title: Selective molecular imaging of viable cancer cells with pH-activatable fluorescence probes.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo, Japan.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Urano
authors.forename: Daisuke
authors.initials: D
authors.lastname: Asanuma
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hama
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Koyama
authors.forename: Tristan
authors.initials: T
authors.lastname: Barrett
authors.forename: Mako
authors.initials: M
authors.lastname: Kamiya
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Akira
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D041702:BALB 3T3 Cells; D002470:Cell Survival; D003952:Diagnostic Imaging / Q000379:methods*; D005260:Female; D005456:Fluorescent Dyes; D006863:Hydrogen-Ion Concentration; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D005456:Fluorescent Dyes; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse