Enzyme-Triggered Degradation of Supramolecularly Cross-Linked Polymersomes of Azobenzene-Based Polyurethane: Cell-Selective Anticancer Drug Release

Enzyme-responsive self-assembled nanostructures for drug delivery applications have gained a lot of attention, as enzymes exhibit dysregulation in many disease-associated microenvironments. Azoreductase enzyme levels are strongly elevated in many tumor tissues; hence, here, we exploited the altered enzyme activity of the azoreductase enzyme and designed a main-chain azobenzene-based amphiphilic polyurethane, which self-assembles into a vesicular nanostructure and is programmed to disassemble in response to a specific enzyme, azoreductase, with the help of the nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme in the hypoxic environment of solid tumors. The vesicular nanostructure sequesters, stabilizes the hydrophobic anticancer drug, and releases the drug in a controlled fashion in response to enzyme-triggered degradation of azo-bonds and disruption of vesicular assembly. The biological evaluation revealed tumor extracellular matrix pH-induced surface charge modulation, selective activated cellular uptake to azoreductase overexpressed lung cancer cells (A549), and the release of the anticancer drug followed by cell death. In contrast, the benign nature of the drug-loaded vesicular nanostructure toward normal cells (H9c2) suggested excellent cell specificity. We envision that the main-chain azobenzene-based polyurethane discussed in this manuscript could be considered as a possible selective chemotherapeutic cargo against the azoreductase overexpressed cancer cells while shielding the normal cells from off-target toxicity.