肿瘤靶向性超分子囊泡体系的设计、构筑及应用研究

Considering the increasing threat of malignant tumor and the side effects of conventional chemotherapy, the development of active tumor targeting supramolecular nanoparticulate drug delivery system has become a hotspot in the field of supramolecular chemistry and nanomedicine in recent years. This proposal aims to design and construct a novel-type of “targeting and intelligent” supramolecular vesicle system, which can not only actively target cancer cells, but aslo show stimuli-responsiveness to the tumor microenvironment. The research content includes: (1) Synthesize the “host-guest” type supramolecular amphiphilic inclusion complex, which is constructed by a mono-targeting group-functionalized water-soluble pillararene and a prodrug guest, and further synthesize the “hydrophilic-hydrophobic-hydrophilic” type supramolecular amphiphile whose both ends are multiple hydrophilic targeting groups and the middle part is the hydrophobic phosphate pillararene group; (2) Base on the further assembly of the above two kinds of supramolecular amphiphiles to get the corresponding tumor-targeting host-guest supramolecular prodrug vesicles and more stable bola-type supramolecular vesicle system, respectively, and further investigate their morphology, stability, and stimuli-responsiveness; (3) Investigate the drug-loading capability of such supramolecular vesicles, not only achieving the encapsulation of a single kind of anti-cancer drugs, but aslo achieving the loading of different kinds of anticancer drugs with synergistic effect. And further evaluate their tumor targeting and tumor suppression effect through cell experiments and in vivo experiments in mice, which will provide more profound reference for the development of safe and efficient tumor targeting supramolecular nanoparticulate drug delivery system.

鉴于恶性肿瘤的威胁及常规化疗药物的毒副作用，开发主动肿瘤靶向的超分子纳米递药系统成为近年来超分子化学和纳米医学领域的研究热点。本项目旨在设计不仅对癌细胞具有主动靶向性，且对肿瘤微环境具有刺激响应性的“靶向智能”超分子囊泡体系。主要研究内容包括：（1）设计合成由单靶向基团修饰的水溶柱芳烃及前药客体分子通过主客体作用形成的“主-客体”型超分子两亲体，以及合成两端是多个亲水靶向基团，中间是疏水磷酸化柱芳烃基团的“亲水-疏水-亲水”型超两亲分子；（2）利用上述超分子两亲体组装得到相应的单靶向主-客体超分子前药囊泡及更为稳定的多靶向bola-型超分子囊泡体系，并考察囊泡的形貌、稳定性及刺激响应性；（3）实现超分子囊泡对单一抗癌药物和具有协同作用的不同抗癌药物的同时包载，并通过细胞实验及小鼠活体实验，综合评价其肿瘤靶向性、抑瘤效果及应用价值。项目结果有望构建安全、高效的肿瘤靶向性超分子纳米递药系统。

超分子化学是一门处于近代化学、材料化学和生命科学交汇点的新兴交叉学科，其发展目标即实现组装体系的功能化，为材料、生命和信息等领域提供新的物质基础与理论指导。1987 和 2016年的诺贝尔化学奖也有力见证了超分子化学突飞猛进的发展。本项目围绕“如何实现超分子体系的功能化”这一热点科学问题，在智能超分子纳米药物载体和超分子功能材料方面开展了较为系统的研究。以具有独特富电子空腔的柱芳烃及其衍生物为研究对象，采用有机化学、超分子化学及材料科学有效结合的方法，正交构筑功能超分子纳米组装体，旨在探讨功能超分子纳米体系的有效构建方法及其在智能纳米药物递送体系和功能材料领域中的潜在应用。主要开展了以下研究内容：1）超分子纳米药物载体的正交构筑及其在抗癌药物转运中的应用；2）正交构建葡萄糖响应性超分子纳米载体并研究其在胰岛素递送与可控释放中的应用；3）基于正交组装，构建功能超分子纳米组装体，进一步拓展其在人工光捕获体系、防伪荧光墨水和新型智能窗材料构建中的应用。上述研究层层深入，希望阐明功能化主体结构、纳米组装体的可控构建与超分子材料性能之间的内在联系，为功能材料的构建及超分子组装过程的调控及其功能化实现提供参考。