新型808nm近红外光激发稀土上转换纳米诊疗剂的构建及在肿瘤协同治疗中的应用

The application based on rare earth upconversion nanocomposites in diagnosis and therapy of tumors has aroused considerable attention in the forefront of materials science and biomedical fields. However, there exists some challenges that need to be resolved. Firstly, the overheating effect associated with conventional 980 nm excitation is a major limitation for in vivo application. Secondly, the treatment model for tumors is relatively routine. Furthermore, the investigations on combinational therapy of tumor eradiation are still in the early stage. Some problems such as the influence mechanism of different therapeutic model as well as the synergistic antitumor effect are not very clear. Finally, it is difficult to real-time monitor the transmission process of carriers in the body. Moreover, the target ability of drug carriers is relatively poor. To address these limitations, in this project, we will focus on the design and synthesis a new kind of nanotheranostics based on 808 nm near-infrared (NIR) light excited rare earth upconversion nanocomposites. Two drug components including photosensitizers and antitumor drug DOX will be incorporated into the surface of UCNPs by reasonably covalent linking. UCNPs as nanotransducers can convert deeply penetrating 808 nm NIR light into ultraviolet light or visible light which further activate photosensitizers to produce single oxygen for photodynamic therapy (PDT). In this case, cooperative therapeutic system for tumor eradiation by combing PDT and chemotherapy is achieved. Then, the surfaces of the nanomateials are modified with dual-targeted molecules based on cell surface receptor and intracellular mRNA. The folic acid can target the folate receptor on the cancer cell surface, and the molecular beacon as DOX carrier can release DOX selectively in cancer cells due to the activated release associated with intracellular tumor mRNA. Such nanocarrier can reduce the dosage and greatly improve the therapeutic effect of drugs in cancer cells. Finally, the mechanism of chemo-photodynamic therapy as well as the combinational antitumor effect will be investigated in detail. In conclusion, this project will aim to combine a variety of technologies such as in vivo imaging, targeted drug delivery and synergistic therapy so as to construct a kind of new diagnosis and treatment method for real-time monitoring, locating diagnosis and tumor synergistic treatment together.

稀土上转换发光纳米材料在肿瘤诊断和治疗领域的应用是近年来材料科学和生物医学领域研究的热点之一，但目前也存在一些亟待解决的问题：(1) 传统的980 nm激光激发所产生的“过热”问题；(2) 治疗模式相对单一，多模式治疗研究刚刚起步，且不同治疗模式之间相互影响机制及协同抗肿瘤效应尚未完全清楚；(3) 载体的体内过程难以实时监测、材料的靶向效果差。针对以上问题，本项目拟设计制备一类基于808 nm激发的稀土上转换纳米 “诊疗剂”，建立稀土上转换纳米粒子与两种药物分子(光敏剂和抗癌药DOX)的连接方式，对肿瘤同时进行化疗和光动力治疗；构建新型的双重靶向药物载体(叶酸和分子信标MB)，实现细胞表面受体和细胞内mRNA的双重主动靶向；揭示不同治疗方式之间的作用机制及治疗效率。本项目旨在综合利用体内成像、靶向药物传递及联合治疗等多种技术，构建一类集实时监测、定位诊断与肿瘤协同治疗于一体的新型诊疗方法。

稀土上转换发光纳米材料在肿瘤诊断和治疗领域应用的应用是近年来材料科学和生物医学领域研究的热点之一，本项目针对该领域的几个问题，如传统的980 nm激光激发所产生的“过热”问题；治疗模式相对单一；载体的体内过程难以实时监测、材料的靶向效果差，设计制备一类基于808 nm激发的稀土上转换纳米 “诊疗剂”，建立了稀土上转换纳米粒子与多种药物分子（光敏分子、化疗药物、光热试剂、葡萄糖氧化酶等）的连接方式，并利用透明质酸等修饰纳米材料实现其靶向传递，重点强调利用近红外光和肿瘤微环境实现药物的控制释放和肿瘤协合治疗，揭示了不同治疗方式之间的作用机制及治疗效率；同时利用上转换荧光、MRI、CT、PA等成像模式监测材料的传递过程。总之，本项目综合利用了体内成像、靶向药物传递及联合治疗等多种技术，构建了一类集实时监测、定位诊断与肿瘤协同治疗于一体的新型诊疗方法。项目执行期间共计在Adv. Mater.、ACS Nano、Adv. Funct. Mater.等相关领域的核心杂志上发表SCI论文30篇，其中影响因子> 10的论文10篇，3篇论文入选ESI高被引论文；申请专利3项；项目负责人2016，2018年入选全球材料学科“高被引学科学家”；出站博士后1名，培养博士生6名，硕士生1名。