Cancer stem cells (CSCs), enabled to self-renew, differentiate, and initiate the bulk
tumor, are recognized as the culprit of treatment resistance,
metastasis, and recurrence. Simultaneously eradicating CSCs and bulk
cancer cells is crucial for successful
cancer therapy. Herein, we reported that
doxorubicin (Dox) and
erastin co-loaded hydroxyethyl
starch-polycaprolactone nanoparticles (DEPH NPs) eliminated CSCs and
cancer cells by regulating redox status. We found that an excellently synergistic effect existed when Dox and
erastin were co-delivered by DEPH NPs. Specifically,
erastin could deplete intracellular
glutathione (GSH), thereby inhibiting the efflux of intracellular Dox and boosting Dox-induced
reactive oxygen species (ROS) to amplify redox imbalance and oxidative stress. The high ROS levels restrained CSCs self-renewal via downregulating Hedgehog pathways, promoted CSCs differentiation, and rendered differentiated
cancer cells vulnerable to apoptosis. As such, DEPH NPs significantly eliminated not only
cancer cells but more importantly CSCs, contributing to suppressed
tumor growth,
tumor-initiating capacity, and
metastasis, in various
tumor models of
triple negative breast cancer. This study demonstrates that the combination of Dox and
erastin is potent in elimination of both
cancer cells and CSCs, and that DEPH NPs represent a promising treatment against CSCs-rich solid
tumors.