阅读说明：本技术 一种侧链含氨基聚乙二醇-脂肪族饱和聚酯嵌段共聚物及其应用 (Polyethylene glycol-aliphatic saturated polyester block copolymer with amino group on side chain and application thereof ) 是由 温锐 李作家 李伟周 于 2020-06-04 设计创作，主要内容包括：本发明涉及一种侧链含氨基的聚乙二醇-脂肪族饱和聚酯嵌段共聚物,该共聚物的化学结构如下式(I)所示。本共聚物是由聚乙二醇单甲醚、丁二酸酐和烯丙基缩水甘油醚开环聚合反应后再与巯基乙胺反应得到。本发明所述的共聚物可用于制备pH响应药物,该药物不仅对pH具有良好的响应性能,而且稳定性好。<Image he="504" wi="700" file="DDA0002523410530000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a polyethylene glycol-aliphatic saturated polyester block copolymer with side chains containing amino groups, and the chemical structure of the copolymer is shown as the following formula (I). The copolymer is obtained by the ring-opening polymerization reaction of polyethylene glycol monomethyl ether, succinic anhydride and allyl glycidyl ether and then the reaction with mercaptoethylamine. The copolymer can be used for preparing pH response medicaments, and the medicaments have good response performance to pH and good stability.)

1. A polyethylene glycol-aliphatic saturated polyester block copolymer with side chain containing amino group, the chemical structure of the copolymer is shown as the following formula (I),

in the formula (I), a is 20-30, and PEG is polyethylene glycol monomethyl ether with molecular weight of 2000.

2. A process for preparing the copolymer of claim 1, which process consists of the following steps: adding polyethylene glycol monomethyl ether, succinic anhydride, allyl glycidyl ether and zinc acetate into DMF (dimethyl glycol monomethyl ether/succinic anhydride/allyl glycidyl ether/zinc acetate) according to the molar ratio of 1: q/n/m, after three times of freeze-thaw cycle, heating to 90 ℃ under the protection of nitrogen for ring-opening polymerization reaction for 8-10 h, then cooling to room temperature, adding into cold methanol for precipitation, taking the precipitate, adding mercaptoethylamine with the dosage of 1.5-3 times of that of the allyl glycidyl ether for reaction for 2-6 h, and dialyzing to remove free mercaptoethylamine to obtain the copolymer; wherein q is 20-30, n is 20-30, m is 0.2-0.3, and q is equal to n; the molecular weight of the polyethylene glycol monomethyl ether is 2000.

3. A pH-responsive medicament prepared by the process of: dissolving the copolymer of claim 1 and lipophilic drugs accounting for 20-30% of the weight of the copolymer in a hydrophilic solvent, and adding water to disperse uniformly; adding glutaraldehyde with the weight of 10-20% of the weight of the copolymer, reacting for 12 hours at room temperature, and removing the hydrophilic solvent to obtain the pH-responsive drug; wherein the hydrophilic solvent is tetrahydrofuran or DMF, and the lipophilic drug is curcumin or adriamycin.

Technical Field

The invention relates to a biomedical polymer material, in particular to an amphiphilic block copolymer.

Background

Due to the advantages of wide material selection range, simple preparation, adjustable structure and performance and the like, the micelle obtained by self-assembly of the amphiphilic block copolymer has good application prospect in the field of controlled release of drugs. The block copolymer of polyethylene glycol and aliphatic polyester is a kind of amphiphilic high molecular material, in which polyethylene glycol is hydrophilic segment and aliphatic polyester is hydrophobic segment. For example, the literature (preparation and performance research of polylactic acid-polyethylene glycol block copolymer micelle, 2016,4, 917 reports chemical engineering reports of colleges and universities) reports that polyethylene glycol monomethyl ether initiates ring-opening polymerization of L-lactide to obtain a polyethylene glycol-polylactic acid diblock copolymer. The literature (International Journal of Nanomedicine,2012,7,547) reports a class of block copolymers of polyethylene glycol and polycaprolactone. The block copolymer of polyethylene glycol and aliphatic polyester can self-assemble in water to form nano micelle, wherein the hydrophilic chain segment polyethylene glycol forms a shell, and the hydrophobic chain segment aliphatic polyester forms a core. The hydrophobic inner core is combined with the micromolecular drug and is positioned in the micelle system, and the hydrophilic shell is uniformly distributed on the outer layer of the micelle, so that the stability of the system is enhanced, and the hydrolysis or enzymolysis of the drug can be effectively avoided while the system is effectively prevented from being cleared by a reticuloendothelial system in the in-vivo circulation process.

pH response groups or structural units are introduced into the amphiphilic block copolymer chain to enable the amphiphilic block copolymer chain to have pH response performance. The purpose of drug release is achieved by the change of pH to cause the change of dissolution/precipitation, swelling/collapse, hydrophilic/hydrophobic transition, bond rupture, degradation and the like of the amphiphilic block copolymer. The patent application with the publication number of CN106565962A discloses a preparation method of a cholesterol grafted pH response triblock amphiphilic copolymer, wherein pH sensitive polyamino ester is introduced into a main chain to synthesize a pH response triblock amphiphilic copolymer, and a nano micelle formed by self-assembly of the copolymer has good pH response characteristics, but the synthesis steps are complex, and the prepared nano micelle has poor stability.

