Iron-doped cross-linked lipoic acid nano-aggregates for ferroptosis-mediated cancer treatment

Recently, Fenton reaction-mediated ferroptosis has attracted great attention in cancer treatment while the metabolism loss of iron and the limited endogenous H₂O₂ level imped its clinical application. Here, a new ferroptosis inducer (Fe@cLANAs) constructed only by Fe(II) and (R)-(+)-lipoic acid (LA) was developed for tumor ablation. After entering the tumor cells, the Fe@cLANAs dissociated into disdihydrolipoic acid (DHLA) and released iron, which would regenerate each other to continuously provide iron and H₂O₂ to enhance ferroptosis. The Fe@cLANAs demonstrated the IC₅₀^Fe below 10 μM against various tumor cells, an anti-tumor effect comparable to many chemotherapy drugs. In vivo antitumor evaluation based on the tumor cell-derived xenograft model showed a tumor inhibitory rate (TIR) of 97.4% at the iron usage of 1.53 mg/kg, the lowest iron usage reported so far in ferrotherapy using iron as the main agent to treat tumors. Notably, the good anti-tumor effect of Fe@cLANAs was further achieved in the glioma patient-derived xenograft (PDX) model. This strategy utilizing the reciprocal circulation of metal iron and LA to delay the metabolism loss of iron and increase the H₂O₂ level in the tumor cells holds a great potential for ferroptosis-mediated cancer treatment. STATEMENT OF SIGNIFICANCE: The metabolism loss of iron and the limited endogenous H₂O₂ level are key factors to impede the clinical application of ferroptosis-mediated cancer treatment. Herein, a new ferroptosis inducer constructed only by lipoic acid and iron is developed to delay the metabolism loss of iron and increase the level of endogenous H₂O₂ by causing a cyclic regeneration of Fe(II)/Fe(III) and LA/DHLA in the tumor cells. According to the previous reports, at least 75 mg/kg of iron dosage was needed to achieve effective antitumor efficacy, here, the use of only 1.53 mg/kg iron in Fe@cLANAs achieved the TIR of 97.4% and 62.8% in the U251 CDX and glioma PDX models, showing the good prospect of Fe@cLANAs in clinic.