Fabrication and characterization of teriflunomide-loaded chondroitin sulfate hybridized zein nanoparticles for the management of triple negative breast cancer.

The objective of this work was to explore the Teriflunomide (TFM) -loaded chondroitin sulfate hybridized zein nanoparticles (TZCNPs) for the treatment of triple-negative breast cancer (TNBC). The particle size, PDI and %EE of optimized TZCNPs was found 208.7 ± 7.26 nm,0.173 ± 0.004, and 80.18 ± 1.03 %, respectively. TZCNPs demonstrate a 7-10 folds increase in cytotoxicity against free TFM in MDA-MB-231 cells and a 4-6 folds increase in MCF-7 cells, respectively. CD44 receptor blocking resulted in a 3.4-fold reduction in anti-cancer efficacy and a 1.7-fold decrease in cellular uptake of TZCNPs in MDA-MB-231 cells, significantly/strongly indicating the critical role of the CD44-mediated uptake mechanism. TZCNPs displayed enhanced apoptosis, mitochondrial depolarization, ROS generation, cell invasion inhibition, and inhibited colony formation compared to free TFM in MDA-MB-231 cells. TZCNPs exhibited approximately 6.8-fold enhanced cytotoxicity and a 1.66-fold decrease in spheroid volume in a multicellular tumor spheroid model of MDA-MB-231 cells compared to free TFM. TZCNPs also exhibited greater disintegration of spheroids and more dead cells (live/dead staining). In pharmacokinetic studies, TZCNPs displayed reduced CL and enhanced the AUC, MRT, and t ½ by 3.64-fold, 2.17-fold, 1.83-fold, and 1.73-fold than the free TFM suspension. An acute toxicity study revealed a good safety profile of TZCNPs, which could be a potential treatment option for TNBC.