近红外光照/酶程序性激活超分子前药系统用于耐药肿瘤的治疗

肺癌是我国发病率第一，致死率第一的肿瘤，其中非小细胞肺癌约占85%且五年生存率极低。以吉非替尼为代表的EGFR-TKI抑制剂被广泛用于治疗EGFR突变的非小细胞肺癌，但是一般在用药9-12个月后就会出现明显的耐药现象，严重的降低了治疗效果。如何开发出高效的克服吉非替尼耐药的策略已经成为科研和临床的重大需求，对于这一复杂现状，急需科研工作者针对不同耐药机制，开发新型的治疗方法有目的性的解决吉非替尼在临床使用中耐药问题。本项目拟通过基于底层逻辑合理设计了一个近红外光照/酶程序性激活的超分子前药系统，通过升高肿瘤组织内活性氧水平以抑制旁路激活和前药抵抗多重耐药性策略相结合实现有效克服吉非替尼治疗的耐药问题，并设计实验去验证设想的药物激活机理，以及在小鼠模型上深入研究其克服耐药肿瘤的分子机制和评估其对耐药肿瘤的治疗效果，并对新型多重响应性纳米载体设计思路做了有意义的尝试和大胆的探索。

Lung cancer is the most-common cancer in terms of both incidence and mortality in our country; non-small cell lung cancer (NSCLC) accounts for about 85% of all types of lung cancer with an extremely low five-year survival rate. EGFR-TKI inhibitors represented by gefitinib remain a popular choice for the treatment of NSCLC; however, within 9-12 months, the emerging drug-resistance severely weakened the therapeutic effect. Therefore, highly efficient solution is urgently sought in both scientific and clinical aspects. This project aims to develop a NIR light/enzyme activated supramolecular nanoprodrug system based on “and” logic gate strategy: the gefitinib resistance can be overcome by improving the intratumoral ROS level to inhibit bypass signaling as well as prodrug involved drug resistance reversal mechanism. Systematic experiments are designed to validate the envisaged drug activation mechanism. Next, in vivo gefitinib-resistant tumor bearing mice model will be established to further evaluate the effectiveness of drug resistance reversal and overall therapeutic effect. This project will also make meaningful attempts and explorations for novel multi-stimuli responsive nanocarriers.