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

Abstract

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 (Fe2+)‐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 α‐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 Q10 (CoQ10) in micelles further alleviates the cardiotoxicity because the reduced CoQ10 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.

Recent progress in biomaterials-driven ferroptosis for cancer therapy

“…102 Chen et al synthesized an amphiphilic α-helical conformation chiral polymer that encapsulated artemisinin and coenzyme Q10. In a mouse breast cancer model, reduced CoQ10 mitigated cardiac toxicity, inhibited lipid peroxidation, and cardiac cell ferroptosis 103 (Fig. 3).…”

Facile Synthesis of High Molecular Weight Poly(ethylene glycol)-b-poly(amino acid)s by Relay Polymerization

“…Zhao et al synthesized copolymer PEG-PGA as the backbone and deferiprone analog as the side chain. 36 The chiral polymer strategically assumed the α-helix conformation, ensuring prolonged retention within the cell membranes. This configuration led to effective iron chelation, inhibition of ferroptosis, and reduction in cardiotoxicity.…”

“…Currently, there is extensive research on PGA, including drug delivery, − nanogels, artificial fibers, etc. Zhao et al synthesized copolymer PEG-PGA as the backbone and deferiprone analog as the side chain . The chiral polymer strategically assumed the α-helix conformation, ensuring prolonged retention within the cell membranes.…”

Polycatechols inhibit ferroptosis and modulate tau liquid–liquid phase separation to mitigate Alzheimer's disease

“…32 In another study, a Fe-chelating amphiphilic polymer with deferiprone functionalization was developed to inhibit ferroptosis involved in cardiomyopathy. 33 Cyclic dipeptide-based copolymer nanocomposites quench Fe-induced ROS and rescue neuronal cells from Aβ42 induced toxicity. 34 Overall, accumulating evidence suggests that ferroptosis and its associated pathways contribute to the pathophysiology of AD, and targeting ferroptosis is a viable option in developing effective AD therapeutics.…”