新型柱芳烃超分子囊泡载药体系的构筑及多功能诊疗一体化

Liposomal formulations of some antitumor drugs have been approved for clinical tumor therapy. Supra-amphiphiles that are formed on the basis of noncovalent interactions have response properties, thus supramolecular vesicles formed from supra-amphiphiles show stimuli-responsive controlled drug release. In this project, new biocompatible macrocyclic molecules (carboxylated pillar[6]arene and phosphonated pillar[6]arene) and three kinds of amphiphiles with various functional building blocks (integrated with near infrared photothermal/photosensitive properties and fluorescent properties) are used to construct new pillararene-based supramolecular vesicles by coassembly; In addition, cosurfactants are introduced to the above system, thus the new method of stepwise self-assembly is developed for the construction of pillararene-based supramolecular vesicles, and the essence and law of host-guest interactions and a variety of synergistic weak interactions are revealed. The concepts of pillararene-based supra-amphiphiles are to be interpreted, and the microstructures of corresponding supramolecular vesicles are clearly elaborated. The supramolecular vesicles show controlled drug release in response to acidic pH, glutathione (reduction of disulfide bonds), and amino acid decarboxylases, which are closely related to the microenvironments of tumors, and tumor therapy is significantly improved and multifunctional tumor theranostics is realized in combination with photothermal therapy/photodynamic therapy and fluorescence imaging. The relationship between the microstructures and functions of the pillararene-based supramolecular vesicles is to be revealed, which will provide important theoretical guidance for the design and construction of function-directed supramolecular vesicles.

一些抗肿瘤药物的脂质体制剂已用于临床肿瘤治疗。基于非共价键作用构建的超两亲分子具有响应性的功能，由此构筑的超分子囊泡具有刺激响应的药物控制释放功能。本项目提出，新型生物相容性的羧基化柱[6]芳烃和膦酸化柱[6]芳烃大环分子，分别与三种含有功能基元（同时具有近红外光热/光敏性质和荧光发射性质）的两亲分子，通过共组装构筑柱芳烃超分子囊泡新体系；此外，引入助两亲分子，发展分步组装构筑柱芳烃超分子囊泡的新方法，揭示主客体相互作用和多种弱键协同作用的本质和规律，诠释柱芳烃超两亲分子的内涵，阐述超分子囊泡的微观结构。实现超分子囊泡载药体系的肿瘤微环境的pH、谷胱甘肽和氨基酸脱羧酶多重响应的药物控制释放功能，并与光热治疗/光动力治疗和荧光影像相结合，显著提高肿瘤治疗效果，实现多功能肿瘤诊疗一体化。揭示柱芳烃超分子囊泡的微观结构与功能的关系，为设计和构筑功能导向的超分子囊泡体系提供重要的理论指导。

柱芳烃是一类新型大环主体，目前报道与柱[6]芳烃高结合亲和性的功能客体分子非常少。基于柱芳烃主客体相互作用（包含多种弱键相互作用）的超分子囊泡具有刺激响应的控制释放性能。构筑了羧基化柱[6]芳烃CPA[6]和具有近红外光热转换性能的IR-780衍生物的超分子囊泡新体系，非传统两亲分子IR-780衍生物具有刚性结构并且疏水部分的体积较大，导致构成的超两亲分子的临界堆积参数增大，形成稳定的囊泡结构。超分子囊泡载药体系实现了酸性、生物胺、热和近红外光响应的药物控制释放性能，显示较好的药物和近红外光热的联合肿瘤治疗效果。分别构筑了CPA[6]和二硫键连接的普罗黄素前药两亲分子PfSS以及膦酸化柱[6]芳烃和PfSS的超分子囊泡新体系。CPA[6]和PfSS共组装形成插指的脂双层结构的超分子囊泡。超分子囊泡载药体系实现了酸性、谷胱甘肽和生物胺响应的药物控制释放性能，显示较好的联合药物肿瘤治疗效果。发展了分步组装新方法，构筑了CPA[6]、普罗黄素和十六烷基三甲基氯化铵三组分的超分子囊泡新体系，形成脂双层和插指的脂双层的多级次的微观结构。分步组装法不仅实现了多种功能基元引入柱芳烃超分子囊泡，而且深入了揭示主客体相互作用和多种弱键协同作用的本质和规律。诠释了柱芳烃超两亲分子的内涵，阐述了柱芳烃超分子囊泡的微观结构，为设计和构筑功能导向的超分子囊泡体系提供重要的理论指导。发展了金属有机框架MOF纳米颗粒表面共价偶联硅烷功能化修饰新方法，构筑了CPA[6]阀控的普罗黄素硅烷化的MOF纳米载药体系，实现了酸性和金属离子响应的药物控制释放性能。硅烷化新方法为MOF功能化开辟了一条新途径，赋予功能化MOF材料在其他领域的广泛应用。此外，还构筑了两种蛋白门控的二硒键连接的上转换纳米颗粒@介孔二氧化硅纳米载药体系、药物配位结合的超薄多孔氮掺杂碳包覆CuSe异质结构纳米载药体系以及三种智能控释纳米农药。