Metal-Organic Framework for Hypoxia/ROS/pH Triple-Responsive Cargo Release.

Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from very short lifetime, limited diffusion distance of reactive oxygen species (ROS). Herein, we designed a hypoxia/ROS/pH triple-responsive metal-organic framework (MOF) to facilitate the on-demand release of photosensitizers and hence enhanced PDT efficacy. Tailored azo-containing imidazole ligand was coordinated with zinc to form MOF where photosensitizer (Chlorin e6/Ce6) was encapsulated. Azo could be reduced by overexpressed azoreductase in hypoxic tumor cells, resulting in depletion of glutathione (GSH) and thioredoxin (Trx) which are major antioxidants against ROS oxidative damage in PDT, resulting in rapid cargo release and additional efficacy amplification. The imidazole ionization caused proton sponge effect ensured the disintegration of the nanocarriers in acidic organelles, allowing the rapid release of Ce6 through lysosome escape. Under light irradiation, ROS produced by Ce6 would oxidize imidazole to urea, resulting in rapid cargo release. All of the triggers were expected to show interactive synergism. The pH- and hypoxia-responsiveness could improve the release rate of Ce6 for enhanced PDT therapy, whereas the consumption of the oxygen by PDT will induce elevated hypoxia and hence in turn enhanced cargo release. This work highlights the role of triple-responsive nanocarriers for triggered photosensitizer release and improved antitumor PDT efficacy. This article is protected by copyright. All rights reserved.