Near-infrared triple-helical peptide with quenched fluorophores for optical imaging of MMP-2 and MMP-9 proteolytic activity in vivo |
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| Institution: | 1. Department of Radiology, University of Pittsburgh, 100 Technology Drive, Suite 452, Pittsburgh, PA 15219, USA;2. Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL 34987, USA;1. Equipe PNSCM, UMR CNRS 6226, Université de Rennes 1, 2 Avenue du Pr. Léon Bernard, F-35043 Rennes, France;2. Université de Toulouse III, 118, Route de Narbonne, F-31062 Toulouse Cedex 09, France;3. Université de Toulouse III, UPS, PHARMA-DEV, UMR 152, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France;4. IRD, UMR 152, F-31062 Toulouse Cedex 9, France;1. Department of Pathology, Medical University of Vienna, A-1090 Vienna, Austria;2. Comprehensive Cancer Center Vienna Gastroesophageal Cancers Unit (CCC-GET), Medical University of Vienna, A-1090 Vienna, Austria;3. Department of Surgery, Medical University of Vienna, A-1090 Vienna, Austria;4. Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, A-1090 Vienna, Austria;1. Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China;2. Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China;3. Lindsley F. Kimball Research Institute, New York Blood Center, NY 10065, USA;4. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA;5. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan;1. School of Materials Science, Japan Advanced Institute of Science and Technology, 1-1 Asahi-dai, Nomi, Ishikawa 923-1292, Japan;2. Research Center for Bio-Architecture, Japan Advanced Institute of Science and Technology, 1-1 Asahi-dai, Nomi, Ishikawa 923-1292, Japan;1. Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany;2. German Cancer Research Center, 69120 Heidelberg, Germany;3. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany;4. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany;5. Division of Thoracic Oncology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, 45239 Essen, Germany;6. Division of Thoracic Surgery, Ruhrlandklinik, West German Lung Center, University Hospital Essen, 45239 Essen, Germany;7. Division of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, 45239 Essen, Germany |
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| Abstract: | The gelatinase members of the MMP family have consistently been associated with tumor invasiveness, which make them an attractive target for molecular imaging. We report new activatable proteolytic optical imaging agents that consist of triple-helical peptide (THP) conjugates, with high specificity to the gelatinases, bearing quenched cypate dyes. With quenching efficiencies up to 51%, the amplified fluorescence signal upon cypate3-THP hydrolysis by the gelatinases (kcat/KM values of 6.4 × 103 M−1 s−1 to 9.1 × 103 M−1 s−1 for MMP-2 and MMP-9, respectively) in mice bearing human fibrosarcoma xenografted tumors was monitored with fluorescence molecular tomography. There was significant fluorescence enhancement within the tumor and this enhancement was reduced by treatment with pan-MMP inhibitor, Ilomastat. These data, combined with the gelatinase substrate specificity observed in vitro, indicated the observed fluorescence at the site of the tumor was due to gelatinase mediated hydrolysis of cypate3-THP. |
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| Keywords: | Matrix metalloproteinase Gelatinase Triple-helical peptides Near-infrared (NIR) optical imaging Fluorescence molecular tomography (FMT) |
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