Enhanced highly toxic reactive oxygen species levels from iron oxide core–shell mesoporous silica nanocarrier-mediated Fenton reactions for cancer therapy

In this study, iron oxide core-shell mesoporous silica nanoparticles (Fe₃O₄@MSN) were prepared via the hydrolysis of tetraethyl orthosilicate on the surfaces of Fe₃O₄ nanoparticles, and these were further conjugated with folate (PEG-FA) and mitochondrial targeting triphenylphosphonium (TPP) to form Fe₃O₄@MSN-TPP/PEG-FA. A reactive oxygen species (ROS) promoting synergistic combined chemotherapy platform was designed through Fe₃O₄@MSN-TPP/PEG-FA encapsulating doxorubicin (DOX) and 3-amino-1,2,4-triazole (AT) for cancer therapy. DOX could stimulate the activation of nicotinamide adenine dinucleotide phosphate oxidases (NOXs), which change oxygen into superoxide radicals, which could be further triggered to produce hydrogen peroxide (H₂O₂) using the superoxide dismutase (SOD) enzyme. AT, as a catalase inhibitor, was employed to inhibit catalase activity to protect the production of H₂O₂. Thereafter, H₂O₂ was catalyzed with the help of Fe²⁺/Fe³⁺ to form highly toxic free hydroxyl radicals through Fenton reactions, which could induce cell death via synergistic DOX therapy. From in vitro assays, the prepared DOX/AT-loaded Fe₃O₄@MSN-TPP/PEG-FA showed remarkable inhibition efficiency (3.23% cell viability and 88.1% cell apoptosis) towards MGC-803 cells. This work has created a novel approach to gradually promote the production of ROS and combine this with chemotherapy to enhance anticancer efficacy.