Amelioration of Cisplatin Nephrotoxicity by Fe-Pt Coordination Exchange-Triggered Ferroptosis Suppression.

Abstract

Ferroptosis is an iron-dependent form of regulated cell death that has emerged as one of the mechanisms underlying cisplatin-induced nephrotoxicity. Here, we report an iron-chelating polymeric micelle for controlled cisplatin activation and ferroptosis suppression to address the above issue. The block copolymer, methoxyl polyethylene glycol-poly(glutamic acid) (mPEG-PGlu) was coupled with an iron chelator, deferiprone (Dfp) to generate the tailored amphiphilic conjugate, mPEG-P(Glu-Dfp) that could coordinate with activated cisplatin and self-assemble into micelles (Pt@M_Dfp). The cisplatin-loaded mPEG-PGlu micelles (Pt@M_Glu) and free cisplatin were employed as controls. Upon endocytosis, the intracellular labile iron could replace cisplatin due to the higher affinity between Dfp and Fe²⁺. This coordination exchange resulted in controlled cargo release and suppressed lipid peroxidation and inflammation in renal tubular cells (HK-2). The proof-of-concept was also validated in the subcutaneous 4T1 mouse breast tumor model using plasma and urine biomarkers of ferroptosis, inflammation, and renal injury as the indices, which concurred well with the histological staining of kidney tissue and fibrosis assessment. Moreover, due to the controlled cargo activation, Pt@M_Dfp significantly enhanced the in vivo antitumor efficacy compared to Pt@M_Glu and free cisplatin. Collectively, the coordination exchange approach is promising in controlled delivery of cisplatin for efficacy enhancement.