A Diazaborine-Based ROS Switch Enables Copper Transfer for Tumor-Specific Prodrug Activation and Therapy

Abstract

Reactive oxygen species (ROS) are significantly elevated in tumor cells, providing an intrinsic trigger for selective drug activation and tumor-specific therapy. However, commonly used ROS-responsive linkers, such as thioketals and boronates, often suffer from limited sensitivity or poor physiological stability, and the development of new ROS-responsive motifs remains scarce. Herein, we develop a hydrazide-derived diazaborine (DAB) scaffold and establish it as a general ROS-responsive linker for small-molecule prodrugs, combining physiological stability with efficient ROS responsiveness. Based on this platform, we construct a DAB-derived ROS-responsive copper complex small-molecule prodrug, DDABD@Cu, for tumor-specific therapy. DDABD@Cu integrates a DAB-caged diethyldithiocarbamate (DTC) moiety with an inert copper donor, in which the DAB group effectively blocks the copper-chelating activity of DTC, enabling inert co-delivery of both components. Upon ROS activation, DTC is released to initiate copper transfer, generating cytotoxic Cu(DTC)₂ in situ to induce proteotoxic stress via ubiquitinated protein accumulation while concomitantly producing quinone methide (QM) to deplete glutathione (GSH) and amplify oxidative stress. This cascade improves antitumor efficacy against non-small cell lung cancer while limiting off-target toxicity. Overall, this work provides a feasible strategy for designing ROS-responsive and copper complex prodrugs.