Design of a Bioreductively-Activated Fluorescent pH Probe for Tumor Hypoxia Imaging

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We have designed and evaluated UTX-12 as a novel fluorescent pH probe for tumor hypoxiaimaging. UTX-12 consists of a p-nitro benzyl moiety, which is a latent hypoxia-selective leavinggroup activated by nitro reduction, directly linked to SNARF. Although UTX-12 itself is colorless andnon-fluorescent in aqueous solution, nitro reduction triggers the release of SNARF which haswell-characterized long wavelength absorption and fluorescence that is sensitive to pH. Theresultant SNARF, released intracellularly by enzymatic reduction of UTX-12, allows measurement ofpH by pH-dependent dual emission shifts. UTX-12 showed clear differences in fluorescencebehavior between hypoxic and aerobic conditions in liver microsomes and inside V79 cells. Thesedata are confirmation that UTX-12 is biologically reduced inside tumor cells and the released SNARFshould monitor intracellular pH of tumor cells selectively with reduced background signal.