title: Design, synthesis, and characterization of urokinase plasminogen-activator-sensitive near-infrared reporter.
abstract: The urokinase-type plasminogen activator (uPA) plays a critical role in malignancies, and its overexpression has been linked to poor clinical prognosis in breast cancer. The ability to noninvasively and serially map uPA expression as a biomarker would thus have significant potential in improving novel cancer therapies. Here, we describe the development of a selective uPA activatable near-infrared (NIR) fluorescent imaging probe. The probe consists of multiple peptide motifs, GGSGRSANAKC-NH2, terminally capped with different NIR fluorochromes (Cy5.5 or Cy7) and a pegylated poly-L-lysine graft copolymer. Upon addition of recombinant human uPA to the probe, significant fluorescence amplification was observed, up to 680% with the optimized preparation. No activation with negative control compounds and uPA inhibitors could be measured. These data indicate that the optimized preparation should be useful for imaging uPA in cancer.
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Benedict
authors.initials: B
authors.lastname: Law
authors.forename: Alejandro
authors.initials: A
authors.lastname: Curino
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Ching-Hsuan
authors.initials: CH
authors.lastname: Tung
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D008856:Microscopy, Fluorescence / Q000295:instrumentation / Q000379:methods; D010446:Peptide Fragments / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D013379:Substrate Specificity; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D005456:Fluorescent Dyes; C524898:PLAUR protein, human; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator