Nitroso-caged upconversion luminescent prodrug: Near infrared light-activatable NO nano-donor for gas therapy

Gas therapy has emerged as an effective cancer treatment for minimal tissue invasiveness and little drug resistance. Particularly, Nitric oxide (NO) gas transmitter has drawn extensive attention for direct cancer-killing efficiency at high concentrations. However, the major drawbacks of the current NO prodrugs are insufficient NO delivery to the target tissues and lack the ability of spatiotemporal release precision. Meanwhile, it is also underestimated for NO prodrugs to achieve real-time deep-tissue drug monitoring visualization with high sensitivity for reliable delivery confirmation. Herein, two near infrared (NIR) light-triggered NO-releasing donors (NRh-Bn-NO and NRh-Et-NO) are synthesized for NO delivery with superb spatiotemporal controllability while tracing drug release mediated by frequency upconversion luminescence (FUCL) readout. FUCL is a unique anti-Stokes luminescence imaging modality that provides superior imaging sensitivity and increased signal-to-noise ratio for high resolution, which takes precedence in deep-seated tumor imaging. Furthermore, a nano-system (PEG-Bn-NO) is constructed with NRh-Bn-NO to guarantee efficient NO generation by direct NIR activation while allowing high-resolution drug monitoring in depth. Following intravenous administration, PEG-Bn-NO is specifically targeted to the tumor site and selectively controlled tumor growth induced by NIR light. The NO nano-prodrug should be inspirational to highly efficient gas therapy integrated with real-time drug delivery monitoring.