Vitamin e succinate-glycol chitosan modified copper ferrite nanocomposites for lung cancer: Targeted oxidative stress regulation induces cuproptosis and ferroptosis

Although platinum-based drugs continue to be the mainstay of chemotherapy for non-small cell lung cancer (NSCLC), drug toxicity and resistance have caused considerable clinical problems. Copper species may overcome cisplatin-induced resistance, have a wider activity range, and be less toxic than platinum-based drugs. Despite the strong potential of copper-based nanomaterials to trigger cuproptosis and ferroptosis for the treatment of NSCLC, effectively targeting cancer cell death remains challenging. The copper ferrite nanocomposite (CF-GV-LBL) was designed to specifically induce tumor cell death by the responsiveness of vitamin E succinate-glycol chitosan (GV) polymers to cellular esterase levels, the protonation action of GV polymers and polylysine (PL) amino acids, and the active targeting of human serum albumin. Copper ferrite (CF) released iron and copper ions, increasing intracellular oxidative stress, depleting cellular glutathione, and initiating cuproptosis and ferroptosis. Because oxidative stress plays a crucial role in the processes of cuproptosis and ferroptosis, this work focuses on selectively regulating oxidative stress levels in intercellulars. In normal cells, GV degraded and produces the antioxidant vitamin E, which decreases cellular oxidative stress and subsequent damage. In cancer cells, GV generated reactive oxygen species, further promoting the occurrence of cuproptosis and ferroptosis. The CF-GV-LBL nanocomposite demonstrated greater anti-tumor efficacy and biocompatibility than carboplatin. Increased oxidative stress may activate the p53 signaling pathway, thus inhibiting tumor cell growth. Significantly, after 15 days of treatment, CF-GV-LBL efficiently suppressed the development of subcutaneous A549 tumors in the nude mice. Overall, this study focuses on providing insights for the treatment of NSCLC.