线粒体内构建金属-多酚网格抑制线粒体活性并增强肿瘤光动力治疗

肿瘤的乏氧耐受降低了光动力治疗（PDT）效率，亟需构建新型纳米体系增强PDT。申请人前期研究证明，生物相容性的两亲性DNA聚合物作为光敏剂的递送载体具有优良的PDT效果。鉴于提升肿瘤微环境中的氧气浓度是解决PDT乏氧耐受的有效途径，本项目拟设计负载光敏剂和单宁酸的二氧化锰纳米层治疗体系，利用肿瘤微环境实现氧化还原和酸性响应，实现肿瘤定点释药和高效产氧，从而提高PDT的疗效。本项目还利用还原产生的靶向线粒体的二价锰离子和单宁酸-多肽衍生物，在线粒体内原位合成金属-多酚网格（MPN）。MPN将抑制线粒体功能介导杀伤肿瘤，实现线粒体靶向的非药物治疗。同时，线粒体失活将减少有氧呼吸消耗氧气而增强PDT，达成非药物-光动力协同治疗。. 本研究发展的线粒体原位合成MPN及协同促进光动力治疗策略将为肿瘤治疗提供了新思路和关键技术。

Hypoxia-induced multidrug resistance can severely decrease the therapeutic efficiency of photodynamic therapy (PDT). As a consequence, novel types of nanosystems are urgently needed to enhance PDT. In our previous research, we utilized biocompatible lipid-modified DNAs as delivery systems for the photosensitizer Foscan, which improved PDT in cell assays. It is well-known that PDT could be dramatically enhanced through improving the oxygen level in tumor intracellular environment. In this project, we are planning to design a novel type of nanosystem for enhanced PDT. In our system, manganese dioxide nanosheets are used as drug carrier for the photosensitizer and tannic acid. And redox-/pH-responsive intracellular release of the photosensitizer can be achieved. Moreover, manganese dioxide-catalyzed oxygen production will dramatically enhance PDT. On the other hand, the produced manganese (Ⅱ) ions and peptide-decorated tannic acids will accumulate into mitochondria to form the metal-phenolic networks (MPNs). And MPNs will disturb the mitochondria function to kill tumor cells and realize the drug-free. In the meantime, the disruption of mitochondria will inhibit the mitochondrial respiration and oxygen consumption to enhance PDT. Finally the drug-free/photodynamic synergistic therapy could be achieved...In our research, we developed a novel therapeutic strategy for hypoxic tumor, namely the drug-free/photodynamic synergistic therapy, which is based on the intra-mitochondrial generation of MPNs.