title: Development of a Bioluminescent Nitroreductase Probe for Preclinical Imaging.
abstract: Bacterial nitroreductases (NTRs) have been widely utilized in the development of novel antibiotics, degradation of pollutants, and gene-directed enzyme prodrug therapy (GDEPT) of cancer that reached clinical trials. In case of GDEPT, since NTR is not naturally present in mammalian cells, the prodrug is activated selectively in NTR-transformed cancer cells, allowing high efficiency treatment of tumors. Currently, no bioluminescent probes exist for sensitive, non-invasive imaging of NTR expression. We therefore developed a "NTR caged luciferin" (NCL) probe that is selectively reduced by NTR, producing light proportional to the NTR activity. Here we report successful application of this probe for imaging of NTR in vitro, in bacteria and cancer cells, as well as in vivo in mouse models of bacterial infection and NTR-expressing tumor xenografts. This novel tool should significantly accelerate the development of cancer therapy approaches based on GDEPT and other fields where NTR expression is important.
authors.affiliation: School of Basic Sciences, Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology of Lausanne, Lausanne, Switzerland.
authors.forename: Anzhelika G
authors.initials: AG
authors.lastname: Vorobyeva
authors.affiliation: Cork Cancer Research Centre, University College Cork, Cork, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Stanton
authors.affiliation: School of Basic Sciences, Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology of Lausanne, Lausanne, Switzerland.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Godinat
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway.
authors.forename: Kjetil B
authors.initials: KB
authors.lastname: Lund
authors.affiliation: School of Basic Sciences, Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology of Lausanne, Lausanne, Switzerland.
authors.forename: Grigory G
authors.initials: GG
authors.lastname: Karateev
authors.affiliation: PerkinElmer, Hopkinton, Massachusetts, United States of America.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Francis
authors.affiliation: School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology of Lausanne, Lausanne, Switzerland.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Allen
authors.affiliation: Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.affiliation: Cork Cancer Research Centre, University College Cork, Cork, Ireland.
authors.forename: Mark
authors.initials: M
authors.lastname: Tangney
authors.affiliation: School of Basic Sciences, Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology of Lausanne, Lausanne, Switzerland.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Dubikovskaya
mesh_terms: D000818:Animals; D002460:Cell Line; D003952:Diagnostic Imaging / Q000379:methods*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000175:diagnosis*; D009601:Nitroreductases / Q000378:metabolism*; D011355:Prodrugs / Q000494:pharmacology
chemical_list: D011355:Prodrugs; D009601:Nitroreductases