Near-Infrared Fluorescent Probe Activated by Nitroreductase for <i>In Vitro</i> and <i>In Vivo</i> Hypoxic Tumor Detection

Abstract

Tumor hypoxia is correlated with increased resistance to chemotherapy and poor overall prognoses across a number of cancer types. We present here a cancer cell-selective and hypoxia-responsive probe (<b>fol-BODIPY</b>) designed on the basis of density functional theory (DFT)-optimized quantum chemical calculations. The <b>fol-BODIPY</b> probe was found to provide a rapid fluorescence "off-on" response to hypoxia relative to controls, which lack the folate or nitro-benzyl moieties. <i>In vitro</i> confocal microscopy and flow cytometry analyses, as well as <i>in vivo</i> near-infrared optical imaging of CT26 solid tumor-bearing mice, provided support for the contention that <b>fol-BODIPY</b> is more readily accepted by folate receptor-positive CT26 cancer cells and provides a superior fluorescence "off-on" signal under hypoxic conditions than the controls. Based on the findings of this study, we propose that <b>fol-BODIPY</b> may serve as a tumor-targeting, hypoxia-activatable probe that allows for direct cancer monitoring both <i>in vitro</i> and <i>in vivo</i>.