title: Nitroreductase, a near-infrared reporter platform for in vivo time-domain optical imaging of metastatic cancer.
abstract: The ability to visualize reporter gene expression in vivo has revolutionized all facets of biologic investigation and none more so than imaging applications in oncology. Near-infrared reporter gene imaging may facilitate more accurate evaluation of chemotherapeutic response in preclinical models of orthotopic and metastatic cancers. We report the development of a cell permeable, quenched squarine probe (CytoCy5S), which is reduced by Escherichia coli nitroreductase (NTR), resulting in a near-infrared fluorescent product. Time-domain molecular imaging of NTR/CytoCy5S reporter platform permitted noninvasive monitoring of disease progression in orthotopic xenografts of disseminated leukemia, lung, and metastatic breast cancer. This methodology facilitated therapeutic evaluation of NTR gene-directed enzymatic prodrug therapy with conventional metronidazole antibiotics. These studies show NTR/CytoCy5S as a near-infrared gene reporter system with broad preclinical and prospective clinical applications within imaging, and gene therapy, of cancer.
authors.affiliation: Institute of Medicine, Hematology Section; Department of Biomedicine, University of Bergen, Norway. emmet.mc.cormack@med.uib.no
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Silden
authors.forename: Richard M
authors.initials: RM
authors.lastname: West
authors.forename: Tina
authors.initials: T
authors.lastname: Pavlin
authors.forename: David R
authors.initials: DR
authors.lastname: Micklem
authors.forename: James B
authors.initials: JB
authors.lastname: Lorens
authors.forename: Bengt Erik
authors.initials: BE
authors.lastname: Haug
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D002232:Carbocyanines / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008795:Metronidazole / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008856:Microscopy, Fluorescence / Q000379:methods; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009593:Nitroimidazoles / Q000378:metabolism / Q000494:pharmacology; D009601:Nitroreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000890:Anti-Infective Agents; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D029968:Escherichia coli Proteins; D009593:Nitroimidazoles; D008795:Metronidazole; D049452:Green Fluorescent Proteins; D008156:Luciferases; D009601:Nitroreductases