A dual-responsive polyurethane nanocarrier for drug release triggered by intracellular GSH and NQO1 enzyme†

The distinct variations in the microenvironment between tumor cells and normal cells have facilitated the feasibility of highly specific and efficient drug delivery at tumor sites. This study is based on the elevated levels of glutathione (GSH) and NAD(P)H quinone oxidoreductase (NQO1 enzyme) in the tumor cells, leading to the development of a novel dual-responsive triblock polyurethane (PEG-PTU-SS-PEG) with heightened sensitivity to stimuli. This biodegradable amphiphilic polyurethane contains disulfide bonds responsive to GSH on the main chain and trimethyl locked benzoquinone structures responsive to NQO1 enzyme on the side chains. The polyurethane forms stable micelles through self-assembly and efficiently encapsulates the hydrophobic drug doxorubicin (DOX). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results indicate that both blank and drug-loaded micelles can be effectively disrupted upon addition of GSH or Na₂S₂O₄ (simulating the NQO1 enzyme environment in vitro). Furthermore, the in vitro drug release behavior of drug-loaded micelles, cellular uptake, and cytotoxicity experiments demonstrate that in the presence of GSH and NQO1 enzyme, polyurethane nanomicelles can achieve specific and efficient drug release, enhance cytotoxicity against tumor cells, and maintain excellent biocompatibility. Therefore, this newly developed polyurethane nanodrug delivery system has tremendous potential in tumor therapy, offering specific drug release and efficient treatment.