State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
Nanotechnology. 2017 May 12;28(19):195602. doi: 10.1088/1361-6528/aa66ba. Epub 2017 Mar 14.
Many effective anti-cancer drugs have limited use in hepatocellular carcinoma (HCC) therapy due to the drug resistance mechanisms in liver cells. In recent years, tumor-targeted drug delivery and the inhibition of drug-resistance-related mechanisms has become an integrated strategy for effectively combating chemo-resistant cancer. Herein, lactobionic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-LA conjugate) has been developed as a potential asialoglycoprotein receptor (ASGPR)-targeted nanocarrier and an efficient inhibitor of P-glycoprotein (P-gp) to enhance etoposide (ETO) efficacy against HCC. The main properties of ETO-loaded TPGS-LA nanoparticles (NPs) were tested through in vitro and in vivo studies after being prepared using the nanoprecipitation method and characterized by dynamic light scattering (DLS). According to the results, smaller (∼141.43 nm), positively charged ETO-loaded TPGS-LA NPs were more suitable for providing efficient delivery to hepatoma cells by avoiding the clearance mechanisms. It was found that ETO-loaded TPGS-LA NPs were noticeably able to enhance the cytotoxicity of ETO in HepG2 cells. Besides this, markedly higher internalization by the ASGPR-overexpressed HepG2 cells and efficient accumulation at the tumor site in vivo were revealed in the TPGS-LA NP group. More importantly, animal studies confirmed that ETO-loaded TPGS-LA NPs achieved the highest therapeutic efficacy against HCC. Interestingly, ETO-loaded TPGS-LA NPs also exhibited a great inhibitory effect on P-gp compared to the ETO-loaded TPGS NPs. These results suggest that TPGS-LA NPs could be used as a potential ETO delivery system against HCC.
由于肝细胞中的耐药机制，许多有效的抗癌药物在肝细胞癌（HCC）治疗中的应用受到限制。近年来，肿瘤靶向药物递送和抑制耐药相关机制已成为有效对抗化疗耐药癌症的综合策略。在此，我们将乳酰化-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS-LA 缀合物）开发为一种潜在的去唾液酸糖蛋白受体（ASGPR）靶向纳米载体和 P 糖蛋白（P-gp）的有效抑制剂，以增强依托泊苷（ETO）对 HCC 的疗效。通过纳米沉淀法制备 ETO 负载的 TPGS-LA 纳米粒子（NPs）后，通过体外和体内研究测试了 ETO 负载的 TPGS-LA NPs 的主要性质，并通过动态光散射（DLS）进行了表征。结果表明，较小的（∼141.43nm）、带正电荷的 ETO 负载的 TPGS-LA NPs 通过避免清除机制更适合为肝癌细胞提供有效的递药。结果发现，ETO 负载的 TPGS-LA NPs 能够显著增强 HepG2 细胞中 ETO 的细胞毒性。除此之外，在 TPGS-LA NP 组中，ASGPR 过表达的 HepG2 细胞的内化明显增强，体内肿瘤部位的积累效率也明显提高。更重要的是，动物研究证实，ETO 负载的 TPGS-LA NPs 对 HCC 具有最高的治疗效果。有趣的是，与 ETO 负载的 TPGS NPs 相比，ETO 负载的 TPGS-LA NPs 对 P-gp 也具有很强的抑制作用。这些结果表明，TPGS-LA NPs 可作为一种潜在的 ETO 递药系统用于 HCC 的治疗。
