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

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。

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.