稀土上转换材料/金属有机框架纳米异质结构的构建及其光诱导肿瘤协同治疗研究

There are some issues that seriously limit the applications of photodynamic therapy (PDT) for cancer treatment, including the poor biocompatibility of photosensitizers, low tissue penetration depth of the excitation light, and the generation of hypoxic areas during PDT. This project aims to controlled growth of porphyrin-based metal-organic frameworks (MOFs) on the surface of upconversion nanoparticle (UCNP) to achieve novel nanoscale core-shell heterostructures (UCNP@MOFs), thereby increasing loading content of photosensitizers (porphyrins) on UCNP and maximizing their energy transfer efficiency, thus constructing efficient PDT system excited by near-infrared light (808 nm). Then, a multifunctional nanoplatform will be developed for cancer synergistic therapy through (1) encapsulating hypoxia-activated prodrugs into the porous structure of the UCNP@MOFs to overcome PDT-related tumor hypoxic problems, and (2) modifying cancer-targeted nucleic acid aptamer onto the surface of UCNP@MOFs to improve their tumor-specificity. We will further study the anti-tumor effect of the system, and clarify the relationship between structural characteristics of the system and mechanism of tumor synergistic therapy. This project will provide a new strategy for building PDT-based tumor treatment platform through the integration of UCNP and MOFs.

本项目拟通过在稀土上转换纳米材料（UCNP）表面可控生长卟啉类金属有机框架（MOFs），合成具有核壳结构的新型纳米异质材料（UCNP@MOFs），以实现光敏剂（卟啉分子）在UCNP表面的高含量复合以及二者间有效能量传递，从而构建近红外光（808 nm）激发的高效PDT体系。在此基础上，本项目将通过以下两个策略构建新型肿瘤协同治疗平台：（1）利用MOFs的孔道结构在UCNP@MOFs中装载乏氧响应型小分子药物，以克服与PDT相关的肿瘤乏氧问题；（2）在UCNP@MOFs表面修饰靶向肿瘤细胞的核酸适配体，提高其用于肿瘤治疗的靶向特异性。进一步研究该体系的抗肿瘤效应，阐明其结构特性影响肿瘤协同治疗的机制。本项目将通过UCNP与MOFs的有机结合，开发一种新型肿瘤协同治疗平台，并为构建PDT系统提供新策略。

光动力治疗（PDT）是一种高效的肿瘤治疗方式，具有高时空选择性、非侵袭性等多重优势。但是，他们通常面临着光敏剂稳定性差、非特异性肿瘤靶向，以及激发光组织穿透深度低等挑战。在本项目的资助下，我们设计并合成了稀土上转换材料（UCNP）/金属有机框架（MOFs）纳米异质结构，实现UCNP与MOFs中卟啉分子间的有效能量传递，从而构建808 nm近红外光激发下的高效PDT体系；同时在UCNP/MOFs表面修饰靶向线粒体的三苯基膦（TPP），促进光敏剂在亚细胞水平的空间特异性分布，实现高效精准的肿瘤光动力治疗。此外，808 nm激发光的使用可有效避免传统980 nm激发上转换发光所产生的热效应和损伤正常组织的问题，提高了激光应用的安全性。这种808 nm近红外光激活+精确空间控制技术的新型肿瘤PDT平台，能够为构建肿瘤治疗系统提供新策略。项目执行期间，已在Sci. Adv.、Angew. Chem. Int. Ed.、Nanoscale、Sci. China Chem.等期刊发表SCI论文8篇（包括影响因子IF>14.0论文3篇，3.0<IF<14.0论文5篇），中文核心期刊1篇（物理学报, 2020, 69, 147801）。辅助培养研究生4名。