Biodegradable Ferric Phosphate Nanocarriers with Tumor-Specific Activation and Glutathione Depletion for Tumor Self-Enhanced Ferroptosis and Chemotherapy

Ferroptosis is a regulatory cell death that is dependent on iron-mediated lipid peroxidation and cell membrane damage. The use of iron-based nanocarriers to activate ferroptosis is of great significance in oncotherapy. However, the limited endogenous hydrogen peroxide (H2O2) and high expression of glutathione (GSH) in tumor cells restrict the efficiency of iron-based nanocarriers in inducing ferroptosis. Herein, a ferric phosphate nanotherapeutic system (denoted as FeP@HCPT-HA) is reported with H2O2-supply and GSH-elimination properties for tumor self-enhanced ferroptosis and chemotherapy. FeP@HCPT-HA is obtained by a coprecipitation method with the in situ loading of 10-hydroxycamptothecin (HCPT), followed by the modification of hyaluronic acid (HA). FeP@HCPT-HA actively targets CD44-overexpressed tumor cells and degrades in acidic tumor microenvironment to release HCPT, Fe2+ and Fe3+. As a chemotherapy drug, HCPT not only induces tumor cell apoptosis but also supplies H2O2 for Fe2+-mediated Fenton reaction to enhance ferroptosis. The released Fe3+ depletes GSH by the redox reaction between Fe3+ and GSH, which down-regulates the expression of glutathione peroxidase 4 (GPX4) and enhances lipid peroxidation, resulting in enhanced ferroptosis. The integration of tumor targeting and tumor-specific activation, as well as H2O2-supply and GSH-elimination, endow the FeP@HCPT-HA with effective tumor growth inhibition by the enhanced ferroptosis and chemotherapy. Herein, a biodegradable and tumor-specific activatable therapeutic system is developed by the in situ encapsulation of 10-hydroxycamptothecin (HCPT) into an amorphous ferric phosphate (FeP) nanocarrier, and then modifying the tumor target ligand hyaluronic acid (HA) on its surface to form FeP@HCPT-HA. The prepared FeP@HCPT-HA exhibits good biocompatibility and high tumor inhibition effects, thus it is promising for cancer management. image