Ferritin-nanocaged copper arsenite minerals with oxidative stress-amplifying activity for targeted cancer therapy

We report copper(II) arsenite-encapsulated ferritin nanoparticles (CuAS-FNs) as oxidative stress-amplifying anticancer agents. The CuAS-FNs were fabricated through CuAS mineralization in the cavity of the FNs. The formation of crystalline CuAS complex minerals in the FNs was systematically identified using various analytical tools, including X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM)-associated energy-dispersive X-ray spectroscopy (TEM-EDS). The CuAS-FNs showed pH-dependent release behavior, in which the CuAS mineral was effectively retained at physiological pH, in contrast, at lysosomal pH, the CuAS complex was dissociated to release arsenite and Cu²⁺ ions. At lysosomal pH, the release rate of arsenite (HAsO₃^2-) and Cu²⁺ ions from the CuAS-FNs more accelerated than at physiological pH. Upon transferrin receptor-1-mediated endocytosis, the CuAS-FNs simultaneously released arsenite and Cu²⁺ ions in cells. The released arsenite ions can increase the intracellular concentration of hydrogen peroxide (H₂O₂), with which the Cu²⁺ ions can elevate the level of hydroxyl radicals (·OH) via Fenton-like reaction. Thus, the CuAS-FNs could target cancer cell through the recognizing ability of FNs and kill cancer cells by amplifying the ·OH level through the synergistic activity of Cu²⁺ and arsenic ions. Importantly, MCF-7 tumors were effectively suppressed by CuAS-FNs without systemic in vivo toxicity. Therefore, the CuAS-FNs is a promising class of Fenton-like catalytic nanosystem for cancer treatment.