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Azoreductase-responsive Metal-organic Frameworks-based Nanodrug for Enhanced Cancer Therapy via Breaking Hypoxia-induced Chemoresistance.

The insufficient oxygen supply may cause hypoxia in solid tumor, which can lead to drug resistance and unsatisfactory chemotherapy effect. To address this issue, a new nanodrug is developed with azoreductase-responsive functional metal-organic frameworks (AMOFs). Since the azobenzene units lied in AMOFs could be reduced to amines by the high expressed azoreductase under the oxygen-deficient environment, chemotherapeutic drugs and small molecule interference RNAs (siRNAs) encapsulated in the core and absorbed on the surface of AMOFs, respectively, could be released under hypoxic condition. The siRNA was designed to contain hypoxic induced factor (HIF)-1α-against RX-0047 which can induce significant downregulation of HIF-1α protein. Once the constructed AMOFs entered the hypoxic cancer cells, the azoreductase-responsive release of siRNA can decrease the efflux of chemotherapeutic drugs via inhibiting the expressions of HIF-1α, multidrug resistance gene 1 (MDR1) and P-glycoprotein (P-gp). This constructed nanodrug can thus efficiently break hypoxia-induced chemoresistance and result in high-efficient cancer therapy in hypoxic tumors. As far as we known, this is the first attempt to construct AMOFs-based nanodrug with hypoxic harvesting behaviors. This proof-of-concept research both provides a simple strategy to the construction of hypoxic-responsive mechanized AMOFs, and offers a unique on-command drug delivery platform which can effectively break hypoxia-induced chemoresistance.