An HOCl-Activated Acyl Hydrazide Platform for Fluorescence-Guided Release of Hydroxyl-Containing Drugs

Hydroxyl-containing small-molecule drugs are widely used in oncology and inflammatory diseases but often suffer from poor aqueous solubility, off-target toxicity, and rapid systemic clearance, which collectively limit their therapeutic index. In parallel, hypochlorous acid (HOCl), a highly reactive myeloperoxidase-derived oxidant, is markedly upregulated in a variety of inflammatory disorders, including psoriasis, and thus represents an attractive endogenous trigger for site-selective prodrug activation. Here we report an HOCl-activated prodrug platform that enables controlled release of hydroxyl drugs together with concomitant fluorescence turn-on for lesion visualization. The platform is based on a reduced Basic Blue 3 (BB3) fluorophore linked to hydroxyl substrates via an acyl hydrazide motif that undergoes HOCl-mediated oxidation and subsequent fragmentation to liberate BB3 and the corresponding hydroxyl compound. Using a series of model alcohols, we demonstrate that BB3 conjugates display rapid, selective, and sensitive response to HOCl under physiologically relevant conditions, with nanomolar detection limits and compatibility with physiological pH. As a representative therapeutic application, we designed a camptothecin (CPT) conjugate, DHU–OH-6, which exhibits markedly improved aqueous solubility and reduced intrinsic cytotoxicity compared to CPT, while retaining efficient HOCl-triggered release of the active drug. DHU–OH-6 enables fluorescence imaging of exogenous and endogenous HOCl in cells and provides fluorescence-guided therapy in an imiquimod-induced psoriasis mouse model, where it alleviates psoriatic skin lesions and mitigates systemic toxicity relative to free CPT. This HOCl-activated hydroxyl drug-release platform offers a generalizable strategy for the design of site-selective, image-guided prodrugs for HOCl-overexpressing diseases.