title: Sensitive β-galactosidase-targeting fluorescence probe for visualizing small peritoneal metastatic tumours in vivo.
abstract: Fluorescence-guided diagnostics is one of the most promising approaches for facile detection of cancer in situ. Here we focus on β-galactosidase, which is overexpressed in primary ovarian cancers, as a molecular target for visualizing peritoneal metastases from ovarian cancers. As existing fluorescence probes are unsuitable, we have designed membrane-permeable HMRef-βGal, in which the optimized intramolecular spirocyclic function affords >1,400-fold fluorescence enhancement on activation. We confirm that HMRef-βGal sensitively detects intracellular β-galactosidase activity in several ovarian cancer lines. In vivo, this probe visualizes metastases as small as <1 mm in diameter in seven mouse models of disseminated human peritoneal ovarian cancer (SHIN3, SKOV3, OVK18, OVCAR3, OVCAR4, OVCAR5 and OVCAR8). Because of its high brightness, real-time detection of metastases with the naked eye is possible. Endoscopic fluorescence detection of metastases is also demonstrated. The results clearly indicate preclinical potential value of the probe for fluorescence-guided diagnosis of peritoneal metastases from ovarian cancers.
authors.affiliation: 1] Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Asanuma
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Sakabe
authors.affiliation: 1] Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Mako
authors.initials: M
authors.lastname: Kamiya
authors.affiliation: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hiratake
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Building 10, Room B3B69, Mail Stop Code 1088, 10 Center Drive, Bethesda, Maryland 20892-1088, USA.
authors.forename: Mikako
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Building 10, Room B3B69, Mail Stop Code 1088, 10 Center Drive, Bethesda, Maryland 20892-1088, USA.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kosaka
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Building 10, Room B3B69, Mail Stop Code 1088, 10 Center Drive, Bethesda, Maryland 20892-1088, USA.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.affiliation: Open Innovation Center for Drug Discovery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Building 10, Room B3B69, Mail Stop Code 1088, 10 Center Drive, Bethesda, Maryland 20892-1088, USA.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: 1] Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan [4] Basic Research Program, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Urano
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004724:Endoscopy; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000175:diagnosis* / Q000556:secondary; D001616:beta-Galactosidase / Q000378:metabolism*
chemical_list: D005456:Fluorescent Dyes; D001616:beta-Galactosidase