Carbon nanoparticles-Fe(II) complex combined with sorafenib for ferroptosis-induced antitumor effects in triple-negative breast cancer.

Triple negative breast cancer (TNBC) represents an aggressive subtype of breast cancer that lacks the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, whose systemic treatment options are currently limited to chemotherapy. Carbon nanoparticles-Fe(II) complex (CNSI-Fe) is a promising antitumor drug that induces ferroptosis to kill tumor cells efficiently. In this study, we combined CNSI-Fe and a ferroptosis inducer sorafenib (SRF) to achieve the efficient chemotherapy of TNBC. CNSI-Fe could adsorb SRF by hydrophobic interaction and π-π stacking with a maximum adsorption capacity of 31 mg/g. During the in vitro assays, CNSI-Fe+SRF combination inhibited the cell viability of 4T1 cells much more efficiently than CNSI-Fe or SRF alone. The high Fe uptake, hydroxyl radical generation and oxidative damages verified the ferroptosis of 4T1 cells upon the CNSI-Fe+SRF treatment. During the in vivo evaluations, SRF enhanced the therapeutic effect of CNSI-Fe as indicated by the higher tumor growth inhibition rate of 67.8 % and the higher survival rate. CNSI captured SRF in tumor to give a 6 mg/kg uptake, which lowered the glutathione peroxidase 4 (GPX4) level and enhanced the hydroxyl radical production of 4T1 tumor. In addition, CNSI-Fe treatment up-regulated the genes associated with antioxidative responses, but the up-regulation was offset by SRF. CNSI-Fe+SRF group showed similar toxicity to mice as SRF alone in the biosafety evaluations. Our results collectively indicated that the combination of CNSI-Fe and SRF could efficiently treat TNBC through ferroptosis.