肿瘤细胞内可顺次诱导激活的肉桂醛基功能有机分子的合成、组装及其抗肿瘤研究

In the treatment of cancer, the development of a new and efficient drug controlled release system has been the main way to improve drug delivery and release mode, enhance the therapeutic effect and reduce side effects. Reactive oxygen species (ROS) activated drug delivery system is an effective drug delivery system, but there is a bottleneck problem: the ROS concentration in tumor cells is low, which is not enough to stimulate the drug delivery system to release active drugs. In the program, a cinnamaldehyde-based amphiphilic polymer anticancer prodrugs which could be activated by sequential induction, will be synthesized and assembled to form prodrug micelle. When the prodrug micelle get into tumor cells by endocytosis, the cinnamaldehyde could be released by the induction of weak acidic environment in lysosomes. A large amount of H2O2 was produced in the tumor cells by induction of the released cinnamaldehyde, and the anti-tumor prodrug which could led to the apoptosis of tumor cells was activated by the induction of H2O2. In the program, cinnamaldehyde-based functional organic molecules can selectively increase the level of H2O2 in tumor cells, which could provide drug release conditions for ROS responsive drug release system by sequentially induced activation, provide theoretical basis and preparation experience for the development of new ROS response drug controlled release system, and provide a new way for the transmission of non stable drug.

在肿瘤治疗中，开发新型高效的药物控制释放系统一直是科研人员探索改善药物输送及释放模式、增强治疗效果、降低毒副作用的主要途径。活性氧（ROS）激活的药物控释体系是一种有效的药物输送方式，然而存在的瓶颈问题是：肿瘤细胞内的ROS浓度较低，不能快速有效地刺激载药系统使其释放活性药物。本项目拟合成一种在肿瘤细胞内可顺次诱导激活的肉桂醛基两亲性高分子抗肿瘤前药，进而将其自组装形成有利于药物传输的前药胶束。当其进入肿瘤细胞后，在溶酶体内弱酸环境的诱导下，肉桂醛得以释放，其在肿瘤细胞内诱导产生大量的H2O2，进而在H2O2的诱导下，抗肿瘤前药被激活，导致肿瘤细胞凋亡。本项目通过构建肉桂醛基功能有机分子，可选择性地提高肿瘤细胞内的H2O2水平，从而通过顺次诱导激活的方式为活性药物释放提供条件，为发展新型的ROS响应性药物控释系统提供理论基础和制备经验，为传统方式无法实现的非稳定性药物输送提供新思路。

本项目的研究目标是设计构建一种可选择性地提高肿瘤细胞内H2O2水平的前药胶束，从而通过顺次诱导激活的方式为ROS响应性药物控释系统提供药物释放条件，为进一步研究开发新型的ROS响应性药物控释系统提供理论基础和制备经验。为了实现本项目设定的研究目标，我们选择β-拉帕醌用以调高肿瘤细胞内的H2O2浓度，成功构建了一系列纳米抗肿瘤前药胶束，解决了传统方式无法输送非稳定药物（如羟基自由基、NO气体以及半衰期较短的氮芥等）的问题。项目自实施以来，研究工作按原定计划进行，并在完成项目目标的前提下，利用已取得的研究成果和经验积累，进一步研究了此“顺次诱导激活”策略用于抗菌的可行性，为以后深入广泛地研究“顺次诱导激活”提供依据，取得了超预期的研究成果。研究结果为“顺次诱导激活”药物输送体系的构建提供了新思路，为肿瘤及细菌感染治疗发展了新方法。在本项目的支持下共发表SCI论文9篇，申请中国发明专利3项，培养研究生完成毕业论文5篇。