Engineering a pH/Glutathione-Responsive Tea Polyphenol Nanodevice as an Apoptosis/Ferroptosis-Inducing Agent

Chemotherapy works against tumors by inducing cell apoptosis; however, evasion of apoptosis is recognized to result in resistance to anticancer therapy. Ferroptosis is an iron-dependent cell death pathway that differs from apoptosis in morphological, biochemical, and genetic levels. Combined ferroptosis and apoptosis may shed light on strategies for cancer treatment. Therefore, we have designed a nanoparticle (NP) that can simultaneously cause tumor cell apoptosis and ferroptosis. This NP is composed of epigallocatechin gallate (EGCG) and Fe³⁺ through a simple and green process and can be used to deliver doxorubicin hydrochloride (DOX) and iron ions to the tumor site at the same time. DOX/Fe³⁺/EGCG (DF) NPs display a great resolubility and long-term storage stability, and efficient DOX and Fe³⁺ release is realized after cellular internalization under the high level of glutathione and acidic nature in tumor. EGCG is likely to chemically reduce the released Fe³⁺ to Fe²⁺. The generated Fe³⁺/Fe²⁺ converts intracellular H₂O₂ to hydroxyl radicals (^•OH) via the Fenton reaction. In addition, the generated ^•OH subsequently induces lethal ferroptosis to improve DOX-induced apoptosis. In vitro and in vivo investigations indicate that a great therapeutic effect was achieved, suggesting that the formation of the DF NP delivery system is a promising strategy to fight against tumors by an apoptosis and ferroptosis combination modality.