介孔二氧化硅包覆上转换发光纳米复合材料构筑和刺激响应药物释放研究及体内近红外光控靶向和肿瘤治疗

Difficulty of early cancer diagnosis and poor treatment to cancer by using small molecule anti-cancer drugs are the important reasons for the high cancer mortality. Therefore, the development of stimuli-responsive drug delivery systems, combination the diagnosis and therapy together and improvement the drug carriers to the targeted tumor site are the key to improve cancer treatment. This project is related to use the multi-core/shell structure upconversion nanoparticles coated with mesoporous silica as drug carriers, tetravalent platinum prodrug molecule as sensitive to restore and build responsive controlled release systems and CuS nanoparticles to block channels of mesoporous silica. In addition, the CuS nanoparticles can also absorb near-infrared light (NIR) and convert the NIR to thermal for cancer therapy. DMNB conjugated YIGSR targeted peptides were modified on the surface of nanocompose for NIR activated target. UCNPs plays double roles. Firstly, UCNPs plays double roles. Firstly, they act as nanotranducers to convert deeply penetrating NIR to UV to activate the targeted peptides. Secondly, they serve as upcoverison luminescence, CT and nuclear magnetic resonance monitor contrast agent to track the drug carrier cyclic process in vivo, tissue distribution and metabolism pathways of the nanocomposes. The cancer treatment effect and NIR activated target of nanocomposes are studied in detail. The project devotes not only the summary of the relevant regularity and mechanisms of nanocomposes distribution and targeting behavior in vivo, but also provides important basic data for clinical diagnosis and therapy.

癌症早期诊断困难并且小分子抗癌药物治疗效果差，是癌症死亡率高的重要原因。因此开发刺激响应控制药物释放系统，将诊断与治疗相结合，提高药物载体到达靶向肿瘤部位的几率是改善癌症治疗的关键。本项目利用多层核壳结构上转换纳米粒子包覆介孔二氧化硅作为药物载体，利用四价还原型铂前药作为敏感分子构筑还原响应型控制释放系统。以CuS为封堵孔道粒子，CuS还可吸收近红外光用做光热治疗。在材料表面修饰DMNB偶联的YIGSR多肽，可以实现近红外光控制靶向的作用。其中上转换纳米粒子发挥着两种作用，一是作为荧光转换器将近红外光转换成紫外光用于激活靶向分子；二是作为上转换荧光成像试剂以及CT和核磁成像造影剂，检测药物载体在体内的循环过程、组织分布及代谢途径。深入研究材料在体内的肿瘤治疗效果，以及光控制靶向行为。总结纳米粒子在体内分布和靶向行为的有关规律与机制，为临床诊断治疗提供重要基本数据。

癌症诊断与治疗是现代医学研究最具挑战的难题之一。为了提高癌症诊疗效率和安全性，近10年里，纳米医学将光学新疗法、多模式治疗/成像和靶向定位等措施引入抗癌诊疗研究，并取得了重要进展，但仍存在选择性差、副作用大、抗癌效率低、诊疗剂单一和评价体系不完善等严重缺陷。针对上述问题，本项目利用多层核壳结构上转换纳米粒子包覆介孔二氧化硅作为药物载体，利用四价还原型铂前药作为敏感分子构筑还原响应型控制释放系统。以CuS为封堵孔道粒子，CuS还可吸收近红外光用做光热治疗。在材料表面修饰DMNB偶联的YIGSR多肽，可以实现近红外光控制靶向的作用。总结纳米粒子在体内分布和靶向行为的有关规律与机制，为临床诊断治疗提供重要基本数据。同时，在细胞和小鼠体内对比研究上述新型诊疗剂与现有诊疗剂相比抗癌效率的增强能力及优越性。最后，利用稀土荧光等成像模式跟踪监测诊疗剂在生物体内的代谢路线、治疗效率、核靶向能力和生物安全性等基本指标。本课题拟为本领域提供新的研究思路，具有重要的理论及应用价值。