两性离子化葡聚糖为骨架的新型长循环药物/基因共递送载体的构建及其性能研究

Combined therapy has attracted more and more attention in the development of tumor therapy, among which combined chemo-/gene therapy is promising in fundamental research and clinical practice. In this proposal, dextran will be firstly conjugated with carboxylbetaine groups via different chemical groups to construct zwitterionic dextran (CB-Dex) that can resist non-specific protein adsorption. Secondly, cationic peptide and hydrophobic polymer will be simultaneously grafted onto CB-Dex backnones to construct amphiphilic polymer as co-delivery vectors for drug and therapeutic RNA. Subsequently, stimuli-responsive and tumor-targeting functionalities will be introduced to improve the performance of the drug/gene vectors. The properties of vectors, such as toxicity and safety, drug/RNA delivery ability, and the anti-tumor efficiency, will be evaluated in detail. Their structure-property relationship will also be studied systematically. This proposal innovatively proposed the construction of zwitterionic dextran-backboned high-performance vectors to realize long-circulating drug/gene co-delivery for tumor therapy, which may provide a new promising new strategy for the clinical treatment of tumor.

联合治疗是肿瘤治疗的发展趋势，其中化疗/基因治疗是非常有研究和临床应用前景的研究领域。本项目通过在葡聚糖上通过不同化学基团连接羧基甜菜碱基团制备出系列抗蛋白吸附的两性离子化葡聚糖骨架，进而将正电性多肽和疏水聚合物同时连接到骨架上以构建两亲性聚合物以递送化疗药物和治疗RNA，并探索引入刺激响应性和肿瘤靶向性等功能化的灵活策略，最终可控构建出高性能药物/基因共递送载体材料；将评价共递送载体的安全性、药物/基因递送能力及肿瘤治疗效果，系统地研究载体的结构与性能的关系。本项目通过构建一系列两性离子化葡聚糖为骨架的长循环药物/基因共递送载体，以实现更好疗效的肿瘤(化疗/基因治疗）联合治疗，有望提供有前景的临床肿瘤治疗新策略。

开发高血清稳定性（血液长循环）、高递送效率高的载体材料对于提高小分子化疗药、核酸（治疗基因）、功能蛋白等多类型药物的体内治疗效果十分重要。通过本项目的研究，合成了系列葡聚糖基核酸递送体系，包括葡聚糖-阳离子多肽偶联载体、两性离子化葡聚糖-阳离子多肽偶联载体和葡聚糖-负电性多肽偶联/阳离子低聚物/核酸三元体系，三类载体均实现了核酸的高效递送；其中后两者实现了递送载体的抗血清蛋白吸附功能，在高血清浓度条件下实现了对多类型细胞的有效递送。在动物模型中进一步评价了所构建递送载体的体内性能，证实其实现了高效的体内基因递送。开展了初步的多糖化学改性与其对血液关键成分影响的构效关系研究，包括抗蛋白吸附结构改性-血清稳定性高（长循环），蛋白吸附结构改性-血清稳定性低（凝血）等。通过本项目的研究，开发了系列新型高效递送载体，提出了高血清稳定性载体的构建思路及性能调控方法，为长循环、高效递送载体的可控构建及在此基础上的药物/基因治疗奠定了基础。