基于上转换-MOF(Zr/Hf)复合体系的构建及药物控释和肿瘤治疗应用研究

The development and application of novel controlled drug release systems for tumor therapy are currently a hot topic in chemistry and nanomedicine. Metal-organic frameworks (MOFs) are emerging as promising drug carriers for their designable structures, high porosity, as well as modifiable pore surface; while lanthanide-doped upconversion nanoparticles (UCNPs) are able to absorb near-infrared light that has remarkably deep tissue penetration, and convert it into high-energy photons in the UV and Vis regions. Inspired by these, this project will use UV-Vis responsive MOF(Zr/Hf) as shell and UCNPs as core to exploit UCNPs@MOF composition that is expected to have high drug uptake, and the drug-release could be remotely controlled by near-infrared light. Besides, both strategies of postsynthetic modification (for grafting the alkane onto the pore surface, which can be served as aperture fences to restrict the adsorbed drug in the MOF) and mixing organic building blocks in the solid solution manner will be introduced to adjust their controlled performance. The stability and drug loading capability, as well as the performance of near-infrared controlled drug release of the UCNPs@MOF-drug will be fully characterized and investigated. Furthermore, in vitro for evaluating the cell phagocytosis effect of the UCNPs@MOF-drug nanoparticles, and in vivo experiments for investigating the near-infrared controlled drug release for the tumor therapeutic effect, and the tissue distribution and pharmacokinetics of the nanoparticles will be carried out. This project will not only provide a new idea for the design of novel MOF-based controlled drug release systems, but also provide important reference for their application in biomedicine.

新型药物控释体系的开发及其在肿瘤治疗中的应用是当前化学和纳米医学等领域的研究热点。金属有机框架（MOF）具有结构可设计、孔洞率高和孔表面可修饰等特点，是一种新兴的具有潜力的药物载体；而上转换纳米粒子（UCNPs）能够吸收具有组织穿透能力强的近红外光并将其转换为紫外或可见光。基于此，本项目拟通过复合紫外-可见光响应的MOF(Zr/Hf)和UCNPs，构建载药性能优异、且药物释放可通过近红外光远程控制的UCNPs@MOF体系；并通过后修饰嫁接窗口栅栏和混合有机构筑模块的方法调控体系的控释性能。系统研究体系的稳定性、载药和光控药物释放性能等，探讨肿瘤细胞对负载药物的UCNPs@MOF纳米粒子的吞噬效果。以小鼠肿瘤模型为对象，研究光控药物释放的治疗效果及纳米粒子在体内的生物分布和代谢动力学。该工作的开展不仅对设计新型的MOF药物控释体系提供新的思路，而且对推动其在肿瘤治疗方面的应用提供重要的参考。

本项目基于金属有机框架（MOF）材料构建肿瘤诊断和治疗试剂，主要开展了3个方面的研究工作：（1）构建了肿瘤微环境响应的药物控释体系DFS@HKUST-1，以及肿瘤微环境触发的T2-T1反转的磁共振造影剂Fe3O4-ZIF-8，探索它们在肿瘤精准诊疗中的应用。（2）基于Mn-卟啉配体和Zr簇自组装构建了多孔MOF PCN-222（Mn），开展了磁共振成像介导氧自供的肿瘤光动力治疗研究。（3）设计合成了2例新型的铱配合物和1例多孔多钼酸簇合物，同时发展通过一步透析法将铱配合物制备成空心多功能纳米粒子的方法；探究了其作为磁共振和超声双模式成像造影剂的应用研究。这些研究成果为构建基于MOF材料的精准诊疗试剂提供新的思路，也为推动它们在肿瘤诊疗应用奠定基础。