多功能含钆稀土上转换纳米复合材料的控制合成及其在光控释药和医学影像方面的应用

Multifunctional inorganic composite nanomaterials have extensive applications in various biomedical fields such as multimodal bioimaging and drug delivery, which provides an unparalleled opportunity and platform for simultaneous diagnostics and therapy of disease. In particular, light can function as a highly orthogonal external stimulus and provides spatial and temporal control in drug delivery, so photo-controlled drug delivery system have attracted much attention in the burgeoning field of nanomedicine. The major hurdle in this process is that phototriggers mostly respond to UV radiation and not to visible or near-infrared (NIR) light. The use of UV irradiation is limited by its toxicity and very low tissue penetration power. In this project, we will open up a kind of novel NIR-to-UV rare earth upconversion nanoparticles containing Gd3+ (labeled as UCNPs) acting as a nanotransducers for photo-controlled drug release as well as upconversion luminescence (UCL) and magnetic resonance imaging (MRI) contrasts. The uniform, monodisperse, core-shell structured nanocarriers (labeled as UCNPs@mSiO2) composed of mesoporous silica coated UCNPs will be designed and fabricated. The size of nanocomposites, the thickness of mesoporous shell and mesoporous size will be tuned carefully by changing various experimental conditions. Then an o-nitrobenzyl ester moiety as a photocleavable linker, and the CD “gatekeeper” that can close the gate of the pore of SiO2 will be conjugated into the surface of mSiO2. And polymer PEG and targeting component folic acid will be used to modify the surface of the materials to increase colloidal stability and water dispersion as well as targeting ability of nanoparticles. Finally, in vitro/in vivo targeting delivery, remote photo-controlled drug release and medical imagings will be investigated in detail so as to obtain a “theranostic” nanocarrier system.

多功能无机纳米复合材料在多种模式生物影像、药物传递等方面有广泛的应用前景，为疾病的同时诊断和治疗提供了一种新颖平台，尤其光控药物传输体系的设计与制备近年来备受关注，这是由于光能够提供高度精准的非物理性接触的外部刺激，可达到时间、空间的同时可控。但目前所用的光触发分子通常用紫外光激发，而紫外光毒性比较大，生物组织穿透深度低。在本项目中，我们拟开发一类新的近红外至紫外、含Gd3+的多功能稀土上转换纳米粒子，以此粒子作为纳米传感器和多种模式的影像试剂组装到介孔SiO2中，通过控制反应条件来调节粒子尺寸、介孔SiO2的壳层厚度及孔径大小等；以硝基苯衍生物作为光触发分子，β-环糊精作为孔道口的“开关”共价连接到介孔SiO2的表面，并用PEG和靶向分子叶酸对材料进行修饰以提高其生物相容性和靶向功能，研究材料在体外、体内的靶向传递、光控药物释放以及医学影像中的应用，最终建立一种“诊疗一体化”的药物载体。

本项目聚焦于稀土上转换发光多功能纳米“诊疗”体系，在稀土上转换发光材料的发光过程调控及近红外光控释药方面取得了系列创新性的研究成果：在上转换发光过程调控方面，解决了稀土上转换发光材料高浓度敏化离子引起的浓度猝灭问题，提高了稀土上转换纳米粒子在紫外区的发光强度，首次发现了纳米尺度下晶格尺寸对能量迁移效率的空间限域效应；首次研究了近红外光激发下准一维上转换微米材料的光波导效应。在此基础上，通过巧妙的设计，合成了多种稀土上转换多功能纳米复合材料，并以此作为载体，担载不同的光敏药物分子如光敏铂药、TiO2光敏剂等，充分利用上转换纳米材料的独特性质，实现近红外光控制的药物释放以及肿瘤的联合治疗。光是一种清洁能源，对环境友好，通过这种非接触性外部刺激方式，可以到达时间和空间的同时控制，这样不但可提高药物的利用率，还可以增加药物在病变部位的累积，从而提高治疗效果。同时也实现了活体内的上转换荧光/核磁共振/CT等多模式生物成像，为肿瘤的“诊疗一体化”治疗提供了新思路。本项目为开发精准、高效、安全的肿瘤诊疗方法提供了材料基础和技术方案，对肿瘤的早期诊断和治疗具有重要的现实意义。项目执行期间共计在Chem. Rev.、Chem. Soc. Rev.、Adv. Mater.、Nat. Commun.、Angew. Chem. Int. Ed.、ACS Nano、Adv. Funct. Mater.等相关领域的核心杂志上发表SCI论文65篇，其中影响因子> 10的论文27篇，16篇论文入选ESI高被引论文，他引超过100次的论文7篇，单篇最高他引685次；撰写英文专著1章节；申请专利4项，授权2项。项目负责人多次入选全球材料领域“高被引科学家”榜单；入选2015-2018英国皇家化学会1%顶尖高被引作者以及爱思唯尔(Elsevier)中国高被引学者榜单。培养中青年学术带头人1名 (优秀青年科学基金项目负责人)，出站博士后1名，培养博士生9名，硕士生1名。