An HOCl-activated chemiluminescent prodrug enabling self-reporting camptothecin release and imaging-guided therapy in...

Prodrug strategies that exploit tumor-microenvironment abnormalities can enable spatiotemporally controlled chemotherapy; however, most prodrugs are intrinsically silent and cannot report their activation in vivo. We designed and synthesized an HOCl-responsive chemiluminescent theranostic prodrug, designated CSCL (a laboratory code, no abbreviation expansion) that self-reports camptothecin (CPT) release through a unified activation mechanism. CSCL integrates an HOCl-cleavable N,N-dimethylthiocarbamate trigger, a Schaap-type phenoxy-1,2-dioxetane chemiluminophore, and a CPT payload, all connected through a self-immolative linker. Upon HOCl exposure, trigger cleavage initiates a cascade that simultaneously releases free camptothecin and produces a 34-fold chemiluminescence turn-on (λ_em = 520 nm) with high selectivity over competing reactive species. CSCL nanoparticles (CSCL NPs), formulated with DSPE-mPEG2000, exhibit HOCl-dependent restoration of cytotoxicity in CT26 and HCT-116 cells. In a murine peritoneal carcinomatosis model, intraperitoneal administration of CSCL nanoparticles enables tumor-localized activation with spatial co-localization between chemiluminescence and tumor burden, affording antitumor efficacy comparable to that of free camptothecin without overt systemic toxicity under the tested regimen. This work provides a proof-of-concept for HOCl-driven chemiluminescent theranostic prodrugs that couple real-time imaging readout with therapeutic payload delivery in oxidative tumor microenvironments.