活性氧介导的光控AIE含硒聚碳酸酯纳米载体系统的构建与研究

Effective delivery of the drugs and overcoming the drug resistance of tumor are the two keys to the cancer treatment. Reactive oxygen species (ROS) can promote the lysosome escape of the nanoparticles in the way of photochemical internalization and accelerate the ROS responsive release of the drugs. Based on our research on the selenium-containing polycarbonate, we propose that the ROS generation groups and responsive groups are integrated into one macromolecule, and the ROS triggers the lysosomal escape and drug release by the light. A photosensitizer monomer with near infrared aggregation-induced emission (AIE) was synthesized. Biodegradable AIE functional groups and selenium containing polyethylene glycol-polycarbonate was prepared by ring opening polymerization, and a photo and ROS responsive nanocarrier is to be constructed. The photosensitizer can effectively promote the formation of ROS nanoparticles with the triggering of light, thus facilitate the lysosomal escape and the acceleration of the disintegration of selenium containing polycarbonate nanoparticles, the drug release is to be promoted accordingly. Moreover, the synergistic therapeutic effect will occur due to the released drug and ROS, which is expected to overcome tumor resistance. Furthermore, the varied fluorescence intensity due to the disintegration of the nanocarriers could be used to monitor the time and site-specific drug release.

实现药物的有效、特异性递送及克服肿瘤耐药性是癌症治疗的关键。活性氧 (ROS)能促进纳米粒子以光化学内化的方式逃逸溶酶体以及加速ROS响应性纳米载体释放药物。基于我们在含硒聚碳酸酯方面的研究基础，本项目提出将ROS的生成基团和响应基团聚合于同一个大分子，以光触发产生ROS调控纳米载体的溶酶体逃逸和药物快速释放。合成具有近红外聚集诱导发光效应(AIE)的碳酸酯光敏剂单体，以开环聚合法制备生物可降解的含硒及AIE功能基团的聚乙二醇-聚碳酸酯嵌段聚合物，构建光控ROS响应性纳米粒子载药系统。在光照射下，光敏剂能够有效生成ROS，促进纳米粒子的溶酶体逃逸；同时加速含硒聚碳酸酯纳米粒子的解体，促进药物快速释放以及ROS与释放的化疗药物产生协同治疗作用，可望克服肿瘤耐药性。纳米载体解体时，键合于聚碳酸酯链的AIE光敏剂发生荧光强度变化，可用于监测药物的光控定位、定时释放。

本项目通过四年的研究，按照项目计划合成得到了含硒碳酸酯单体，并将该含硒碳酸酯的合成方法拓展到了含硫族元素和氮元素的碳酸酯单体合成，得到了系列含有不同元素的大环碳酸酯单体，增添了碳酸酯单体家族成员。另外，合成了具有近红外聚集诱导发光效应(AIE)的碳酸酯光敏剂单体。基于以上系列碳酸酯单体，研究了该系列单体的开环聚合制备功能性生物可降解聚碳酸酯，并开展了相关物理化学性能研究。基于以上聚合物携带的具有ROS响应以及AIE功能基团，构建了光控ROS响应性纳米粒子载药系统。研究了在光照射下，光敏剂能够有效生成ROS，促进纳米粒子的溶酶体逃逸；同时加速含硒聚碳酸酯纳米粒子的解体，促进释放的化疗药物产生协同治疗作用。纳米载体解体时，键合于聚碳酸酯链的AIE光敏剂发生荧光强度变化，用于监测药物的光控定位、定时释放。