适用于抗肿瘤药物载体的含介孔结构的多重响应复合微球

Nanoparticles used as drug delivery system have unique advantages. Nanoparticles can easily reach specific sites, or even cross blood-brain barrier. Recently, it is found that nanoscale particles (50-200nm) have enhanced permeability and retention (EPR) effect for tumor tissues, which facilitates the delivery of drugs exclusively to the intended tissues with passive targeting effect. The different physicochemical properties between tumor tissues and normal tissues could be exploited as active targeting drug delivery system to tumor region. The environment responsive nanoparticles (microspheres) could change their physicochemical and colloidal properties with external environment change (such as temperature, pH, redox, light, electric field, magnetic field and so on), so they have great potentials to utilized as controlled drug release system. Here we propose a project to invesitigate the multi-responsive (pH/temperature, light/temperature, reduction/temperature) composite microspheres containg mesoporous channels applied as anti-cancer drug delivery system systematically, where the interaction between the anticancer drugs and drug delivery system was also invetigated. Based on the "storehouse" effect of mesoporous channels, high loading capacity could be achieved, and the environment stimuli acts like as a trigger to control the release of anticancer drugs in human physiological condition with the help of the synergistic effect of multi-responsiveness. In addition, we will study the cytotoxicity of multi-responsive composite microspheres to tumor cells, exploring potential nanoparticles used as anticancer drug delivery system.

纳米粒子载药系统具有独特的优势，容易到达各个部位，甚至可以穿透血脑屏障；近来发现特定尺度(50-200nm)的纳米粒子对肿瘤组织具有增强渗透与停留效应(EPR)，从而对肿瘤组织具有一定的被动靶向作用。由于肿瘤部位的一些物理化学性质与正常组织不同，也可利用这些性质实现对肿瘤部位的主动靶向给药。环境响应纳米粒子(微球)由于其物理化学性质及胶体性质可随环境改变(如温度，pH，氧化还原，光，电场，磁场等)，具有作为药物控释载体的潜力。我们提出系统研究含介孔结构的多重环境响应(pH/热、光/热、还原/热)复合微球在抗肿瘤药物载体方面的应用，研究典型抗肿瘤药物与载体的作用机理，基于介孔结构实现较高的载药率，将介孔作为药物的仓库，环境刺激作为开关，发挥多重响应的协同作用，实现人体温附近药物的可控释放；研究多重响应载药微球对肿瘤细胞的杀伤作用，发展具有应用前景的抗肿瘤纳米粒子载药系统。

环境响应性微球由于其物理化学性质及胶体性质可随环境(如温度、pH、氧化还原、光、电场、磁场等)改变，因此外界环境刺激可以从分子水平上改变聚合物链之间或聚合物与溶剂分子的相互作用，从而控制药物的释放，可望实现药物定点、定时、定量的释放。我们制备出一系列功能性介孔二氧化硅纳米粒子，考察了这些纳米粒子用作药物载体，基于介孔结构实现了较高的载药率，其中响铃型Fe3O4@mSiO2粒子载紫杉醇可达45%。我们还制备出具有pH响应、还原响应、还原/热和pH/还原/热响应的含介孔结构的复合微球，实现了弱酸环境、还原环境、稍高于体温环境(39oC)等条件下的单一和多重环境响应的药物释放。细胞实验表明我们制备的各种空白微球均具有良好的细胞相容性，而载药复合微球具有显著的细胞毒性，其中表面修饰转铁蛋白的载紫杉醇的响铃型粒子的细胞杀伤能力甚至优于纯紫杉醇。动物实验中，我们也获得了多种有效抑制肿瘤生长的载药体系；结合光热治疗，甚至能完全消除肿瘤；从而说明含介孔结构的环境响应微球是一类具有应用前景的抗肿瘤药物载体。另外，我们还构建出一种新型的谷胱甘肽(GSH)检测探针，实现了细胞内GSH浓度的直接测量，具有重要的应用价值。本项目已发表SCI论文20篇，其中在影响因子大于8.0的杂志发表论文8篇；包含本项目部分成果的项目获教育部2014年度自然科学二等奖；培养博士2名，硕士4名。