title: Non-invasive imaging and cellular tracking of pulmonary emboli by near-infrared fluorescence and positron-emission tomography.
abstract: Functional imaging of proteolytic activity is an emerging strategy to quantify disease and response to therapy at the molecular level. We present a new peptide-based imaging probe technology that advances these goals by exploiting enzymatic activity to deposit probes labelled with near-infrared (NIR) fluorophores or radioisotopes in cell membranes of disease-associated proteolysis. This strategy allows for non-invasive detection of protease activity in vivo and ex vivo by tracking deposited probes in tissues. We demonstrate non-invasive detection of thrombin generation in a murine model of pulmonary embolism using our protease-activated peptide probes in microscopic clots within the lungs with NIR fluorescence optical imaging and positron-emission tomography. Thrombin activity is imaged deep in tissue and tracked predominantly to platelets within the lumen of blood vessels. The modular design of our probes allows for facile investigation of other proteases, and their contributions to disease by tailoring the protease activation and cell-binding elements.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Page
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517, USA.|CAPES Foundation, Ministry of Education of Brazil, Brasília DF 70040-020, Brazil.|LABiEMol, Postgraduate Program in Pathology, Universidade Federal Fluminense, Niterói, Rio de Janeiro RJ 23230-060, Brazil.
authors.forename: André L
authors.initials: AL
authors.lastname: Lourenço
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, California 94158-9001, USA.
authors.forename: Tovo
authors.initials: T
authors.lastname: David
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: LeBeau
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517, USA.
authors.forename: Fiore
authors.initials: F
authors.lastname: Cattaruzza
authors.affiliation: LABiEMol, Postgraduate Program in Pathology, Universidade Federal Fluminense, Niterói, Rio de Janeiro RJ 23230-060, Brazil.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94107, USA.
authors.forename: Henry F
authors.initials: HF
authors.lastname: VanBrocklin
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, California 94158-9001, USA.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods*; D011655:Pulmonary Embolism / Q000000981:diagnostic imaging*; D011859:Radiography; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D013917:Thrombin / Q000494:pharmacology
chemical_list: D013917:Thrombin