UCNPs@Mn(III)TCPP新型智能纳米平台的构建及“off/on”肿瘤协同治疗

化学动力学疗法CDT和光动力治疗PDT是基于活性氧ROS的肿瘤治疗新策略，但也存在亟待解决的问题，一是肿瘤细胞内高表达的谷胱甘肽GSH对ROS的清除降低其疗效；二是治疗初期产生的原癌因子促进肿瘤的再生、复发及转移。本项目拟构建一类 “off/on” 新型智能纳米材料UCNPs@Mn(III)TCPP，探索其在肿瘤抗血管生成/CDT/PDT联合治疗中的应用。拟将UCNPs与光敏剂TCPP键连直接作为构筑单元与高价态Mn3+组装，调控其构效关系，优化其性能；抗血管生成剂阿帕替尼担载到MnTCPP孔道中。该材料在正常组织中保持“惰性”，只有在肿瘤微环境中才被GSH特异性激活，导致MnTCPP降解释放芬顿试剂Mn2+、UCNP-TCPP和阿帕替尼，分别实现CDT、近红外光激发下的PDT和抑制肿瘤血管生成，从而探索原位提高ROS和按需给药的有效策略，揭示协同治疗机制，为实现肿瘤精准诊疗提供新思路。

Chemodynamic therapy (CDT) and photodynamic therapy (PDT) are ROS-based new strategies for tumor therapy. However, there are several problems to be solved in this field. One is that the consumption of ROS by highly expressed GSH in tumor cells compromises their tumor cell killing efficacy. The other is that a large number of cell death and vascular shutdown initially caused by early treatment are usually accompanied by the production of many protumor factors by the surviving tumor cells, which promotes tumor regeneration, recurrence and metastasis. Aimed at these problems, in this project rare earth upconversion nanoparticles (UCNPs) will be connected directly with photosensitizers TCPP, facilitating to make full use of upconversion luminescence spectrum and ensure the effective energy transfer between them so as to improve the amount of ROS. Then UCNPs-TCPP can act as the building units and assemble with high valence metal ion Mn3+ to prepare a new type of “off/on” smart nanocomposites UCNPs@Mn(III)TCPP. The relationship between structure and properties will be regulated systematically. Furthermore, apatinib, an antiangiogenic agent, will combine with UCNPs@Mn(III)TCPP to explore their application in the synergistic tumor treatment of antiangiogenesis/CDT/PDT. More importantly, the nanocomposites will remain “inert” in normal tissues, and can only be activated specifically by GSH in tumor microenvironment so as to release Fenton reagents Mn2+, UCNP-TCPP and apatinib, which can not only consume GSH but also increase the amount of ROS in situ. CDT and NIR-mediated PDT will be achieved, respectively. Meanwhile, apatinib will be released from the channels of MOFs to regulate tumor angiogenesis and strengthen the therapeutic effect. As such, in this project we will explore the effective strategies for in situ ROS enhancement and on-demand drug delivery, reveal the mechanism of collaborative treatment and provide new ideas for the accurate diagnosis and treatment of tumors.