响应/可降解型铁基MOF纳米诊疗平台构筑及其“铁”协同的肿瘤杀伤效应研究

Nanoparticle-induced modulation of iron and ROS levels within cancer cells and the tumour microenvironment could provide a new strategy for cancer treatment, which needs to be deeply studied. Meanwhile, both the contradiction between the stability of the nanoparticles and their biodegrability in the body and their difficulty in the deep penetration into tumors, resulting from high tumor interstitial fluid pressure, are the major challenge confronted in the development of nanoplatform at the current stage. Considering the above background, this proposal attempts to develop responsive/degradable theranostic nanoplatform using the iron ion-organic framework (Fe based MOF) with the coordinate bond, in which the ROS-generating drug, near-infrared light dye, Gd-DOTA, and other functional molecules are doped. Such design in the nanocomposite provides a chance to integrate near-infrared light/ low pH triggered release into one system. In future, their diagnosis and imaging functions provided by this smart theranostic nanoplatform, especially in the tumor-killing effect brought by iron, will be deeply studied with mouse model of human breast cancer. In comparison with the traditional organic/inorganic nanocarriers, this nanocomposite has higher stability and good degradability due to the coordinating bond. In addition, the pH/NIR laser-responsive release profile for the resulting nanocomposites can improve tumor penetration by releasing these functional molecules encapsulated in particles when exposed to external stimuli. Therefore, if this proposal is funded, it is expected that the results obtained from this project will be helpful for the establishment of new Fe-associated treatment of cancer, and to enhance the understanding of the role of MOF as the framework material in the construction of theranostic nanoplatform.

借助纳米粒子调控肿瘤微环境中的铁含量及活性氧物种（ROS）水平将可能成为一种新的肿瘤治疗策略，亟待深入探讨。同时，粒子的稳定性与其在体内降解性之间的矛盾及如何穿透肿瘤间质组织到达肿瘤细胞均是传统纳米载体所面临的重要挑战。鉴于此，本项目提出以铁有机框架材料（MOF）为载体，通过掺杂ROS生成剂、近红外染料、Gd-DOTA等功能分子，将其构筑成一个具有pH/近红外光双响应、可降解的诊/疗一体化纳米平台。利用小鼠模型研究该平台对肿瘤的治疗与成像效果，特别是降解后的富铁离子氛围所引发的ROS致肿瘤死亡现象与相应机制。相比于传统有机/无机载体材料，MOF结构中因使用了配位键，从而有助于解决粒子稳定性与降解性之间的矛盾。同时，响应降解过程提高了功能分子或微粒子对肿瘤细胞的渗透。所以，本项目的开展，将深化认识铁在肿瘤治疗中的作用，并对MOF这种新型载体材料如何用于构建纳米诊疗平台有所借鉴与指导。

依据课题“响应/可降解型铁基MOF纳米诊疗平台构筑及其“铁”协同的肿瘤杀伤效应研究”的预定目标，在过去的四年中，基本完成项目设定的各项任务，取得如下成果：（1）在MOF纳米诊疗平台的构建方面，先后构建了常用的pH响应降解的ZIF-8、MIL-100(Fe)、Fe3+/单宁的纳米复合材料、铁/单宁酸包覆聚乙烯亚胺/阿霉素/吲哚菁绿复合物的纳米聚合物和铁铜合金材料，创新性地制备出磺基水杨酸/Fe3+配位的纳米配位聚合物和Cu-二甲双胍配位的纳米配位聚合物，所构建的MOF材料为药物的负载提供了便利；（2）在响应/可降解型MOF纳米诊疗平台构筑方面，发现所制备的响应/可降解型MOF相对于中空介孔结构的二氧化硅纳米粒子和介孔有机二氧化硅纳米片，其体内降解速率更快、药物负载效率更高；（3）在铁基MOF材料用于“铁”协同的肿瘤杀伤效应中，探讨了水杨酸/Fe3+配位的纳米配位聚合物、铁铜纳米合金和Fe3+/单宁的纳米复合材料对肿瘤细胞和小鼠肿瘤的杀伤作用，Fe3+的存在可以显著增强肿瘤的杀伤效果；在铁基MOF材料促进肿瘤细胞铁死亡方面，水杨酸/Fe3+配位的纳米配位聚合物、铁铜纳米合金和Fe3+/单宁的纳米复合材料能够能明显增加细胞内的ROS含量，且对肿瘤细胞表现出明显的细胞出现了明显的“铁死亡”的特征形貌；同时“铁”与其他治疗分子相结合用于肿瘤杀伤效应方面，小分子化疗药物（阿霉素）、光敏剂（吲哚菁绿）、酶（葡萄糖氧化酶）以及阿司匹林等药物都能够进一步增强肿瘤杀伤效应；（4）在肿瘤联合治疗方面，探究了以类芬顿反应、免疫治疗等为基础的肿瘤联合治疗效果。上述系列研究结果拓宽了对MOF材料作为药物载体的认识，加深了对降解后的富铁离子氛围所引发的ROS致肿瘤死亡现象与相应机制生物的理解，对构建新型 “铁死亡”为模式的肿瘤治疗具有较好的借鉴与指导作用。.在本课题的完成过程中，共计发表标注基金号文章共 24 篇SCI论文，培养硕士生10名，博士生4名，其中毕业硕士生7名，博士生2名。