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

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.

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。

癌症仍然是最致命的杀手之一，声动力疗法（sonodynamic therapy, SDT）是一种新兴的癌症治疗方法，具有精确度高、组织穿透力优良、病人依从性高、副作用少等优点，临床应用前景广阔，然而受限于肿瘤乏氧。此外，化学动力学治疗（CDT）和化疗被证明是非常有效治疗癌症的单一疗法。但是，这些单一疗法往往效率都不高。.本项目通过设计基于二氧化锰MnO2的多功能纳米材料将联合两种治疗方法提高肿瘤治疗效果。.1）我们设计了基于中空MnO2的智能联合治疗平台（HMDNs）。通过中空MnO2包载化疗药物DOX，并用柠檬酸酐（cit）修饰的聚乙烯亚胺（PEI）和聚赖氨酸（PLL）封装，得到DOX@HMDN-PEI-PLL(cit)纳米颗粒。由于马来酰胺在酸性肿瘤组织中的裂解，发生负电荷到正电荷的逆转可增强肿瘤细胞的摄取能力。在肿瘤细胞内外壳破裂释放出DOX进行化疗。同时MnO2分解释放Mn2+进行CDT。最终，实现了对癌症的化疗与CDT联合治疗。.2）我们基于中空MnO2纳米粒子同时负载声敏剂司帕沙星（SPX）与线粒体呼吸链抑制剂阿托伐醌（ATO），并以金属离子与单宁酸修饰的透明质酸（HA）交联的金属多酚网格（MPN）作为阀门封装，得到MnO2@SPX/ATO@HA/MPN（MSAHM）纳米颗粒。MSAHM可以利用HA将药物靶向递送进入乳腺癌细胞中，然后利用MnO2催化高浓度H2O2产生SDT所需氧气，并释放的ATO减少线粒体对氧气的消耗，产氧与节氧联合作用增强SDT。此外，MnO2分解释放的Mn2+可进行CDT，实现了CDT/SDT联合治疗乳腺癌。.本研究所构建的基于MnO2的多功能纳米药物减少了治疗的副作用并实现了高效的联合治疗，为CDT与SDT实现早日临床转化提供了新策略。