介孔二氧化硅包覆上转换发光纳米复合材料的研制及在光动力治疗肿瘤中的应用

Photodynamic therapy (PDT) is an extraordinary theranostic modality for a number of malignant and nonmalignant diseases in recent years. Conventional PDT has the two challenges. On the hand, many of the photosensitizers such as porphyrin-based molecules have a limited solubility in water and therefore easily aggregate in the physiological environment, which would limit their applications in PDT. On the other hand, PS generally is excited by UV light that shows very limited penetration depth. To address these limitations, in this project, we will focus on the design and fabrication of uniform, monodisperse, water-dispersed and core-shell structured nanocarriers composed of mesoporous silica coated upconversion nanoparticles (UCNPs) including β-NaYF4:Yb3+, Er3+@β-NaGdF4:Yb3+, LiYF4:Yb3+, Er3+, etc. Then photosensitizers (PS) will be grafted convalently into the channel of mesoporous silica to construct multifunctional nanomaterials UCNPs@mSiO2(PS). Covalently incorporating the photosensitizers inside the silica matrices with rational coupling method can greatly enhance their water solubility and stability, avoid inactivation in the physiological environment, and particularly improve the accumulation of the photosensitizer drugs in the tumor site. UCNPs plays double roles. Firstly, they act as nanotranducers to convert deeply penetrating near-infrared light to photosensitizers. Secondly, they serve as upcoverison luminescence contrasts to monitor and track the delivery process, biodistribution and metabolic pathway of nanomaterials. In addition, the nanocomposites are further surface-functionalized by TAT peptide (YGRKKRRQRRR) to gain the nuclear targeting capacity. Finally, the biodistribution, in vitro and in vivo PDT effect of nanomaterials will be investigated in detail.

光动力治疗(PDT)是近年来迅速发展起来的一种新的疾病治疗手段，但目前它也存在一些问题：一是绝大多数光敏剂是疏水性的，在生理环境中溶解性较差，因此容易发生严重团聚，这就降低了其光敏化效率；二是用紫外-可见光辐照组织部位以激发光敏剂分子。针对这些问题，在本项目中，我们将制备一类均匀、单分散、尺寸可控(50-100 nm)、介孔SiO2直接包覆上转换发光核的纳米载体UCNPs@mSiO2，并且通过适当的偶联方法将光敏药物分子(PS)共价连接到介孔SiO2骨架中构筑多功能的复合材料。上转换纳米粒子发挥着两种作用，一是作为纳米传感器将穿透深度较高的近红外光传递给光敏分子；二是作为上转换荧光成像试剂监测材料的传递过程、生物分布和代谢途径。同时，用TAT肽(YGRKKRRQRRR)修饰介孔SiO2的表面将纳米材料靶向输送到细胞核，提高PDT效果；深入研究材料的活体生物分布以及体外、体内的PDT效果。

集医学诊断和治疗为一体的多功能纳米复合材料在新型“诊疗”纳米医学领域具有广泛的应用前景，已成为纳米医学的前沿领域。本项目结合上转换纳米粒子(无荧光背景干扰、穿透深度高、对组织光损伤小等) 和介孔SiO2 (具有优良的生物相容性、均一可调的介孔孔径、较高的比表面积、易于修饰的内表面等)的独特优势，设计合成了集多孔、上转换发光或核磁共振成像多种功能于一体的纳米复合材料UCNPs@mSiO2，系统、深入研究了材料在刺激-响应药物传递及多种模式生物成像中的应用，这些研究克服了紫外光在生物应用领域存在的缺点、光敏分子的光敏化效率低和自聚集以及传统药物载体材料靶向效果差等问题，为未来的癌症诊疗研究提供了新思路，为发展安全高效的生物医用功能材料并实现肿瘤的分子影像诊断和靶向精准治疗奠定了良好的科学基础。项目执行期间在Chem. Soc. Rev.、Adv. Mater.等核心杂志上发表SCI论文27篇 (IF> 5的14篇)，7篇论文入选ESI高被引论文；授权中国发明专利1项。2014年获得“吉林省自然科学一等奖”1项，“吉林省自然科学学术成果一等奖”1项；获2014年汤森路透中国引文桂冠奖，2014-2016年连续三次当选汤森路透全球 “高被引学者”；入选2015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。培养博士生4名，硕士生2名。