新颖的靶向多级纳米载体的构建与智能分步控制释药研究

Nowadays, the development of nano-drug carriers opens a new route for the tumor treatment. However, a wide range of biological barriers make their function inside the organism decreased. Tumor is still endangering human health seriously. Three novel multistage nano-drug carriers with targeted, stepwise controlled release and biological imaging functions will be designed and constructed in this project for reducing side effects, improving the effect of anti-tumor and realizing the real-time monitoring of curative effect. Three first-stage carriers are molecular targeted pH sensitive inorganic nano-materials, light-sensitive crosslinked micelles and temperature-sensitive block polymer, respectively. These carriers with effective particle marginalization effect that can protect the secondary nano-carrier from degradation by enzymes and phagocytosis by eneothelial system in vivo which make the carriers more close to the vessel wall in the circulation of the blood. The accumulation of drug carrier in tumor vascular endothelial tissue can improve targeting and therapeutic effect. The secondary carriers are composited of nano-mesoporous materials or sensitive smart material in small size. The multistage carriers can unite drug multi-stage release with drug combination, active targeting with passive targeting, intelligent anti-tumor carriers cooperate with chemotherapy. The carriers, drugs as well as imaging agents reach to the targeted tumor site together. Therefore to design and exploit an ideal tumor treatment system is significant in theory and practice for us.

当今纳米药物载体技术为肿瘤的治疗开辟了新的途径，但繁多的生物障碍使其在生物体内的作用很小，肿瘤依然严重地危害着人类的健康。为此，本项目设计和构建三种全新的集多靶向、药物分步控释和生物成像等功能为一体的多级纳米药物载体，以期达到降低毒副作用、提高肿瘤治疗效果并实现疗效实时监测的目的。一级载体分别为具有分子靶向的pH敏感无机纳米材料、光敏感的胶束和温度敏感的嵌段高分子，其能够保护二级纳米载体及治疗颗粒在体内运输过程中不被生物体内的酶降解和吞噬系统清除；并且具有有效的颗粒边缘化效应，使整个体系在血液循环中，更加靠近血管壁，从而形成在血管内皮组织处的富集。其二级载体为小尺寸的纳米介孔材料或敏感材料。该多级载运体系将药物多级释放与药物联用结合、主动靶向与被动靶向结合、载体自身智能抗肿瘤与化疗协同，载体或药物兼显像剂一起靶向输送到肿瘤部位，这对于设计和开拓更加理想的治疗体系具有重要的理论和实践意义。

当今纳米药物载体技术为肿瘤的治疗开辟了新的途径，但繁多的生物障碍使其在生物体内的作用很小，肿瘤依然严重地危害着人类的健康。本项目设计和构建了磁靶向、分子靶向、线粒体靶向和电荷靶向的多种全新的集靶向、药物分步控释、环境响应以及生物成像与抗肿瘤等功能于一体的多级纳米药物载体，达到了降低毒副作用、提高肿瘤治疗效果、并实现疗效实时监测的目的。研究结果表明，制备的靶向多孔纳米药物复合载体的一级载体为HA和ZnO等无机纳米材料，作为壳层门控具有良好的生物相容性、较高的载药量及pH敏感性，可以在肿瘤酸性环境下降解，实现pH控制的一级药物释放；且能够保护二级纳米载体及治疗药物在体内运输过程中不被生物体内的酶降解和吞噬系统清除。上述药物载体还复合了MnO2，MoS2、rGO、Au团簇等纳米光催化剂和光敏剂，可以使其具备光动力和光热抗肿瘤作用 并且通过催化肿瘤微环境过氧化氢和水的分解，解决其肿瘤低氧状况，提升光动力学效果。细胞和动物实验还进一步表明，药物载体的荧光成像和光热成像能力有助于对肿瘤的定位治疗。该多级载运体系将主动靶向与被动靶向结合、药物多级释放与药物联用结合、载体自身智能抗肿瘤与化疗协同作用，成像技术与治疗相结合，对于设计和开拓更加理想的靶向诊疗一体化的多级结构平台具有重要的理论和实践意义。