抗PD-L1抗体修饰负载BRAF抑制剂的金纳米笼控释系统靶向治疗黑素瘤的研究

项目名称： 抗PD-L1抗体修饰负载BRAF抑制剂的金纳米笼控释系统靶向治疗黑素瘤的研究

项目编号： No.81502367

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 董励耘

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 恶性黑素瘤易早期转移且高度耐药，患者死亡率高。小分子抑制剂靶向治疗虽起效迅速，但极易发生耐药。免疫治疗虽疗效确定，但起效慢且易发生副反应。上述药物联合治疗可减少耐药发生，提高疗效，已成国外耐药黑素瘤的新型治疗方案；但其缺乏对肿瘤的特异靶向性，并不能降低毒副作用。多功能纳米载药系统能较好克服以上缺陷。本研究拟以包被BRAF抑制剂Vemurafenib的金纳米笼为载体，偶联PD-L1单克隆抗体BMS-936559，特异性靶向黑素瘤细胞高表达的PD-L1，阻断PD-L1-PD-1信号通路而增强杀伤黑素瘤活性，并通过PD-L1受体介导的内吞作用促进黑素瘤细胞对金笼的摄取，提高胞内药物浓度克服耐药；此外金笼表面修饰的核酸适配体AS1411除具选择性抑瘤效应，作为“分子开关”实现笼内药物在胞内的控制释放。金笼本身的荧光效应可示踪纳米药物的分布，并通过其光热效应杀灭黑素瘤，为黑素瘤治疗提供新的思路。

中文关键词： 黑色素细胞肿瘤；BRAF抑制剂；抗PD-L1抗体；金纳米笼；靶向治疗

英文摘要： Malignant melanoma tend to early metastasis and highly drug-resistant, and has high mortality. Targeted therapy of small molecule inhibitors has rapid onset, but easily get resistant. Immunotherapy has certain effect, however the effect is slow and usually side effects occur. Combination of the two above could decrease the resistant and increase the curative effect, which has became the new treatment for the resistant melanoma abroad. However, the combination treatment is lack of tumor targeting and can not reduce side effects. Multi-functional nano drug delivery system can conquer these disadvantages. Our study intends to design a nano-system in which gold nanocage as a carrier carrying BRAF-inhibitor Vemurafenib, modified with anti-PD-L1 antibody BMS-936559 and aptamer AS1411. BMS-936559 is supposed to target the high expression of PD-L1 on melanoma cells to block PD-1/PD-L1 pathway that enhance killing melanoma cells, and promote tumor cells taking in nanocages via PD-L1-mediated endocytosis. Moreover, AS1411 can act as “molecule switch” to control releasing drugs within tumor cells besides of its tumor-suppression effect. Meanwhile, nanocages has fluorescent effect to tracking distribution of nano-sytstem and photothermal effect to kill tumor cells, hoping to bring some new ideas on the effective treatment for melanoma.

英文关键词： melanoma;BRAF inhibitor;anti-PD-L1 antibody;gold nanocage;targeted therapy