Mesoporous Nanocarriers with Stimulus-Responsive Cyclodextrin Gatekeeper for Targeting Tumor Hypoxia
Tissue hypoxia developed in most malignant tumors makes significant difference to normal tissues in the reduction potential and the activity of various bioreductive enzymes. Given the superior enzymatic activity of NAD(P)H:quinone oxidoreductase 1 (NQO1, a cytosolic reductase up-regulated in many human cancers) in hypoxia relative to that in normoxia, NQO1 has great potential for targeting hypoxic tumor cells. In the present report, the core concept of the hypoxic NQO1-responsive mesoporous silica nanoparticles (MSNs) is based on the reasoning that the superior enzymatic activity of NQO1 within hypoxic cancer cells can be utilized as a key stimulus for selective cleavage of an azobenzene stalk triggering the on-off gatekeeping for controlled release of guest drugs. We corroborate that the NQO1 specifically triggers to release the entrapped drug in the nanochannel of MSNs by reductive cleavage of azobenzene linker only under hypoxic conditions in a controlled manner not only in vitro but also in vivo. Therefore, our results indicate that Si-Azo-CD-PEG could be utilized as a hypoxic cancer-targeting drug delivery carrier, and further suggest that the azobenzene linker could be generally useful for the construction of hypoxic NQO1-responsive nanomaterials.