The low sensitivity of hypoxic regions in solid
tumors to
radiotherapy and
chemotherapy remains a major obstacle to
cancer treatment. By taking advantage of hypoxic-activated
prodrugs,
tirapazamine (TPZ), generating cytotoxic reductive products and the
glucose oxidase (GOx)-based
glucose oxidation reaction, we designed a nanodrug-loading system that combined TPZ-induced
chemotherapy with GOx-mediated
cancer-orchestrated
starvation therapy and
cancer oxidation
therapy. In this work, we first prepared mesoporous
silica (MSN) loaded with TPZ. Then, in order to prevent the leakage of TPZ in advance, the surface was coated with a layer of carMOF formed by Fe3+ and
carbenicillin (car), and GOx was adsorbed on the outermost layer to form the final nanosystem MSN-TPZ@carMOF-GOx (MT@c-G). GOx could effectively consume
oxygen and catalyzed
glucose into
gluconic acid and
hydrogen peroxide. First, the generated
gluconic acid lowered the pH of
tumor tissues, promoted the decomposition of carMOF, and released TPZ. Second, oxygen consumption could improve the degree of
hypoxia in
tumor tissues, so that enhanced the activity of TPZ. Furthermore, GOx could generate
cancer-orchestrated
starvation/oxidation
therapy. Therefore, our study provided a new strategy that TPZ combined with GOx achieved
starvation/oxidation/
chemotherapy for enhancing anticancer effects in hypoxic regions.