Liu Gan, Tsai Hsiang-I, Zeng Xiaowei, Cheng Wei, Jiang Lijuan, Chen Hongbo, Zhang Xudong, Zhang Jinxie, Mei Lin
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, No. 132 Waihuan East Road, Guangzhou University City, Panyu District, Guangzhou 510275, P. R. China.
School of Life Sciences, Tsinghua University, Hai Dian, Beijing 100084, P. R. China.
ACS Biomater Sci Eng. 2018 May 14;4(5):1679-1686. doi: 10.1021/acsbiomaterials.8b00152. Epub 2018 Mar 27.
Improving the anticancer efficacy of chemotherapeutics not only demands for efficient delivery into tumor sites, but also always needs to combat the multidrug resistance of cancer. Here we attempted to conquer both these problems by decorating D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) onto a phosphorylcholine-based stealthy nanocapsule. This TPGS-decorated stealthy nanocapsule, referred as nBSA-TPGS-Dox, conjugated anticancer drug doxorubicin (Dox) through an acid-responsive benzoic-imine bond. nBSA-TPGS-Dox was demonstrated to be stable in PBS and exhibited acid-responsive Dox release behavior. In vitro results showed this nanocapsule could be efficiently uptaken by the Dox-resistant HepG2/ADR human liver cancer cells through clathrin-mediated endocytosis and greatly prevented the Dox efflux, causing much more cytotoxicity than free Dox and non-TPGS-decorated nBSA-Dox. Furthermore, nBSA-TPGS-Dox exhibited much prolonged in vivo half-life compared to conventional PEGylated nanoparticles and achieved excellent tumor accumulation. Finally, this TPGS-decorated stealthy nanocapsule performed outstanding suppression of Dox-resistant tumor, much superior than non TPGS-decorated nBSA-Dox and free Dox. Thus, this TPGS-decorated stealthy nanocapsule provides a novel powerful nanomedicine platform for combatting multi-drug-resistant cancer.
提高化疗药物的抗癌疗效不仅需要将其有效地递送至肿瘤部位，还始终需要对抗癌症的多药耐药性。在此，我们试图通过将D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）修饰到基于磷酸胆碱的隐形纳米胶囊上来解决这两个问题。这种修饰了TPGS的隐形纳米胶囊，称为nBSA-TPGS-Dox，通过酸响应性苯甲酰亚胺键偶联抗癌药物阿霉素（Dox）。nBSA-TPGS-Dox在磷酸盐缓冲液（PBS）中表现出稳定性，并呈现出酸响应性的阿霉素释放行为。体外实验结果表明，这种纳米胶囊能够通过网格蛋白介导的内吞作用被耐阿霉素的人肝癌细胞HepG2/ADR有效摄取，并极大地阻止了阿霉素的外排，其细胞毒性比游离阿霉素和未修饰TPGS的nBSA-Dox大得多。此外，与传统的聚乙二醇化纳米颗粒相比，nBSA-TPGS-Dox在体内的半衰期显著延长，并实现了优异的肿瘤蓄积。最后，这种修饰了TPGS的隐形纳米胶囊对耐阿霉素肿瘤具有出色的抑制作用，远优于未修饰TPGS的nBSA-Dox和游离阿霉素。因此，这种修饰了TPGS的隐形纳米胶囊为对抗多药耐药癌症提供了一种新型且强大的纳米药物平台。
