Redox-Responsive Polyprodrugs: Recent Innovations in Reduction- and Oxidation-Responsive Drug Delivery Systems

Abstract

Redox-responsive polyprodrugs are innovative drug delivery systems that exploit the fact that diseased tissues display distinct microenvironments. These systems feature polymeric backbones or side chains displaying redox-sensitive bonds, enabling a targeted, site-specific drug release in response to oxidation or reduction. This approach minimizes off-target effects and enhances the therapeutic outcomes. Reduction-responsive polyprodrugs contain cleavable bonds, such as disulfide linkages and Pt–ligand bonds in platinum complexes, which can be cleaved through reduction reactions. Disulfide bonds are cleaved in the presence of increased concentrations of intracellular glutathione, hence specifically triggering drug release within tumor cells. The reduction of Pt(IV) to Pt(II) converts inactive platinum prodrugs into active chemotherapeutic agents, enabling targeted cancer treatment. Oxidation-responsive bonds, including boronate esters, thioketal, oxalate, and thiolacetal bonds, are cleaved by reactive oxygen species (ROS) such as hydrogen peroxide, releasing drugs in ROS-rich tumor microenvironments. Furthermore, combining both reduction- and oxidation-responsive bonds in a single polyprodrug enhances selectivity and efficacy, allowing for synchronized drug release in complex tumor environments characterized by both oxidative stress and high glutathione levels. Additionally, redox-responsive polyprodrugs can be engineered to lead to greater stability, controlled degradation, and multifunctional responsiveness, making them versatile tools in precision medicine. Beyond cancer, these polyprodrugs have potential applications in treating inflammatory diseases and creating smart materials for industrial use, such as anticorrosion coatings.