Strategic Development of Activatable Turn-On Fluorogenic Prodrugs of Celecoxib with Selective Anticancer Activity and Attenuated Cardiotoxicity.

Herein, we report the first examples of ROS-responsive fluorogenic prodrugs that enable sustained intracellular delivery of celecoxib with a fluorescence turn-on readout and exhibit selective anticancer activity with reduced cardiotoxicity. Spectroscopic and HPLC analysis confirmed efficient ROS-mediated activation and time-dependent release of both celecoxib and the fluorophore, providing mechanistic insights into the stimuli-triggered prodrug activation and the self-immolative drug release profile under physiological conditions. The lead prodrug Cou-Coxib exhibited selective anticancer activity in triple-negative breast cancer (MDA-MB-231) cells over non-malignant cells and showed excellent therapeutic efficacy by S phase arrest. Furthermore, Cou-Coxib ameliorated celecoxib-induced cardiotoxicity in H9C2 cardiomyoblasts. The fluorogenic drug delivery process was validated with turn-on fluorescence readout in aqueous and cellular media and subsequently in developing zebrafish embryos. Overall, this study underscores the rational design of fluorogenic prodrugs of celecoxib exhibiting selective anticancer activity in breast cancer with attenuated cardiotoxicity, thereby offering improved therapeutic potential.