Herein, we describe an energy balance strategy between fluorescence and photoacoustic effects by sulfur substitution to transform existing hemicyanine dyes (Cy) into optimized NIRF/PA dual ratiometric scaffolds. Based on this optimized scaffold, we reported the first dual-ratio response of nitroreductase probe AS-Cy-NO 2 , which allows quantitative visualization of tumor hypoxia in vivo. AS-Cy-NO 2 , composed of a new NIRF/PA scaffold thioxanthene-hemicyanine (AS-Cy-1) and a 4-nitrobenzene moiety, showed a 10-fold ratiometric NIRF enhancement (I 773 /I 733 ) and 2.4-fold ratiometric PA enhancement (PA 730 /PA 670 ) upon activation by a biomarker (nitroreductase, NTR) associated with tumor hypoxia. Moreover, the dual ratiometric NIRF/PA imaging accurately quantified the hypoxia extent with high sensitivity and high imaging depth in xenograft breast cancer models. More importantly, the 3D maximal intensity projection (MIP) PA images of the probe can precisely differentiate the highly heterogeneous oxygen distribution in solid tumor. Thus, this study provides a promising NIRF/PA scaffold that may be generalized for the dual ratiometric imaging of other disease-relevant biomarkers.

Herein, we describe an energy balance strategy between fluorescence and photoacoustic effects by sulfur substitution to transform existing hemicyanine dyes (Cy) into optimized NIRF/PA dual ratiometric scaffolds. Based on this optimized scaffold, we reported the first dual-ratio response of nitroreductase probe AS-Cy-NO 2 , which allows quantitative visualization of tumor hypoxia in vivo. AS-Cy-NO 2 , composed of a new NIRF/PA scaffold thioxanthene-hemicyanine (AS-Cy-1) and a 4-nitrobenzene moiety, showed a 10-fold ratiometric NIRF enhancement (I 773 /I 733 ) and 2.4-fold ratiometric PA enhancement (PA 730 /PA 670 ) upon activation by a biomarker (nitroreductase, NTR) associated with tumor hypoxia. Moreover, the dual ratiometric NIRF/PA imaging accurately quantified the hypoxia extent with high sensitivity and high imaging depth in xenograft breast cancer models. More importantly, the 3D maximal intensity projection (MIP) PA images of the probe can precisely differentiate the highly heterogeneous oxygen distribution in solid tumor. Thus, this study provides a promising NIRF/PA scaffold that may be generalized for the dual ratiometric imaging of other disease-relevant biomarkers.

Pancreatic cancer (PC) is one of the deadliest human malignancies, and exploring the complex molecular mechanisms behind cell death will greatly promote the clinical treatment of PC. Here, we reported a cascading-response fluorescent-imaging probe, Cy-Cys-pH, for the sequential detection of cysteine (Cys) and pH in pancreatic cancer cells. In the presence of Cys, Cys-mediated cleavage of the acrylate group caused Cy-Cys-pH to be transformed into Cy-Cys-O, which induced intense fluorescence enhancement at 725 nm. Then, Cy-Cys-O was protonated to obtain Cy-Cys-OH and the fluorescence emission shifted to 682 nm, showing a ratiometric pH response. Furthermore, Cy-Cys-pH can monitor the intracellular pH during the therapeutic process with anticancer drugs and evaluated the ability of three anticancer drugs to kill Panc-1 cells, proving that associating Cys and pH is in part an effective anticancer strategy in the treatment of pancreatic cancer. Significantly, Cy-Cys-pH is able to monitor and image pH changes during Cys depletion in real-time, which further reveals the molecular mechanism of Cys-depleted pancreatic cancer cell death, providing a powerful molecular tool for the precise treatment of PC.

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