多层亲水壳胶束的构建及其对客体药物加载的热力学研究

The loading drug in the carrier, the targeted drug delivery in vivo, the environmental stimulus release and sustained release from the carrier are the crucial stages in therapy for various diseases. Each stage is closely related to the interaction between drug and carrier in different environments and the microstructure of the carrier. Microcalorimetry can reveal the thermodynamic properties of intermolecular interaction processes and sensitively detect the microstructure transition of the carrier. The proposal of project will address mainly to study the construction of hydrophilic multishell micelles and the thermodynamics of drug loading. We intend to design and synthesize a series of amphiphilic dextran, the amphiphilic dendritic oligo glycerol and amino-based surfactants. They will be initially used to self-assemble into the three kinds of precursor micelles with a variety of hydrophilic multishells, leading to load of either the water soluble or insoluble drug in the polar shell. Further physical modification on hydrophilic shells of precursor micelles will be made by adding other kinds of amphiphilic molecules with different functional groups, which leads to the enhancement on the interaction of drug/micelles and the recognition ability to drug molecules. The formation and structure transition of these micellar carriers, the interaction between drug and the carrier, the stability of the carriers and their environmental stimulus response will be studied by calorimetric and spectroscopic methods. Functional micelles that are suitable to load model drugs (Rutin, α-CT, CAT) might be optimized by thermodynamic method. Finally, the relationships of the construction of hydrophilic multishell micelles and their physical modification with the properties of different drugs will be summarized, which will provide an important thermodynamic insight into further extending the study on other kinds of drug loading.

载体对药物的加载、体内靶向输送、环境刺激释放与缓释是解决诸多疾病治疗难题的关键环节，每个环节都与在不同环境下药物/载体之间相互作用及载体微结构变化密切相关。微量热法能够揭示分子间相互作用热力学性质并能敏感地探测载体的微结构转变。本项目主要是研究多层亲水壳胶束载体的构建及对药物加载的热力学。拟设计合成系列双亲葡聚糖、双亲树枝状寡聚丙三醇及氨基酸表面活性剂，以此构建各种多层亲水壳母体胶束，实现在极性壳区加载水溶或难溶性药物；用不同官能团的两亲小分子对母体胶束进行物理改性，增强载体对药物的识别功能。利用量热与光谱方法结合，研究多层亲水壳胶束载体形成与结构转化、药物与载体相互作用、载体稳定性及环境刺激响应。通过优化适合模型药物(Rutin，α-CT，CAT)加载的功能性胶束，总结多层亲水壳胶束构建及物理改性与药物性质的关系，为进一步拓展到对其他药物加载的研究提供基础热力学依据。

多层亲水壳胶束有丰富多样的功能性极性基团，能够大大增强与客体分子的相互作用，载体在体液内的载药输送过程中能有效地保护药物活性和减小药物的副作用，当胶束的极性壳与疏水核有同样的径向尺寸时，其极性壳有远大于疏水核的载药空间。由不同极性头基的两亲分子混杂能够构建并调控结构多样的多层亲水壳胶束，这很可能使其成为一类极具应用前景的新型药物载体。本项目针对不同的目标药物分子优化混合胶束的组成，通过选择极性官能团、调节电荷密度与分布及药物分子与亲水壳的相互作用得到了性能优异的多层亲水壳胶束。源于两性离子表面活性剂形成多层亲水壳胶束的理念，实现了通过共价交连、平衡反应及分子间弱相互作用的方法对极性基团为葡聚糖、树枝状聚甘油的双亲分子母体胶束极性层的改性，得到了具有不同功能的多层极性壳胶束载体。①对于具有不同分子量的葡聚糖烷基改性双亲分子胶束，用羧酸-苯硼酸双头分子（SA‒APBA）或双乙烯基分子（BVSM）交联得到单分子胶束；将SA‒APBA和BVSM双重连接的单分子胶束在酸性介质中分解其中的硼酸酯键，再与表没食子儿茶素作用，得到单分子胶束前药。②用两性离子表面活性剂对烷基树枝状聚甘油双亲分子胶束改性，得到了pH响应的Rutin口服药物；用偶氮苯基表面活性剂改性，得到了UV响应的载体。③通过SDS调控两性离子表面活性剂胶束的表面电荷，再加入萘基改性咪唑离子液体，结果诱导球形胶束溶液转化为蠕虫状胶束凝胶。本项目以客体模型药物很好地诠释了多层极性壳胶束作为功能性载体的意义。以热力学研究为主线，结合各种光谱、显微成像等多种技术，研究了这些多层亲水壳胶束微结构的变化和载药的热力学机理，获得了具有广泛意义的主-客体相互作用的热力学规律。按计划完成了预期研究目标，研究成果表明多层亲水壳胶束是优于单一极性壳胶束的新型载体，为靶向客体或其他与功能性加载和释放相关的领域提供了新的研究思路。