过氧化氢响应性联合递送基因/药物纳米载体的构建及在动脉粥样硬化防治中的应用

Endothelial dysfunction and inflammatory reaction are two key factors for the pathogenesis of atherosclerosis. Antioxidant therapy or immunoregulation have been relatively effective. However, their therapeutic outcomes are still less than satisfactory due to accumulation of hydrogen peroxide (H2O2) at the diseases area, resulting in continued oxidative damage. In this project, considering the two above-mentioned factors as well as excessive H2O2 that impair therapeutic development against atherosclerosis, the peroxide oxalate ester bond has shown specificity for hydrogen peroxide recognition, we aim to prepare different reaction modules，then a series of H2O2-responsive polymers will be designed and synthesized following the specification of synthetic route, using peroxalate esters as linkages for H2O2 responsiveness. We would also standardize the synthetic routes, which would ideally enable facile and easy-to-adopt synthetic methods for large-scale industrial production. In addition, the relationship between local H2O2 accumulation and onset of atherosclerosis and its underlying mechanisms would also be revealed. Co-drug delivery system was designed using new H2O2-responsive polymers as nano carrier, which combine endothelial function restoration cytokine and immune regulating drug. We hypothesize under pathological microenvironment where abundant H2O2 was present, follow chemical breakdown of multifunctional H2O2-responsive polymers and drugs released, H2O2 would be eliminated, endothelium correct the inflammatory tones while improve endothelial function at the diseases area was observed, both of which are beneficial for atherosclerosis recovery.

氧化损伤造成的内皮功能紊乱和炎症反应是动脉粥样硬化性心脏病(ATH)两个重要形成原因。抗氧化治疗或免疫调控初见成效，但距理想还有差距，主要原因是活性氧产物ROS聚集于病灶部位，持续造成氧化损伤。课题针对ATH形成两大关键因素，结合病灶部位ROS（H2O2为主）过量的特性，提出合成H2O2响应性聚合物载体治疗氧化损伤的构想：研究将以H2O2特异响应性的过氧草酸酯键为核心，构建不同高分子反应模块，建立标准化模块组装技术，灵活合成一系列H2O2响应、可调节病理微环境的治疗型聚合物载体；载体联合递送程序释放内皮功能修复因子和免疫调控药物，在动物模型体内验证预防治疗ATH效果；研究将探讨ATH病程与H2O2微环境相关性；考察血管内皮功能修复联合免疫调控防治ATH思路可行性，为ATH临床治疗探索新途径；最终总结出具有治疗功能聚合物载体在缺血、缺氧心血管疾病中应用的普适作用规律，推动临床治疗发展进程。

氧化损伤造成的内皮功能紊乱和炎症反应是动脉粥样硬化性心脏病(ATH)两个重要形成原因。抗氧化治疗或免疫调控初见成效，但距理想还有差距，主要原因是ROS聚集于病灶部位，持续造成氧化损伤。课题针对ATH形成两大关键因素，结合病灶部位ROS（H2O2为主）过量的特性，提出合成H2O2响应性聚合物载体治疗氧化损伤的构想：研究以H2O2特异响应性的过氧草酸酯键为核心，构建不同高分子反应模块，建立标准化模块组装技术，灵活合成一系列H2O2响应、可调节病理微环境的治疗型聚合物载体；载体联合递送程序释放内皮功能修复因子和免疫调控药物，在动物模型体内验证治疗ATH效果；研究探讨了ATH病程与H2O2微环境的相关性，首次发现ROS 会严重影响紫杉醇的治疗效果，而另一抗增殖药物西罗莫司受ROS 水平的影响不明显，为ATH临床药物的选择提供指导；考察了血管内皮功能修复联合免疫调控防治ATH思路可行性，为ATH临床治疗探索新途径。 .课题组还设计合成了一系列具有ＲＯＳ清除功能的金属有机框架材料，材料具有抗氧化功能、高灵敏度的特性；合成材料可有效的保护细胞免受病理微环境的损伤，可作为细胞治疗的辅助技术，提高干细胞活率，改善治疗效果，降低治疗成本，具有积极的临床意义；高灵敏度的 H2O2响应性聚合物载体推广应用到了严重下肢缺血的治疗中，验证了其作为治疗性载体的功能，为载体在该类疾病普适性规律的归纳总结积累了经验，探索了一条全新的道路，开辟崭新的临床选择。.构建ROS响应性递送系统，实现了抗原诱导的细胞和体液免疫反应增强，为疫苗更好地发挥免疫效果提供了有价值的参考；拓展ROS响应性材料应用于辐射损伤应急救治药物的研发，为核战争或核事故等突发事件储备应急救治药物，相关技术的储备是国家综合国力的体现。