Cholecalciferol-PEG Conjugate Based Nanomicelles of Doxorubicin for Treatment of Triple-Negative Breast Cancer

Abstract

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 PEG2000 (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.

Microneedle array systems for long-acting drug delivery

“…Nano/microparticles offer several benefits over conventional drug delivery systems. They permit sustained drug release over a prolonged period of time while protecting encapsulated materials against chemical or proteolytic degradation [134,135]. A best possible approach to increase the permeability of such sustained-release particulate system through the skin/eye is through the combined use of MNs.…”

Vitamin D in Triple-Negative and BRCA1-Deficient Breast Cancer—Implications for Pathogenesis and Therapy

“…One of the successful strategies to overcome cancer drug resistance is the application of nanoscale drug delivery carriers [112]. Kutlehria et al, designed a conjugate of cholecalciferol glutarate with poly (ethylene glycol) 2000 (PEGCCF) [113]. This conjugate self-assembled to form micelles that could be loaded with doxorubicin (DOX) and improved the chemotherapeutic potential of this anthracycline.…”

Repositioning of Anti-parasitic Drugs in Cyclodextrin Inclusion Complexes for Treatment of Triple-Negative Breast Cancer

“…Castro et al (2016) reported an interesting study on MCF7 breast cancer cells, showing that ABZ promotes oxidative DNA damage, which induces DNA fragmentation, apoptosis, and cell death [1]. In addition, Sorlie et al (2003) described the effect of ABZ on MCF7, an estrogen receptorpositive cell line, extending the putative use of ABZ for the treatment of triple-negative breast tumors, the type of breast cancer with worse associated prognosis and limited therapeutic options [27,28].…”