豆荚蛋白酶响应的功能化金纳米粒用于皮下移植瘤靶向药物递送和治疗

发布时间：2018-12-29 20:54

【摘要】：豆荚蛋白酶(legumain)是一种天冬氨酸内切酶,在一些高转移性和高侵袭性肿瘤中高表达,能水解特定的多肽底物。基于此,本文构建了一种豆荚蛋白酶响应的功能化金纳米粒递药系统(GNPs-AC),由丙氨酸-丙氨酸-天冬酰胺-半胱氨酸-赖氨酸(AK多肽)修饰的金纳米粒(GNPs-AK)与2-氰基-6-氨基苯并噻唑(CABT)修饰的金纳米粒(GNPs-CABT)组成。GNPs-AC进入血液循环后可以通过增强的渗透和滞留(EPR)效应到达肿瘤部位并渗透进入内部,在肿瘤高表达的豆荚蛋白酶作用下内切AK序列,暴露出半胱氨酸上的1,2-巯基氨基,进而与CABT上的氰基发生点击反应,引起纳米粒聚集,形成粒径更大的聚集体,更好滞留在肿瘤内部。活体成像表明,GNPs-AC在豆荚蛋白酶高表达的脑胶质瘤(C6)中具有良好的靶向性和蓄积能力,同时载有多柔比星(DOX)功能化金纳米粒递药系统(GNPs-DOX-AC)展示了显著的抗肿瘤效果并降低了DOX的心肌毒性。
[Abstract]:Pod protease (legumain) is a aspartate endonuclease that is highly expressed in some highly metastatic and aggressive tumors and can hydrolyze specific polypeptide substrates. Based on this, a functional Jinnanmi delivery system (GNPs-AC) based on the response of pod protease was constructed. Jinnanmi granules (GNPs-AK) modified by alanine asparagine cysteine lysine (AK polypeptide) and GNPs-CABT modified by 2-cyano-6-aminobenzothiazole (CABT) are made up of alanine asparagine cysteine lysine polypeptide (GNPs-AK) and 2-cyano-6-aminobenzothiazole (CABT) modified Jinnanmi granules (GNPs-CABT). When GNPs-AC enters the blood circulation, it can reach the tumor site and penetrate into the inside through the enhanced osmotic and residual (EPR) effects. Under the action of high expression of soybean podase, the AK sequence was exposed to the 1-thioglycol-amino group on the cysteine, and then clicked with the cyanide group on the CABT, resulting in the aggregation of nanoparticles and the formation of a larger aggregate. It's better to stay inside the tumor. In vivo imaging showed that GNPs-AC had good targeting and accumulation ability in gliomas (C6) with high expression of pod protease. At the same time, doxorubicin (DOX) functionalized Jinnanmi delivery system (GNPs-DOX-AC) showed significant antitumor effect and reduced myocardial toxicity of DOX.
【作者单位】：四川大学华西药学院靶向药物及释药系统教育部重点实验室;
【基金】：国家自然科学基金资助项目(31571016,81402866)
【分类号】：R943

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