Apatinib and silver nanoparticles synergize against gastric cancer through the PI3K/Akt signaling pathway-mediated ferroptosis.

Ferroptosis, a regulated form of cell death characterized by lipid peroxidation (LPO), has emerged as a promising target in cancer therapy. In this study, we detected elevated levels of glutathione (GSH) peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) in human gastric adenocarcinoma tissues, indicating a suppression of ferroptosis in gastric cancer (GC). Apatinib (Apa), a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, was found to induce ferroptosis through the classical SLC7A11/GSH/GPX4 pathway. However, long-term administration of high-dose Apa is associated with adverse side effects and the risk of drug resistance. To address these limitations, we developed a novel drug delivery system (DDSs) using hyaluronic acid (HA)-modified poly (lactic--glycolic acid) (PLGA) nanoparticles for targeted co-delivery of Apa and chitosan-coated silver nanoparticles (Chi-Ag). Our results demonstrated that the combination of Apa and Chi-Ag exerted a synergistic cytotoxic effect against GC cells. This co-delivery system evidently increased oxidative stress at the tumor site and effectively promoted ferroptosis via modulation of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway. In summary, we present a targeted nanoplatform that enhances the antitumor efficacy of Apa at lower dosages by leveraging ferroptosis induction. This strategy holds promise for improving the clinical outcomes in patients with GC.