侧链功能化聚氨基酸的合成与应用

发布时间：2018-07-02 21:07

本文选题：聚氨基酸 + 侧链修饰　；参考：《东北师范大学》2017年硕士论文

【摘要】：本论文采用氨基聚乙二醇单甲醚作为大分子引发剂,通过开环聚合α-氨基-N-羧基内酸酐(NCA)单体,合成了具有功能化侧链的1,4-二噻烷聚谷氨酸、4-溴苯酚聚赖氨酸,含炔基聚赖氨酸和含双键聚赖氨酸等聚合物。对其中含有炔基侧基的聚赖氨酸进行了进一步的修饰,将带有叠氮基团的还原响应性叠氮二硫醚酯通过“click”点击化学引入侧链,利用其两亲性和谷胱甘肽还原响应的特性,可作为抗癌药物载体担载抗癌药物,并实现在癌症部位的响应性释放。本论文进一步以阿霉素(DOX)为担载的药物,利用动态光散射(DLS)测定了合成的两亲性聚赖氨酸载体所形成的胶束粒径大约为120纳米。运用透射电镜(TEM)也进一步证实了粒径大小在120纳米左右。以MCF-7癌细胞为基础进行了体外细胞毒性实验。运用共聚焦激光扫描显微镜(CLSM)检测了药物内吞效果,用流式细胞仪和MTT检测了所合成的聚合物对癌细胞的杀伤效果,并且我们还用正常细胞L929来检测了载体本身对正常细胞的毒性。体外释放试验是在模拟癌细胞酸性环境和还原性条件下验证担载药物的聚合物在癌细胞环境下的释放行为。实验结果表明,合成的侧链修饰聚赖氨酸本身对正常细胞基本没有毒性,在长循环过程中保证载体本身不会对正常人体造成伤害,担载了DOX后,CLSM测试结果可以看出DOX内吞入癌细胞,流式和MTT表明聚合物对癌细胞有良好的杀伤的效果。体外释放表明在癌细胞高谷胱甘肽环境下,因为引入了谷胱甘肽响应的还原性侧基,DOX更易于从聚合物中释放出来并进入细胞核杀伤癌细胞。总体来说,侧基修饰后的聚赖氨酸聚合物有很好的应用前景,可以用作治疗癌症的药物载体。
[Abstract]:In this paper, using amino poly (ethylene glycol) monomethyl ether as macromolecular initiator, we synthesized 1 '4-dithiothioane polyglutamic acid 4 bromophenol polylysine with functionalized side chain by ring-opening polymerization of 伪 -amino-N-carboxylic anhydride (NCA). Poly (lysine) containing acetylene group and poly (lysine) containing double bond. Poly (lysine) containing alkynyl side group was further modified by introducing azide disulfide with azido group into the side chain through "click" click chemistry to make use of its amphiphilic properties and glutathione reduction response. It can be used as a carrier of anticancer drugs to carry anticancer drugs and achieve responsive release in cancer sites. In this paper, doxorubicin (DOX) was used as the carrier to measure the particle size of the synthesized amphiphilic poly (lysine) carrier with a particle size of about 120 nm by dynamic light scattering (DLS). Transmission electron microscopy (TEM) was used to further confirm that the particle size was about 120 nm. The cytotoxicity of MCF-7 cancer cells in vitro was studied. Confocal laser scanning microscopy (CLSM) was used to detect the endocytosis, flow cytometry and MTT were used to detect the cytotoxicity of the synthesized polymer to cancer cells. We also used normal cell L 929 to detect the cytotoxicity of the vector itself to normal cells. In vitro release test was used to verify the release behavior of the loaded polymer in the cancer cell environment under simulated acidic and reductive conditions. The results showed that the synthesized side chain modified poly (lysine) itself was not toxic to normal cells, and the carrier itself would not be harmful to normal human body during long cycle. After loading DOX, the results of CLSM test showed that DOX ingested the cancer cells, and flow and MTT showed that the polymer had a good killing effect on cancer cells. In vitro release indicated that in the presence of high glutathione the reductive side group DOX which responded to glutathione was easier to release from the polymer and enter the nucleus to kill cancer cells. In general, the side-modified poly-lysine polymer has a good application prospect and can be used as a drug carrier for cancer treatment.
【学位授予单位】：东北师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O632.6

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