薯蓣皂苷元衍生物自组装纳米粒的制备及抗肿瘤活性评价

Preparation and antitumor activity evaluation of self-assembled nanoparticles of diosgenin derivative

目的:研究由透明质酸(HA)表面修饰的薯蓣皂苷元衍生物/二十二碳六烯酸(DGG/DHA)自组装纳米粒DDHs的体外抗肿瘤活性。方法:将DGG和DHA等比混合,采用纳米沉淀法制备双药自组装纳米给药系统并进行制剂学表征,用HA对DDHs自组装纳米粒进行表面修饰并对其制剂学特征进行表征,包括粒径、Zeta电位、稳定性、安全性等。研究自组装纳米粒对A549、HepG-2、SMMC-7721、MCF-7、4T1和MGC癌细胞的抑制活性,进一步以MGC为模型细胞研究其对自组装纳米粒的细胞摄取情况。结果:经HA表面修饰后的自组装纳米粒DDHs表面光滑、结构稳定,DDHs平均粒径为(196.8±3.1)nm,PDI值为0.158±0.01,Zeta电位为–(30.73±0.76)mV;血浆稳定性和存贮稳定性良好;在人正常pH值条件下DDHs相对于未用HA表面修饰的纳米粒溶血性明显降低。单独给药组及自组装纳米粒组对上述癌细胞的抑制活性大小均呈浓度依赖性,且自组装纳米粒DDHs相对于单独使用DGG和DHA表现出协同增效的作用,对上述癌细胞的协同指数均小于1。结论:HA表面修饰的双药自组装纳米粒粒径小,稳定性和安全性良好,体外抗肿瘤实验结果表明,HA修饰后的自组装纳米粒DDHs对上述不同肿瘤细胞表现出广谱的抗肿瘤活性,且自组装后的纳米复合物相对于单独给药发挥了良好的协同增效作用。

OBJECTIVE To explore the antitumor activity of diosgenin derivative and docosahexaenoic acid(DGG/DHA)self-assembled nanoparticle DDHs modified by hyaluronic acid(HA)in vitro.METHODS DGG/DHA were mixed in equal proportions and dual-drug self-assembled nanoparticle was prepared by the nanoprecipitation.The self-assembled nanoparticle DDHs were modified and characterized by HA.The preparation characteristics were summarized,including particle size,Zeta potential,stability and safety.The inhibitory activities of DDHs on A549,HepG-2,SMMC-7721,MCF-7,4T1 and MGC cancer cells were examined by CCK-8 assay.Cellular uptake of DDHs in MGC was further studied.RESULTS DDHs modified by HA became smooth and stable.The average particle size of DDHs was(196.8±3.1)nm,PDI(0.158±0.01)and Zeta potential-(30.73±0.76)mV.The stability of DDHS was decent and hemolytic activity of DDHs was significantly lower than that of nanoparticles without HA surface modification at normal pH value.DDHs showed a dose-dependent inhibition in the growth of A549,HepG-2,SMMC-7721,MCF-7,4T1 and MGC.As compared with DGG and DHA alone,DDHs showed synergistic effect against cancer cells with synergistic indices<1.DDHs showed a higher cellular uptake in human gastric cancer cells.CONCLUSION Self-assembled nanoparticles modified by HA have a small particle size and decent profiles of stability and safety.HA modified self-assembled nanoparticle DDHs have exhibited strong inhibitory effect on cancer cell lines with an excellent synergistic effect.