A Ferroptosis-Inducing and Leukemic Cell-Targeting Drug Nanocarrier Formed by Redox-Responsive Cysteine Polymer for Acute Myeloid Leukemia Therapy

Abstract

Ferroptosis is an alternative strategy to overcome chemoresistance, but effective therapeutic approaches to induce ferroptosis for acute myeloid leukemia (AML) treatment are limited. Here, we developed glutathione (GSH)-responsive cysteine polymer-based ferroptosis-inducing nanomedicine (GCFN) as an efficient ferroptosis inducer and chemotherapeutic drug nanocarrier for AML treatment. GCFN depleted intracellular GSH and inhibited glutathione peroxidase 4, a GSH-dependent hydroperoxidase, to cause lipid peroxidation and ferroptosis in AML cells. Furthermore, GCFN-loaded paclitaxel (PTX@GCFN) targeted AML cells and spared normal hematopoietic cells to limit the myeloablation side effects caused by paclitaxel. PTX@GCFN treatment extended the survival of AML mice by specifically releasing paclitaxel and simultaneously inducing ferroptosis in AML cells with restricted myeloablation and tissue damage side effects. Overall, the dual-functional GCFN acts as an effective ferroptosis inducer and a chemotherapeutic drug carrier for AML treatment.