A long-term goal of cancer diagnosis is to develop tumor-imaging techniques that have sufficient specificity and sensitivity. To achieve this goal, minimizing the background signal originating from nontarget tissues is crucial. Here we achieve highly specific in vivo cancer visualization by using a newly designed targeted 'activatable' fluorescent imaging probe. This agent is activated after cellular internalization by sensing the pH change in the lysosome. Novel acidic pH–activatable probes based on the boron-dipyrromethene fluorophore were synthesized and then conjugated to a cancer-targeting monoclonal antibody. As proof of concept, ex vivo and in vivo imaging of human epidermal growth factor receptor type 2–positive lung cancer cells in mice was performed. The probe was highly specific for tumors with minimal background signal. Furthermore, because the acidic pH in lysosomes is maintained by the energy-consuming proton pump, only viable cancer cells were successfully visualized. The design concept can be widely adapted to cancer-specific, cell surface–targeting molecules that result in cellular internalization.
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This study was supported in part by the Precursory Research for Embryonic Sciences and Technology from the Japan Science and Technology Agency, by research grants 19021010 and 19205021 to Y.U. and by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research to Y.H., Y.K., T.B., P.L.C. and H.K.
Supplementary Figs. 1–4, Supplementary Tables 1–3 and Supplementary Methods (PDF 563 kb)
Reversible activation by altering the pH. (AVI 4293 kb)
Fluorescence-guided Laparoscope (MOV 12792 kb)
Fluorescence-guided Laparoscope (MOV 5792 kb)
Fluorescence-guided Laparoscope (MOV 8635 kb)
pH-activatable rhodamine (MOV 2877 kb)
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Urano, Y., Asanuma, D., Hama, Y. et al. Selective molecular imaging of viable cancer cells with pH-activatable fluorescence probes. Nat Med 15, 104–109 (2009). https://doi.org/10.1038/nm.1854
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