Zhu Xiumei, Tsend-Ayush Altansukh, Yuan Zhongyue, Wen Jing, Cai Jiaxin, Luo Shifu, Yao Jianxu, Bian Junxing, Yin Linfang, Zhou Jianping, Yao Jing
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Qixia District, Nanjing, Jiangsu 210097, China.
Int J Pharm. 2017 Aug 30;529(1-2):451-464. doi: 10.1016/j.ijpharm.2017.07.011. Epub 2017 Jul 8.
In this study, glycyrrhetinic acid (GA)-modified D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) polymeric micelles (TGA PMs) were developed for the delivery of etoposide (ETO) to hepatoma cells. GA was incorporated as a ligand because of its high affinity to the hepatocytes, while TPGS functioned as a P-gp inhibitor to reverse multidrug resistance. ETO-loaded TGA PMs (ETO-TGA PMs) displayed a mean particle size of 133.6±1.2nm with a low poly-dispersity index (0.224±0.013) and negative zeta potential (-16.30mV). The drug loading and entrapment efficiency of ETO-TGA PMs were 10.4% and 79.8%, respectively. ETO-TGA PMs also exhibited faster drug release behavior at pH 5.8 and relatively stable drug release at pH 7.4. Confocal laser scanning microscope (CLSM) observations and in vivo imaging studies revealed that TGA PMs displayed higher cellular uptake and selective accumulation at the tumor site, indicating good tumor targetability. Furthermore, ETO-TGA PMs displayed significant cytotoxicity towards HepG2 cells and higher anti-tumor efficacy (75.96%), compared to the control group. This could be due to TGA-mediated targeted drug delivery to the hepatocytes as well as P-gp inhibition. These findings suggest that TGA PMs have the potential to be used as a targeted drug delivery system for hepatic cancer therapy.
在本研究中，开发了甘草次酸（GA）修饰的聚乙二醇1000琥珀酸酯D-α-生育酚（TPGS）聚合物胶束（TGA PMs）用于将依托泊苷（ETO）递送至肝癌细胞。由于GA对肝细胞具有高亲和力，因此将其作为配体掺入，而TPGS作为P-糖蛋白抑制剂发挥作用以逆转多药耐药性。负载ETO的TGA PMs（ETO-TGA PMs）的平均粒径为133.6±1.2nm，多分散指数较低（0.224±0.013），zeta电位为负（-16.30mV）。ETO-TGA PMs的载药量和包封率分别为10.4%和79.8%。ETO-TGA PMs在pH 5.8时也表现出更快的药物释放行为，在pH 7.4时药物释放相对稳定。共聚焦激光扫描显微镜（CLSM）观察和体内成像研究表明，TGA PMs在肿瘤部位表现出更高的细胞摄取和选择性积累，表明具有良好的肿瘤靶向性。此外，与对照组相比，ETO-TGA PMs对HepG2细胞显示出显著的细胞毒性和更高的抗肿瘤疗效（75.96%）。这可能是由于TGA介导的靶向药物递送至肝细胞以及P-糖蛋白抑制作用。这些发现表明，TGA PMs有潜力用作肝癌治疗的靶向药物递送系统。
