Multifunctional and endogenous stimuli-responsive vinblastine sulfate/manganese dioxide nanodrugs for enhancing chemotherapeutic efficacy against hypoxic tumors.

Several solid tumors contain large hypoxic regions, diminishing drug responses and resulting in limited therapeutic outcomes. Vinblastine sulfate (VBL) targets the tubulin molecule, causing microtubule depolymerization and inducing mitotic arrest, leading to tumor regression. However, hypoxia causes microtubule depolymerization in tumor cells, reducing the number of intact microtubules for drug binding and diminishing the efficacy of microtubule-targeting agents like VBL. Therefore, to relieve tumor hypoxia and enhance chemotherapeutic responses to hypoxic tumors, we developed multifunctional and endogenous stimuli-responsive VBL/manganese dioxide (VBL/MnO(2)) nanodrugs. The VBL/MnO(2) nanodrugs demonstrated colloidal stability and were readily degraded by endogenous stimuli, including acidic pH, hydrogen peroxide, and glutathione, resulting in the release of VBL and in situ oxygen generation. In addition, oxygen-generating VBL/MnO(2) nanodrugs can alleviate hypoxia in tumor cells with high H(2)O(2) levels after their intracellular uptake, thereby improving therapeutic efficacy better than VBL owing to enhanced drug responses and microtubule depolymerization. Furthermore, the accumulation of VBL/MnO(2) nanodrugs in tumor tissues via passive targeting resulted in the effective reduction of hypoxia regions and hypoxia-inducible factor-1α expression in vivo. Owing to their remarkable ability to relieve tumor hypoxia, biocompatible VBL/MnO(2) nanodrugs improve drug responses and tubulin aggregation in tumor tissues, ultimately enhancing tumor apoptosis and regression. These findings suggest that the VBL/MnO(2) nanodrugs are a promising therapeutic strategy for enhancing chemotherapeutic responses to hypoxic tumors by ameliorating tumor hypoxia.