阅读说明：本技术 光敏型两性离子聚氨酯及制备方法、聚氨酯胶束制备方法 (Photosensitive zwitterionic polyurethane, preparation method thereof and preparation method of polyurethane micelle ) 是由 王海波 任碧波 许峻槐 杜晓声 成煦 杜宗良 于 2020-07-31 设计创作，主要内容包括：本发明公开了光敏型两性离子聚氨酯及制备方法、聚氨酯胶束制备方法,将双羟基两性离子及三苯胺基甲基吡啶阳离子季铵盐配合物与六亚甲基二异氰酸酯反应生成聚氨酯。将生成的聚氨酯固体溶解于二甲基亚砜溶液中,缓慢滴加去离子水,持续搅拌。搅拌结束后装入M<Sub>W</Sub>＝3500的透析袋中,透析后去除有机溶剂及未反应完全的有机小分子,最后得到稳定的具有光动力的两性抗菌聚氨酯胶束。本发明中的聚氨酯抗菌胶束制备方法简单新颖,结合新型的白光引发的光敏剂-吡啶季铵盐配合物。该聚氨酯在水中可以自组装成为胶束结构,其具有白光响应释放ROS的基团聚集在胶束核心内,亲水的两性离子在外层作为保护层,一经白光引发便可发挥ROS与阳离子季铵盐的协同抗菌作用。(The invention discloses photosensitive zwitterionic polyurethane, a preparation method thereof and a preparation method of a polyurethane micelle. Dissolving the generated polyurethane solid in dimethyl sulfoxide solution, slowly dripping deionized water,stirring was continued. After the stirring is finished, M is added W And (3) removing the organic solvent and the small organic molecules which are not completely reacted after dialysis in the dialysis bag of 3500, and finally obtaining the stable amphoteric antibacterial polyurethane micelle with photodynamic. The preparation method of the polyurethane antibacterial micelle is simple and novel, and is combined with a novel white light initiated photosensitizer-pyridine quaternary ammonium salt complex. The polyurethane can be self-assembled into a micelle structure in water, has white light response, can release radicals of ROS and gather in the core of the micelle, and hydrophilic zwitterions are used as protective layers on the outer layers, so that the synergistic antibacterial effect of ROS and cationic quaternary ammonium salt can be exerted once white light is initiated.)

1. The photosensitive zwitterionic polyurethane is characterized in that: a copolymer having the structural formula IV,

wherein the content of the first and second substances,

r represents

x and y represent polymerization degrees and independently range from 1 to 100.

2. The preparation method of the photosensitive zwitterionic polyurethane is characterized by comprising the following steps: the method comprises the following steps:

s1, dissolving carboxylic acid betaine or sulfonic acid betaine or phosphorylcholine in an organic solvent, adjusting the pH value of the solution, adding 3-mercapto-1, 2-propylene glycol to prepare a dihydroxyl zwitterionic monomer (formula I),

wherein R represents

S2, adding 4-methylpyridine into an organic solvent, uniformly mixing, adding 3-chloro-1, 2-propanediol, refluxing, carrying out rotary evaporation and concentration on reaction liquid, dropwise adding the reaction liquid into glacial ethyl ether while stirring, and precipitating to obtain 1- (2, 3-dihydroxypropyl) -4-methylpyridine cations (formula II),

s3, adding 4-diphenylaminobenzaldehyde and 1- (2, 3-dihydroxypropyl) -4-methylpyridine cation (formula II) obtained in S2 into an organic solvent, uniformly mixing, carrying out reflux reaction under the action of a catalyst, removing the solvent by rotary evaporation, purifying the product by using a silica gel column to obtain a red solid dihydroxytriphenylmethyl pyridine cation quaternary ammonium salt complex (formula III),

s4, vacuumizing the amphoteric dihydroxy zwitterion (formula I) obtained in S1 and the dihydroxy triphenylamine methyl pyridine cation quaternary ammonium salt complex (formula III) obtained in S3 under the heating condition, removing water, adding an organic solvent, uniformly mixing, adding hexamethylene diisocyanate, adding a catalyst dibutyltin dilaurate for reaction, then adding methanol for end capping, and separating out in the organic solvent after the end to obtain a polyurethane solid (formula IV),

wherein R represents

x and y represent polymerization degrees and independently range from 1 to 100.

3. The method for preparing a photosensitive zwitterionic polyurethane according to claim 2, further comprising: in the S1, carboxylic acid betaine or sulfonic acid betaine or phosphorylcholine is dissolved in any organic solvent, then diethanolamine is added to adjust the pH value of the solution to 10, 3-mercapto-1, 2-propanediol is added, the reaction is continuously stirred for 24 hours at room temperature, after the reaction is finished, the reaction liquid is subjected to rotary evaporation and drying, and then silica gel column purification is carried out, so as to prepare the dihydroxy zwitterionic monomer (formula I) with the tert-butyl group.