Nanomicelles are thermally stable and there is a balance of aggregation and disaggregation. When the nano-micelle enters the circulation in the body, depolymerization easily occurs due to dilution or interaction with other substances in the body, so that the stability of the nano-micelle is reduced. The stability of the micelle is improved by crosslinking the hydrophobic core in the polymer micelle, the circulation time of the polymer micelle in vivo can be prolonged, and the encapsulated drug can be released at a specific position in a specific time. An omnipotent academic paper (preparation of nuclear cross-linked polycarbonate micelle, university of Hunan, 2016, Master paper) reports an amphiphilic block polymer with a polycarbonate structure, a hydrophilic chain segment of which is a polyethylene glycol structure and a hydrophobic chain segment of which is a side chain containing acryloyl, and the nuclear cross-linked polymer micelle is prepared by adopting a thiol-ene click chemistry method and 1, 6-hexanedithiol as a cross-linking agent, so that the stability of the micelle is improved. And because a beta-thiopropionate structure with pH response performance is introduced into the inner core of the polymer in the nuclear crosslinking reaction, the polymer shows better pH response performance in the drug release process, but the preparation process is complex by adopting polycarbonate as a hydrophobic chain segment.

Disclosure of Invention

The invention aims to solve the technical problem of providing a polyethylene glycol-aliphatic saturated polyester block copolymer with a side chain containing amino, and the medicine prepared from the copolymer has good response performance to pH and good stability.

The technical scheme for solving the problems is as follows:

a polyethylene glycol-aliphatic saturated polyester block copolymer with side chain containing amino group, the chemical structure of the copolymer is shown as the following formula (I),

in the formula (I), a is 20-30, and PEG is polyethylene glycol monomethyl ether with molecular weight of 2000.

The copolymer is prepared by the following method: mixing polyethylene glycol monomethyl ether, succinic anhydride, allyl glycidyl ether and zinc acetate according to the ratio of polyethylene glycol monomethyl ether, succinic anhydride, allyl glycidyl ether and zinc acetate of 1: q: n: m is added into DMF, after three times of freeze thawing cycle, the temperature is raised to 90 ℃ under the protection of nitrogen for ring opening polymerization reaction for 8-10 h, then the temperature is reduced to room temperature, the mixture is added into cold methanol for precipitation, the precipitate is taken and added with mercaptoethylamine with the dosage of 1.5-3 times of that of the allyl glycidyl ether for reaction for 2-6 h, and free mercaptoethylamine is removed through dialysis to obtain the copolymer; wherein q is 20-30, n is 20-30, m is 0.2-0.3, and q is equal to n; the molecular weight of the polyethylene glycol monomethyl ether is 2000.

In the scheme, the CAS number of the polyethylene glycol monomethyl ether is 9004-74-4.

The polyethylene glycol-aliphatic saturated polyester block copolymer with the side chain containing amino can be used for preparing pH response medicines, and the medicines are prepared by the following method:

dissolving the copolymer and lipophilic drugs accounting for 20-30% of the weight of the copolymer in a hydrophilic solvent, and adding water to disperse uniformly; adding glutaraldehyde with the weight of 10-20% of the weight of the copolymer, reacting for 12 hours at room temperature, and removing the hydrophilic solvent to obtain the pH-responsive drug; wherein the hydrophilic solvent is tetrahydrofuran or DMF, and the lipophilic drug is curcumin or adriamycin.

The copolymer consists of a hydrophilic polyethylene glycol chain segment and a hydrophobic polyester chain segment, and can be self-assembled in water to form nano micelle particles, wherein the hydrophobic polyester chain segment forms a core, the hydrophilic polyethylene glycol chain segment forms a shell, and the lipophilic medicament enters the formed core; glutaraldehyde is used as a cross-linking agent, and aldehyde groups on the glutaraldehyde react with amino groups on the amphiphilic polymer to generate a core cross-linked micelle, so that the stability of the medicine is improved. Aldehyde groups on the glutaraldehyde react with amino groups on the amphiphilic polymer to form Schiff bases. Under the weak acidic condition, the Schiff base is broken to release amino, improve the hydrophilicity of the nuclear polyester, promote the micelle disintegration and improve the drug release performance.

Drawings

FIG. 1 is a graph of the effect of different pH on pH responsive drug release performance.

FIG. 2 is a laser scattering spectrum of pH on the influence of pH on drug particle size.

Figure 3 is a graph of the effect of storage time in PBS on pH-responsive drug particle size.

FIG. 4 is a graph showing the effect of storage time in 0.7% saline on pH-responsive drug particle size.

Detailed Description

The production method and effects of the present invention will be described in further detail with specific examples.