Autocatalytic oncotherapy nanosystem with glucose depletion for the cascade amplification of hypoxia-activated chemotherapy and H2O2-dependent chemodynamic therapy

Abstract

Employing hypoxia-activated prodrugs is an appealing oncotherapy strategy, but limited by insufficient tumor hypoxia. Moreover, a standalone prodrug fails to treat tumors satisfactorily due to tumor complexity. Herein, a nanosystem (TPZ@FeMSN-GOX) was established for triple synergetic cancer starvation therapy, hypoxia-activated chemotherapy and chemodynamic therapy (CDT). TPZ@FeMSN-GOX was prepared by synthesizing iron-doped mesoporous silica nanoparticles (FeMSNs) followed by surface conjugation with glucose oxidase (GOX), and then loading with hypoxia-activated prodrug tirapazamine (TPZ). When TPZ@FeMSN-GOX entered the tumor cells, GOX could not only exhaust glucose to starve cancer cells and concomitantly produce H₂O₂, but also consume O₂ to aggravate the hypoxia environment and amplify TPZ-mediated chemotherapy. Meanwhile, the released Fe³⁺ was reduced to reactive Fe²⁺ by endogenous glutathione, which ultimately decomposed the produced H₂O₂ and endogenous H₂O₂ into highly toxic ˙OH, guaranteeing highly efficient CDT. Together, TPZ@FeMSN-GOX could effectively kill cancer cells and significantly inhibit tumor growth, providing a good paradigm for effective tumor treatment.