title: Near-infrared triple-helical peptide with quenched fluorophores for optical imaging of MMP-2 and MMP-9 proteolytic activity in vivo.
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 6.4×10(3) M(-1) s(-1) to 9.1×10(3) 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.
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Jamee
authors.initials: J
authors.lastname: Bresee
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, 34987, USA.
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Fields
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: W Barry
authors.initials: WB
authors.lastname: Edwards
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids; D007211:Indoles / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000175:diagnosis* / Q000201:enzymology / Q000378:metabolism; D061848:Optical Imaging; D010455:Peptides / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D006877:Hydroxamic Acids; D007211:Indoles; D010455:Peptides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C119203:ilomastat
keywords: Fluorescence molecular tomography (FMT); Gelatinase; Matrix metalloproteinase; Near-infrared (NIR) optical imaging; Triple-helical peptides