Nitroreductase (NTR)-Triggered Degradable Polymeric Sulfur Dioxide (SO 2 ) Prodrug

A nitroreductase (NTR)-responsive sulfur dioxide (SO₂)-releasing polyurethane-based polyprodrug system is developed to execute enzyme-responsive gas therapy under hypoxic conditions. The self-assembled characteristics of the amphiphilic polyurethanes are thoroughly investigated, and their enzyme-triggered degradation is elucidated by size exclusion chromatography (SEC), hydrodynamic diameter (D_h) measurement, and microscopic study. Additionally, NTR and SO₂-responsive small molecular and polymeric fluorescent probes are synthesized, and the respective responsiveness is studied by ¹H NMR and fluorescence spectroscopy. Hypoxia-activated anticancer drug tirapazamine (TPZ) is encapsulated into the polymeric nanoaggregates, and 63% drug release is observed at pH 6.0 in the presence of NTR. Anticancer activity of the polyprodrug (SO₂ as a cytotoxic agent) and TPZ-loaded polymeric nanoaggregate (SO₂ and TPZ as cytotoxic agents) is demonstrated with cobalt chloride (CoCl₂, hypoxia mimetic mediator). Overall, the present work reveals the impact of the NTR-responsive degradable polyprodrug as an anticancer therapeutic and gives a new perspective on enzyme-responsive gas therapy.