Ascorbate Tumor Chemotherapy by An Iron-Engineered Nanomedicine-Catalyzed Tumor-Specific Pro-Oxidation

Ascorbate, a kind of polyhydroxy compound with a long history, has been extensively considered as an efficient antioxidant. However, only in the past several decades its pro-oxidation characteristic in the presence of transition metal catalysts has been gradually uncovered, attracting broad attention from researchers in chemistry and biology for benefiting various practical applications, such as anticancer therapy. In this work, we report catalytic ascorbate oxidation and reactive oxygen species generation for efficient tumor chemotherapy by an iron-engineered and ascorbate-loaded hollow mesoporous silica nanomedicine. The -Si-O-Fe- hybrid framework of nanomedicine not only enables acidity-triggered degradability and ascorbate release capability but also provides an abundant Fe ion source for catalyzing ascorbate oxidation, hydrogen peroxide formation, and subsequent Fenton reactions. The detailed chemical mechanism of Fe³⁺-catalyzed ascorbate oxidation has been explored in detail as two one-electron reaction processes, between which the first one involves the sequential Fe³⁺ and O₂ captures by ascorbate to form a metal-ascorbate-oxygen ternary complex favoring hydrogen peroxide generation. Both in vitro and in vivo results demonstrate the significantly enhanced anticancer efficacy of ascorbate oxidation catalyzed by the composite nanomedicine, demonstrating high feasibility of this synergistic therapeutic concept. It is expected that such a nanomedicine design would be beneficial to future advances in the field of ascorbate.