Biotinylated ATP-Proton AND-Logic Fluorescent Probe toward Precision Tumor Imaging

ATP, the main energy source for proliferating cancer cells, is far more abundant in the intratumoral extracellular space of tumors, making it a potent biomarker for tumor detection. We present the ATP probe, which targets biotin receptors and is activated under the mildly acidic tumor microenvironment. The detection proceeds within seconds, by reversibly forming a probe-ATP complex only under mildly acidic conditions, with insignificant interference from various metal anions, inorganic anions, and other biologically relevant species. The probe distinguishes cancer cells from normal cells, with a remarkable selectivity of 17-fold higher signal enhancement from mixed-cell experiments. Furthermore, the probe selectively illuminates tumor tissue over normal tissue, as observed by two-photon microscopy, with a remarkable 13.6-fold signal enhancement, which infers synergistic activation by ATP, biotin receptor-mediated endocytosis, and the mildly acidic tumor microenvironment. Finally, in vivo imaging of tumors in mice demonstrates that the probe distinguishes the receptor-positive tumors from normal tissue, with signal enhancements of 7.7-fold. Such a multitargeting approach is promising for precision tumor imaging.