Chiral Polymer Micelles Alleviate Adriamycin Cardiotoxicity via Iron Chelation and Ferroptosis Inhibition

The dose-dependent cardiomyopathy of adriamycin (doxorubicin) limits its long-term clinical use, which is revealed as a consequence of cardiomyocyte ferroptosis. As a ferrous iron (Fe-2(+))-dependent regulated cell death pathway, ferroptosis is induced by the tailored lipid peroxides in the cell membranes. Herein, iron-chelating polymer micelles are reported for concurrent doxorubicin delivery and cardiotoxicity reduction. The amphiphilic polymer consists of methoxy poly (ethylene glycol)-co-poly (glutamic acid) copolymer as the backbone and deferiprone analog as the side chain. The chiral polymer adopted the a-helix conformation to enable prolonged retention in the cell membranes, resulting in efficient iron chelation, ferroptosis inhibition, and cardiotoxicity reduction. The co-encapsulation of doxorubicin and coenzyme Q(10) (CoQ(10)) in micelles further alleviates the cardiotoxicity because the reduced CoQ(10) can act as a radical trapping agent to constrain lipid peroxidation and cardiomyocyte ferroptosis. The reduction of cardiotoxicity is accompanied by enhanced anticancer efficacy in an in vivo murine breast cancer model. The chiral iron-chelating polymer micelles can be a promising platform for enhanced doxorubicin delivery and reduced cardiac adverse effects.