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.
| Original language | English (US) |
|---|---|
| Article number | 8448 |
| Journal | Nature communications |
| Volume | 6 |
| DOIs | |
| State | Published - Oct 1 2015 |
Bibliographical note
Funding Information:We thank Kurt Thorn and Alice Thwin of the Nikon Imaging Center at UCSF for assistance, Anthony O’Donoghue for scientific support and Byron Hann in the Preclinical Therapeutics Core at UCSF for assistance with the animal studies. Lilley Leong and Gail Lee from Bayer Healthcare are gratefully acknowledged for the use of their platelet aggregometer. This work was supported by the American Heart Association Scientist Development Grant (to M.J.P), National Institutes of Health Grants CA128765 and CA186077 (to C.S.C.), CAPES Foundation, Ministry of Education of Brazil PDSE Scholarship (ID: 99999.006613/2014-04) Fluminense Federal University and the University of California San Francisco CTSI Novel Methods and Catalyst Grant (to M.J.P and C.S.C.).