两性离子类脂质药物载体改善肿瘤耐药性的研究

Nanoparticles have been widely employed as delivery vehicles for antitumor therapy. However, it is well-known that nanoparticles are prone to be sequestrated by the mononuclear phagocyte system (MPS), which is triggered by the adsorption of plasma protein onto nanoparticles. Zwitterionic lipid-like prodrug is designed as a drug delivery carrier of the nanoparticles, which use zwitterionic materials as the hydrophilic block due to their superior resistance to nonspecific protein adsorption, and anticancer drug as the hydrophobic block to increase the drug loading of the nanoparticles. A high drug-loading, long-circulating, stimulus-responsive and sequential-release drug delivery system is constructed. The behavior of the drug release is adjusted by altering the linkage of the zwitterionic lipid-like prodrug, which is used to control the release of the drug in tumor cells. The drug delivery system will be tested for in vitro and in vivo studies to demonstrate the mechanism of the system for improving drug resistance. Animal model of drug-resistant cells will be established to investigate the inhibition of the tumor with the drug delivery system.

为了改善药物输送过程中体系的稳定性，提高肿瘤细胞内的有效药物浓度，改善肿瘤的耐药性，本项目利用纳米技术在输送药物和改善肿瘤耐药性方面的优势，采用两性离子隐形材料和抗肿瘤药物设计一类类脂质药物前体作为纳米药物输送体系的载体，构建具有高载药量、长循环的、响应性循序控释的纳米给药系统。通过改变载体键合的化学键，结合联合给药技术，优化不同作用功能的药物的释放行为，改善肿瘤的耐药性，提高肿瘤的治疗效果。 将构建的纳米药物输送体系进行体外、体内实验，并结合靶向基团和荧光基团研究体系在细胞水平上的作用机理；构建耐药细胞株的动物模型，从动物水平上考察纳米药物体系对肿瘤的抑制效果，阐明体系的组成、结构与性质对改善肿瘤耐药性的作用机制。

重复的化药治疗使得肿瘤患者产生耐药性，肿瘤细胞内的有效药物浓度低，最终导致临床治疗失败。为了改善肿瘤的耐药性，发挥化疗药物高效治疗肿瘤的作用，关键是要提高化疗药物在肿瘤细胞内的有效药物浓度。针对上述问题，本课题采取“键合-联合”的药物输递策略，成功构建了具有长循环、高载药量、响应性循序控释的纳米药物输递体系。体系在体外、体内实现了pH响应性循序释放，药物半衰期分别延长了3.8和3.5倍，显著增加了药物在耐药肿瘤细胞中的药物浓度，对耐药肿瘤的抑制率达到91.8%。通过本课题的研究，将进一步开发能应用于肿瘤临床治疗的高效、安全的药物剂型，为肿瘤治疗的基础研究和临床治疗提供可行的思路，推动我国肿瘤治疗研究进展。