Sensitive β-galactosidase-targeting fluorescence probe for visualizing small peritoneal metastatic tumours in vivo

  • Nat Commun. 2015 Mar 13:6:6463. doi: 10.1038/ncomms7463.
Daisuke Asanuma  1 ,  Masayo Sakabe  2 ,  Mako Kamiya  3 ,  Kyoko Yamamoto  4 ,  Jun Hiratake  5 ,  Mikako Ogawa  6 ,  Nobuyuki Kosaka  6 ,  Peter L Choyke  6 ,  Tetsuo Nagano  7 ,  Hisataka Kobayashi  6 ,  Yasuteru Urano  8
Affiliations
  • 1. 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.
  • 2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 3. 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.
  • 4. Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 5. Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
  • 6. 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.
  • 7. Open Innovation Center for Drug Discovery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 8. 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.
PMID: 25765713 DOI: 10.1038/ncomms7463
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.

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