A Nitroreductase-Activated Chemiluminescent Prodrug for Real-Time Monitoring of Camptothecin Release in Peritoneal Metastasis Theranostics

While most theranostic prodrugs utilize fluorescence
for reporting,
chemiluminescence offers superior signal-to-noise ratios. However,
chemiluminescence-based prodrug systems remain relatively scarce.
Herein, we report the development of CPT-NBz-CL, a novel hypoxia-responsive
theranostic prodrug activated by nitroreductase (NTR) via a self-immolative
linker mechanism. This activation concomitantly releases a potent
chemotherapeutic camptothecin (CPT) and generates a robust chemiluminescence
signal for reporting. Encapsulation of CPT-NBz-CL into nanoparticles
(CPT-NBz-CL NPs) facilitated in vivo application. In vitro studies
demonstrated hypoxia-selective cytotoxicity and chemiluminescence
generation. In a murine 4T1-Luc1 peritoneal metastasis model, CPT-NBz-CL
NPs delineated hypoxic tumor regions through in vivo chemiluminescence
imaging, reflecting the endogenous NTR activity. Crucially, CPT-NBz-CL
NPs showed antitumor efficacy comparable to free CPT while significantly
mitigating the parent drug’s systemic toxicity. This work validates
an NTR-triggered, self-immolative chemiluminescence platform as a
promising strategy for integrating high-sensitivity imaging with potent,
targeted cancer therapy, offering an improved safety profile.