ratio of the lipoic acid, the hydroxyethyl methacrylate to the dichloromethane is 1 mol: 1 mol: 3-4L.

In a preferred embodiment of the present invention, the water absorbing agent is one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and dicyclohexylcarbodiimide; the esterifying agent is 4-dimethylamino pyridine.

2) Preparing methacrylate polymerizable monomers containing aldehyde groups by using methacryloyl chloride and p-hydroxybenzaldehyde as raw materials, and marking the monomers as MAHA;

taking p-hydroxybenzaldehyde and triethylamine, adding dichloromethane serving as a solvent, and stirring and dissolving in ice bath;

dissolving methacryloyl chloride, then dropwise adding the dissolved methacryloyl chloride into the solution obtained in the step I, sealing and stirring, moving to an ice bath device, and stirring at room temperature to react for 12-24 hours;

after the reaction is finished, extracting and drying by a drying agent to obtain a hydrophobic monomer MAHA;

wherein the dosage ratio of the p-hydroxybenzaldehyde, the triethylamine, the methacryloyl chloride and the dichloromethane is 5-6 mol: 5-6 mol: 5-6 mol: 10-11L.

In a preferred embodiment of the present invention, the methacryloyl chloride is dissolved in dichloromethane, wherein the ratio of the usage amount of the methacryloyl chloride to the usage amount of the dichloromethane is 8 to 9 mol: 3L.

In a preferred embodiment of the present invention, the drying agent is anhydrous magnesium sulfate.

3) Polyethylene glycol methacrylate is used as a hydrophilic monomer, MAHA is used as a hydrophobic monomer, and MALA is used as a functional monomer to carry out RAFT polymerization, so that an amphiphilic random copolymer containing disulfide bonds is obtained and is marked as P (MAPEG-co-MALA-co-MAHA).

Adding a chain transfer agent and an initiator into polyethylene glycol Maleate (MAPEG), MALA and MAHA, dissolving in Tetrahydrofuran (THF), performing freezing-air extraction-unfreezing circulation by using liquid nitrogen and an air extractor, and polymerizing for 24-60 h at 65 ℃ under the protection of inert gas;

secondly, adding a precipitator to precipitate a sample, and drying in vacuum to obtain light red solid powder, namely amphiphilic copolymer, which is marked as P (MAPEG-co-MALA-co-MAHA);

wherein the dosage ratio of the maleic acid polyethylene glycol monoester, the MALA, the MAHA, the tetrahydrofuran, the chain transfer agent and the initiator is 5-25 mol: 20-25 mol: 20-25 mol: 3-5L: 1 mol: 0.2 mol.

In a preferred embodiment of the present invention, the chain transfer agent is isopropyl phenyl dithiobenzoate (CDB), the chain initiator is Azobisisobutyronitrile (AIBN), and the precipitant is one of dehydrated ether and n-hexane.

The second technical scheme adopted by the invention for solving the technical problems is as follows: provides the application of the amphiphilic random copolymer containing the disulfide bond in the preparation of water-soluble nanocrystals.

Compared with the prior art, the invention has the following beneficial effects:

(1) MAPEG introduced into the polymer has good hydrophilicity and biocompatibility, and MAHA monomers endow the polymer with hydrophobic performance;

(2) the amphiphilic polymer synthesized by the invention contains a functional group MALA, a terminal disulfide bond is opened under the photocatalysis condition, and a free radical is captured in the form of-SH, so that the amphiphilic polymer has an excellent chelating function on gold nanoparticles;

(3) the invention creatively prepares an amphiphilic random copolymer containing disulfide bonds, and the copolymer based on disulfide bonds shows great potential application in the aspect of preparing water-soluble nanocrystals due to good hydrophilic and hydrophobic properties.

Drawings

FIG. 1 is a nuclear magnetic map of amphiphilic copolymer P (MAPEG-co-MALA-co-MAHA) prepared in example 1.

FIG. 2 shows an IR spectrum of amphiphilic copolymer P (MAPEG-co-MALA-co-MAHA) prepared in example 1.

FIG. 3 is an absorption spectrum of Au, amphiphilic copolymer P and water-soluble nanocrystal Au @ P of example 5.

Detailed Description