4. The method for preparing a photosensitive zwitterionic polyurethane according to claim 2, further comprising: in the S1, carboxylic acid betaine or sulfonic acid betaine or phosphorylcholine is dissolved in any organic solvent, then triethylamine is added to adjust the pH value of the solution to 10, 3-mercapto-1, 2-propanediol is added, the reaction is continuously stirred for 24 hours at room temperature, after the reaction is finished, the reaction liquid is subjected to rotary evaporation and drying, and then silica gel column purification is carried out, so as to prepare the dihydroxy zwitterionic monomer (formula I) with the tert-butyl group.

5. The method for preparing a photosensitive zwitterionic polyurethane according to claim 2, further comprising: in the S2, the mass part ratio of the 4-methylpyridine to the 3-chloro-1, 2-propanediol is 4:5, the temperature of the reflux link is 85 ℃, and the reflux time is 5 hours.

6. The method for preparing a photosensitive zwitterionic polyurethane according to claim 2, further comprising: in the S3, the mass part ratio of the 1- (2, 3-dihydroxypropyl) -4-methylpyridine cation (formula II) to the 4-diphenylaminobenzaldehyde is 1:2, the temperature of the reflux link is 85 ℃, and the reflux time is 72 hours.

7. The method for preparing a photosensitive zwitterionic polyurethane according to claim 2, further comprising: in said S4, the heating temperature is 100 ℃, after removing the water, the organic solvent added is N-N dimethylformamide, and the organic solvent used for the precipitation of the product is diethyl ether.

8. The method for preparing a photosensitive zwitterionic polyurethane according to claim 2, further comprising: in the S1 and S3, the eluent in the silica gel column is selected from petroleum ether and ethanol, and the volume part ratio of the petroleum ether to the ethanol is 2: 1.

9. The preparation method of the polyurethane micelle is characterized by comprising the following steps: dissolving the polyurethane solid (formula iv) prepared in claim 2 in dimethyl sulfoxide solution, slowly adding deionized water dropwise under continuous vigorous stirring, filling into a dialysis bag with MW of 3500 after stirring is finished, wherein the dialysis time is 2 days, and dialyzing to remove organic solvent and small organic molecules which are not completely reacted, thereby obtaining the stable amphipathic antibacterial polyurethane polymer micelle with photodynamic.

10. The method of preparing polyurethane strands according to claim 9, wherein: deionized water was replaced every four hours during dialysis.

Technical Field

The invention relates to the field of macromolecules, in particular to photosensitive zwitterionic polyurethane, a preparation method thereof and a preparation method of a polyurethane micelle.

Background

In recent years, more commonly used nonionic biomaterials can cause immune reaction of human body under complex environment in vivo, and zwitterionic polyurethane gains more and more attention due to excellent biocompatibility and nonspecific protein adsorption resistance. Therefore, the method for modifying the surface of the nano-drug carrier by adopting zwitterions which have excellent performance and can be synthesized simply becomes an ideal way. The characteristics of the zwitterionic polymer are beneficial to the long-time blood circulation of a nano-drug system, and the zwitterionic polymer has wide and attractive application prospect in the field of nano-drug carriers. However, the currently synthesized nonionic biomaterials have poor biocompatibility and antibacterial effect.

Disclosure of Invention

Aiming at the problems in the prior art, the invention aims to provide a photosensitive zwitterionic polyurethane, a preparation method thereof and a polyurethane micelle preparation method. The ROS obtained by white light initiation is combined with quaternary ammonium salt in the photosensitive component to realize synergistic antibiosis, the photodynamic zwitterionic polyurethane excites photosensitizer in the ingested polyurethane by white light, the excited photosensitizer transfers the energy to surrounding ground state oxygen molecules, so that ROS is obtained, and the ROS is used for inducing bacterial apoptosis to realize antibiosis. Compared with the traditional antibacterial material, the polyurethane material which generates ROS (reactive oxygen species) antibacterial caused by white light has the advantages of small adverse reaction, few complications, no harm to normal tissues and cells and the like, and the photodynamic therapy has a remarkable effect on resisting drug-resistant bacteria. Meanwhile, ROS obtained by white light initiation can achieve a synergistic antibacterial effect by combining with quaternary ammonium salt in the photosensitive component, so that the antibacterial efficiency is improved, and a new thought and method are provided for antibiosis.

In order to solve the above problems, the present invention adopts the following technical solutions.

A polyurethane, a copolymer having the structural formula IV,

wherein R represents

x and y represent polymerization degrees and independently range from 1 to 100.

The preparation method of the polyurethane comprises the following steps:

s1, dissolving carboxylic acid betaine or sulfonic acid betaine or phosphorylcholine in any organic solvent, adjusting the pH value of the solution, adding 3-mercapto-1, 2-propylene glycol to prepare a dihydroxyl zwitterionic monomer (formula I),

wherein R represents

S2, adding 4-methylpyridine into an organic solvent, uniformly mixing, adding 3-chloro-1, 2-propanediol, refluxing, carrying out rotary evaporation and concentration on reaction liquid, dropwise adding the reaction liquid into glacial ethyl ether while stirring, and precipitating to obtain 1- (2, 3-dihydroxypropyl) -4-methylpyridine cations (formula II),

