肿瘤血管靶向和还原响应性紫杉醇纳米粒抗肿瘤作用研究

Low bioavailability and multidrug resistance of chemotherapeutic drugs are unsolved problems in the clinical treatment of tumors. In this project, nanocarriers was developed by using anti-angiogenic peptides and chemotherapy drugs for improving the efficacy of drugs. Diselenium bond was used to conjugate with paclitaxel (PTX) and target peptide (UPI), and the resulting compound could assemble into nanoparticles, which possess the ability to target vascular endothelial cell receptor (VEGFR2). Once the nanoparticles were transported to the tumor sites, the UIM segment embedded in the UPI block would specifically to prevent the endogenous epsin protein from binding to VEGFR2, and inhibit the formation of tumor blood vessels. The specific release of conjugated PTX in tumor tissue would be realized based on the glutathione sensitivity of diselenium bonds. The synergistic effect of chemotherapeutic drugs and anti-tumor angiogenic peptides is expected to improve the efficiency of anti-tumor therapy and greatly reduce the side effects of chemotherapeutic drugs. This project is not only expected to inhibit the growth of tumor cells, but also to provide a new way for antitumor treatment in clinic.

化疗药物生物利用度低和多药耐药是肿瘤临床治疗中尚未解决的难题。本项目以抗肿瘤血管生成肽和化疗药物构建纳米药物，期望提高疗效。以二硒键共价偶联肿瘤化疗药物紫衫醇(PTX)和靶向肽(UPI)，进而组装形成纳米颗粒，从而得到靶向肿瘤血管内皮细胞受体(VEGFR2)的纳米载药体系。纳米颗粒经靶向运输至肿瘤部位后，通过UPI中嵌入的UIM节段阻断肿瘤血管内源性epsin蛋白与VEGFR2的特异性结合从而阻止肿瘤血管生成。利用二硒键的谷胱甘肽敏感性实现纳米粒在肿瘤组织中PTX的特异性释放。化疗药物和抗肿瘤血管生成多肽的协同作用有望提高抗肿瘤治疗效率，并极大地减轻化疗药物的毒副作用。本项目不仅有望从根源上抑制肿瘤细胞的生长，还可能为临床抗肿瘤治疗提供一种新的思路。

化疗药物生物利用度低和多药耐药是肿瘤临床治疗中尚未解决的难题。本项目以抗肿瘤血管生成肽和化疗药物构建纳米药物，期望提高疗效。以二硒键共价偶联肿瘤化疗药物紫衫醇和靶向肽(UPI)，进而组装形成纳米颗粒，从而得到靶向肿瘤血管内皮细胞受体(VEGFR2)的纳米载药体系。纳米颗粒经靶向运输至肿瘤部位后，通过UPI中嵌入的UIM节段阻断肿瘤血管内源性Epsin蛋白与VEGFR2的特异性结合从而阻止肿瘤血管生成。利用二硒键的谷胱甘肽敏感性实现纳米粒在肿瘤组织中紫杉醇的特异性释放。与单药纳米粒组相比，本项目制备的多功能硒纳米粒在不同GSH浓度刺激下出现明显的GSH浓度依赖性释药性能，对肿瘤细胞增殖有明显的抑制作用，对VEGFR2信号通路相关蛋白及细胞凋亡相关蛋白表达有明显调控作用，显著降低CD31及Ki-67表达，有明显的抑瘤效果，有较低的体内毒性。本项目中，化疗药物和抗肿瘤血管生成多肽的协同作用显著增强了抗肿瘤治疗效果，极大地减轻了化疗药物的毒副作用。本项目不仅有望从根源上抑制肿瘤细胞的生长，还可能为临床抗肿瘤治疗提供一种新的思路。