氟硼吡咯锰光激活氧化及肿瘤监测治疗体系的构建和作用机制的研究

Multifunctional molecules with image and inhibitory properties can find applications in monitoring the sites of drugs and resistant responses during clinic process. Labeled photodynamic therapy agent (PDT) has recently been played great attention due to its potential application in the treatment for cancers. However, the clinic use of traditional PDT is still limited due to the hypoxic environment and the dependence of PDT therapy on the oxygen concentration in cells. Therefore, it is necessary to develop new generation of PDT agents which can attenuate the environment of tumor tissues and produce enough singlet oxygen in hypoxic environment of cancer tissues. The light activated PDT agent based on water as oxygen supplier will change the state for the dependence of PDT agents on the concentration of oxygen. This project focuses on the construction of DOBIPY-Mn(II) complexes and the photooxidation of water catalyzed by DOBIPY-complexes in order to obtain the photodynamic therapy agent with water as oxygen suppliers. Moreover, the photo-irradiated oxidation of N-substitued indole derivatives, and the structure-bioactive relationaship for the Mn(II) complexes will be explored. Next, the assembly of aptamers or pepetides with Mn(II) complexes will form a new kinds of multifunctional Mn(II) nanocomplexes to be as special agents for cancer cells 3D MRI target image and monitoring photodynamic therapy. Therefore, a complex-organic molecules system for light controlling therapy will be found. In this way, we can find a new kind of photodynamic therapy method based on complexes - organic molecules system, which is different from the traditional cell dioxygen dependent PDT agent. The results found in this project will give new concepts and new theory on the light-controlled therapy and controlling oxidation methods.

具备示踪效应和治疗作用的多功能分子能在线监测药物位置和治疗过程应激响应，多功能肿瘤靶向光动力学治疗剂（PDT）成为目前癌症可控治疗领域研究的热点。针对肿瘤细胞缺氧的微环境导致氧浓度依赖的PDT试剂治疗效率低的缺陷，以水为氧源的新一代PDT试剂将在缺氧肿瘤PDT试剂发展上取得突破。本项目研究近红外光响应的氟硼吡咯锰超分子配合物组装，探索其催化光激活水为氧源N-取代吲哚的氧化反应，揭示氧化产物的结构与抗肿瘤活性的关系，进而发现一类全新光控制治疗用体系。其次，通过核酸适配体、肿瘤靶向肽与光活性锰配合物组装构建肿瘤靶向多效应锰复合物；探索其肿瘤靶向性3D MRI成像特性及抗肿瘤效应，研发影像监测治疗用新型PDT试剂，一改长期以来细胞内氧浓度依赖的光动力学治疗模式。本项目光控制抗肿瘤活性分子合成体系的建立，将为发展水为氧源的可控氧化新方法和可控光启动的治疗新模式提供新的理论基础。

本项目探索了具备MRI示踪和治疗作用的氟硼吡咯锰，发现了以水为氧源的光动力治疗（PDT）试剂；揭示了锰配合物缺氧信号调控的机制，发现了缺氧诱导因子羟化酶（PHD）激活途径及基因干预HIF信号肿瘤治疗的新途径。具体研究内容与结果如下：.1） 筛选出线粒体靶向性氟硼吡咯衍生物，发现了TrxR2的抑制剂与血液中金属离子检测试剂。研究了氟硼吡咯锰配合物及其纳米复合物的构效关系和MRI影像性能，筛选出靶向缺氧肿瘤干细胞及肿瘤线粒体的多效应纳米氟硼吡咯锰复合物。.2）研究了锰配合物对缺氧诱导因子（HIF-1）的干预机制，首次发现运用锰配合物协同干预脂肪酶与乳酸脱氢酶能实现HIF途径调节肿瘤能量代谢的信号通路及乳腺癌和胰腺癌的治疗。.3）研究了锰铁配合物水为氧源的光驱动氧化机制， 发现了新型环境友好的集催化剂-电子受体为一体的催化体系，并将其运用于光驱动的氧化-环化反应， 建立了水为氧源的氧化新方法。.4）系统研究了光活性锰配合物对乳酸的氧化机制，揭示了氧化产物的结构与抗肿瘤活性的关系，探索了纳米锰复合物肿瘤靶向性3D MRI成像，筛选出可用于MRI影像监测治疗用新型NIR驱动的PDT试剂。.5）研究了核酸适配体、肿瘤靶向肽与光活性锰配合物的组装，构建了靶向肿瘤线粒体、肿瘤细胞核的纳米核酸铁（锰）药物输送体。我们率先报道了线粒体靶向调控HIF-1的siRNA，并运用荧光纳米核酸输送siRNA实现HIF-1信号的调控与胰腺癌的生长的抑制。. 6） 探索了纳米金属核酸诱导PHD的上调与线粒体动力蛋白（Drp1）功能修复的机制，发现了上调乳腺癌PHD与协同干预Drp1，修复肿瘤线粒体这一肿瘤治疗的新模式。我们的研究为肿瘤化学治疗和免疫激活为一体的纳米金属药物的研究提供了理论基础，将成为生物无机化学领域新的生长点。. 已申请中国发明专利 6项， 获授权中国发明专利3项； 已发表SCI收录的论文19篇、中文专家论坛1篇。培养研究生7名。