s3, adding 4-diphenylaminobenzaldehyde and 1- (2, 3-dihydroxypropyl) -4-methylpyridine cation (formula II) obtained in S2 into an organic solvent, uniformly mixing, carrying out reflux reaction under the action of a catalyst, removing the solvent by rotary evaporation, purifying the product by using a silica gel column to obtain a red solid dihydroxytriphenylmethyl pyridine cation quaternary ammonium salt complex (formula III),

s4, vacuumizing the amphoteric dihydroxy zwitterion (formula I) obtained in S1 and the dihydroxy triphenylamine methyl pyridine cation quaternary ammonium salt complex (formula III) obtained in S3 under the heating condition, removing water, adding an organic solvent, uniformly mixing, adding hexamethylene diisocyanate, adding a catalyst dibutyltin dilaurate for reaction, then adding methanol for end capping, and separating out in the organic solvent after the end to obtain a polyurethane solid (formula IV),

wherein R represents

x and y represent polymerization degrees and independently range from 1 to 100.

Preferably, in S1, carboxylic acid betaine or sulfonic acid betaine or phosphorylcholine is dissolved in an organic solvent, then diethanolamine is added to adjust the pH value of the solution to 10, 3-mercapto-1, 2-propanediol is added, the reaction is continuously stirred at room temperature for 24 hours, after the reaction is finished, the reaction solution is subjected to rotary evaporation and drying, and then silica gel column purification is performed to obtain the dihydroxy zwitterionic monomer (formula i) with the tert-butyl group. Among them, the organic solvent is preferably dichloromethane.

Preferably, in S1, carboxylic acid betaine or sulfonic acid betaine or phosphorylcholine is dissolved in an organic solvent, triethylamine is added to adjust the pH value of the solution to 10, 3-mercapto-1, 2-propanediol is added, the reaction is continuously stirred at room temperature for 24 hours, after the reaction is finished, the reaction solution is subjected to rotary evaporation and drying, and then purified by a silica gel column to obtain the dihydroxy zwitterionic monomer (formula i) with a tert-butyl group. Among them, the organic solvent is preferably dichloromethane.

Preferably, in the S2, the mass portion ratio of the 4-methylpyridine to the 3-chloro-1, 2-propanediol is 4:5, the temperature of the reflux unit is 85 ℃, the reflux time is 5 hours, and the organic solvent is any organic solvent, preferably N-N dimethylformamide.

Preferably, in the S3, the mass part ratio of the 1- (2, 3-dihydroxypropyl) -4-methylpyridine cation (formula ii) to the 4-diphenylaminobenzaldehyde is 1:2, the temperature of the reflux link is 85 ℃, the reflux time is 72 hours, and the organic solvent is any organic solvent, preferably ethanol.

Preferably, in the S4, the heating temperature is 100 ℃, the organic solvent added after removing the water is N-N dimethylformamide, and the organic solvent used for the precipitation of the product is diethyl ether.

Preferably, in S1 and S3, the eluent in the silica gel column is selected from petroleum ether and ethanol, and the volume part ratio of the petroleum ether to the ethanol is 2: 1.

Dissolving the prepared polyurethane solid (formula IV) in dimethyl sulfoxide solution, slowly dropwise adding deionized water under continuous and violent stirring, filling the mixture into a dialysis bag with MW (3500) after the stirring is finished, wherein the dialysis time is 2 days, and dialyzing to remove organic solvent and unreacted organic micromolecules, thereby finally obtaining the stable amphoteric antibacterial polyurethane polymer micelle with photodynamic.

Preferably, the deionized water is replaced every four hours during dialysis.

Advantageous effects

Compared with the prior art, the invention has the advantages that:

(1) the synthesized photodynamic zwitterionic polyurethane polymer micelle has the diameter of about 80nm-110nm, has a zwitterionic polyurethane antibacterial micelle with white light response, and has good hydrophilicity, biocompatibility and protein adhesion resistance;

(2) the amphoteric ion type polyurethane polymer micelle for synthesizing the photodynamic power is stably dispersed in a water phase, under the excitation of white light, the excited photosensitizer transfers the energy to surrounding ground state oxygen molecules, can excite the excited photosensitizer to be converted into ROS (reactive oxygen species), plays an antibacterial role, and can achieve a synergistic antibacterial effect by combining with quaternary ammonium salt in a photosensitive component, thereby improving the antibacterial efficiency;

(3) the preparation method of the polyurethane drug-loaded micelle is simple and novel, and compared with the previously reported antibacterial materials, the novel photodynamic zwitterionic polyurethane polymer has better biocompatibility and antibacterial effect, and can play a role in high-efficiency antibacterial action once being initiated.

Drawings

FIG. 1 is a nuclear magnetic diagram of a dihydroxytriphenylamine methyl pyridine cation quaternary ammonium salt complex;

FIG. 2 is an infrared spectrum of a polyurethane micelle;

FIG. 3 is a TEM photograph of a polyurethane micelle;

FIG. 4 is a photograph showing the antibacterial effect of the polyurethane resin beam.

Detailed Description

The technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention; it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and all other embodiments obtained by those skilled in the art without any inventive work are within the scope of the present invention.