A Nitroreductase-Activated Chemiluminescent Prodrug for Real-Time Monitoring of Camptothecin Release in Peritoneal Metastasis Theranostics
Lianzhu Wei, Yumei Wu, Yanhan Zhou, Maocheng Yang, Hongyu Li, Wen‐Chao Geng, Zeli Yuan, Jie Gao
Abstract
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.