College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, 32307, USA.
College of Pharmacy and Health Sciences, St. John's University, New York, 11439, USA.
AAPS PharmSciTech. 2018 Feb;19(2):792-802. doi: 10.1208/s12249-017-0885-z. Epub 2017 Oct 10.
Triple-negative breast cancer (TNBC) is the leading cancer in women. Chemotherapeutic agents used for TNBC are mainly associated with dose-dependent toxicities and development of resistance. Hence, novel strategies to overcome resistance and to offer dose reduction are warranted. In this study, we designed a novel dual-functioning agent, conjugate of cholecalciferol with PEG (PEGCCF) which can self-assemble into micelles to encapsulate doxorubicin (DOX) and act as a chemosensitizer to improve the therapeutic potential of DOX. DOX-loaded PEGCCF (PEGCCF-DOX) micelles have particle size, polydispersity index (PDI), and zeta potential of 40 ± 8.7 nm, 0.180 ± 0.051, and 2.39 ± 0.157 mV, respectively. Cellular accumulation studies confirmed that PEGCCF was able to concentration-dependently enhance the cellular accumulation of DOX and rhodamine 123 in MDA-MB-231 cells through its P-glycoprotein (P-gp) inhibition activity. PEGCCF-DOX exhibited 1.8-, 1.5-, and 2.9-fold enhancement in cytotoxicity of DOX in MDA-MB-231, MDA-MB-468, and MDA-MB-231DR (DOX-resistant) cell lines, respectively. Western blot analyses showed that PEGCCF-DOX caused significant reduction in tumor markers including mTOR, c-Myc, and antiapoptotic marker Bcl-xl along with upregulation of preapoptotic marker Bax. Further, reduction in mTOR activity by PEGCCF-DOX indicates reduced P-gp activity due to P-gp downregulation as well and, hence, PEGCCF causes enhanced chemosensitization and induces apoptosis. Substantially enhanced apoptotic activity of DOX (10-fold) in MDA-MB-231(DR) cells confirmed apoptotic potential of PEGCCF. Conclusively, PEGCCF nanomicelles are promising delivery systems for improving anticancer activity of DOX in TNBC, thereby reducing its side effects and may act as a potential carrier for other chemotherapeutic agents.
三阴性乳腺癌（TNBC）是女性中最主要的癌症。用于 TNBC 的化疗药物主要与剂量依赖性毒性和耐药性的发展有关。因此，需要新的策略来克服耐药性并减少剂量。在这项研究中，我们设计了一种新型的双功能药物，即胆钙化醇与 PEG 的缀合物（PEGCCF），它可以自组装成胶束以包封阿霉素（DOX）并作为化疗增敏剂，以提高 DOX 的治疗潜力。载 DOX 的 PEGCCF（PEGCCF-DOX）胶束的粒径、多分散指数（PDI）和 Zeta 电位分别为 40±8.7nm、0.180±0.051 和 2.39±0.157mV。细胞积累研究证实，PEGCCF 能够通过其 P-糖蛋白（P-gp）抑制活性，浓度依赖性地增强 MDA-MB-231 细胞中 DOX 和罗丹明 123 的细胞积累。PEGCCF-DOX 分别使 MDA-MB-231、MDA-MB-468 和 MDA-MB-231DR（多柔比星耐药）细胞系中 DOX 的细胞毒性增强了 1.8、1.5 和 2.9 倍。Western blot 分析表明，PEGCCF-DOX 导致肿瘤标志物包括 mTOR、c-Myc 和抗凋亡标志物 Bcl-xl 的显著减少，同时上调了前凋亡标志物 Bax。此外，PEGCCF-DOX 降低 mTOR 活性表明由于 P-gp 下调，P-gp 活性降低，因此，PEGCCF 引起增强的化疗增敏作用并诱导细胞凋亡。在 MDA-MB-231（DR）细胞中 DOX（10 倍）的凋亡活性显著增强证实了 PEGCCF 的凋亡潜力。总之，PEGCCF 纳米胶束是提高 TNBC 中 DOX 抗癌活性的有前途的递送系统，从而减少其副作用，并可能成为其他化疗药物的潜在载体。
