Self-Reporting Fluorescent Prodrug for Esterase-Guided Drug Release and Inflammation-Triggered Bioimaging

Stimuli-responsive prodrugs that combine therapeutic efficacy with optical reporting offer promising avenues for precision medicine. This study presents a dicyanoisophorone−naproxen (DCIP−Nap) conjugate, which merges the anti-inflammatory effects of naproxen with a donor−π−acceptor fluorescent scaffold. Initially, the conjugate is nonfluorescent due to suppressed intramolecular charge transfer. However, it shows a notable fluorescence “turn-on” response upon ester bond cleavage, facilitated by serum albumin. This selective release of active naproxen also restores the ICT process, resulting in a red-shifted emission. The probe further exhibits selective responsiveness toward peroxynitrite (ONOO−), a reactive nitrogen species abundantly generated in inflamed cells. Confocal microscopy using human glioblastoma (U-87 MG) and human leukemia monocytic (THP-1) cells demonstrated increased fluorescence intensity under inflammatory conditions, confirming ONOO−-mediated drug release. In vivo studies in LPS-treated mice showed fluorescence activation and decreased pro-inflammatory cytokines (TNF-α and IL-6), highlighting the therapeutic potential of DCIP−Nap. This study positions DCIP−Nap as an innovative fluorescent prodrug for targeted therapy and real-time monitoring in complex diseases.