Combination of magnetic targeting with synergistic inhibition of NF-κB and glutathione via micellar drug nanomedicine enhances its anti-tumor efficacy.

Breast cancer is not only one of the most prevalent types of cancer, but also it is a prime cause of death in women aged between 20 and 59. Although chemotherapy is the most common therapy approach, multiple side effects can result from lack of specificity and the use of overdose as safe doses may not completely cure cancer. Therefore, we aimed in this study is to combine the merits of NF-κB inhibiting potential of celastrol (CST) with glutathione inhibitory effect of sulfasalazine (SFZ) which prevents CST inactivation and thus enhances its anti-tumor activity. Inspired by the CD44-mediated tumor targeting effect of the hydrophilic polysaccharide chondroitin sulphate (ChS), we chemically synthesized amphiphilic zein-ChS micelles. While the water insoluble SFZ was chemically coupled to zein, CST was physically entrapped within the hydrophobic zein/SFZ micellar core. Moreover, physical encapsulation of oleic acid-capped SPIONs in the hydrophobic core of micelles enabled both magnetic tumor targeting as well as MRI theranostic capacity. Combining magnetic targeting to with the active targeting effect of ChS resulted in enhanced cellular internalization of the micelles in MCF-7 cancer cells and hence higher cytotoxic effect against MCF-7 and MDA-MB-231 breast cancer cells. In the in vivo experiments, magnetically-targeted micelles (154.4 nm) succeeded in achieving the lowest percentage increase in the tumor volume in tumor bearing mice, the highest percentage of tumor necrosis associated with significant reduction in the levels of TNF-α, Ki-67, NF-κB, VEGF, COX-2 markers compared to non-magnetically targeted micelles-, free drug-treated and positive control groups. Collectively, the developed magnetically targeted micelles pave the way for design of cancer nano-theranostic drug combinations.

Co-Administration of Tretinoin Enhances the Anti-Cancer Efficacy of Etoposide via Tumor-Targeted Green Nano-Micelles.

Herein we report promoted anti-cancer activity via a combination strategy of synergistic chemotherapy/retinoid-based breast cancer therapy with shell-stabilized micellar green nanomedicine. Amphiphilic zein-chondroitin sulfate (ChS)-based copolymeric micelles (PMs) were successfully developed via carbodiimide coupling for concomitant delivery of etoposide (ETP) and all-trans retinoic acid (ATRA) to breast cancer. The micelles exhibited low critical micellar concentration (CMC) of 0.008 mg/mL with high encapsulation efficiencies of ETP and ATRA (61.2 and 84.29%, respectively). Calcium-mediated crosslinking of the anionic ChS micellar shell resulted in prolonged drug release with small micellar size of 222.7 nm. The micelles exhibited augmented internalization into MCF-7 breast cancer cells by virtue of ChS binding affinity to CD44 receptors overexpressed by cancer cells. Consequently, the ETP/ATRA-loaded micelles exhibited synergistic cytotoxicity against breast cancer cells as revealed by their significantly lower IC50, combination index (CI), and higherdose reduction index (DRI) in comparison to the free ETP and free ATRA or their combination. Micelles displayed superiority in reducing tumor volume, decreasing proliferation, and promoting necrosis in mice bearing Ehrlich Ascites Tumor (EAT) upon comparison to free ETP and free ATRA or their combination. Overall, the developed green zein-ChS micelles offer a promising platform for tumor-targeted delivery of hydrophobic therapeutic agents.