Platinum(IV) Prodrug with a Docosahexaenoic Acid Ligand Preferentially Accumulates in Drug-Resistant Cells and Triggers Ferroptosis to Overcome Drug Resistance

Platinum-based antitumor drugs face significant challenges due to drug resistance, driven by reduced drug uptake, increased efflux, and apoptosis pathway inactivation. Overcoming platinum resistance holds paramount importance. Herein, we utilized docosahexaenoic acid as axial ligands to synthesize two Pt^IV prodrugs, Pt-DHA and Pt-BisDHA, and explored their potentials to overcome drug resistance. Pt-DHA exhibited extremely potent antitumor efficacy, outperforming both Pt-BisDHA and cisplatin. Notably, unlike other platinum drugs, Pt-DHA uniquely accumulates more in cisplatin-resistant cells than in parental sensitive cells. Additionally, experimental results show that Pt-DHA induces notable ferroptosis in tumor cells even at very low concentrations, thereby highly augmenting its cytotoxicity against resistant cells. This dual capability, preferential accumulation in resistant cells and ferroptosis activation, enables Pt-DHA to reverse platinum resistance <i>in vitro</i> and <i>in vivo</i> effectively. This work provides a typical instance of developing platinum drugs with special mechanisms of action to overcome drug resistance.