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In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activityElectronic supplementary information (ESI) available. See DOI: 10.1039/c2ib00161f

Thrombin and other coagulation enzymes have been shown to be important during atherosclerotic disease development. Study of these proteases is currently limited because of lack of robust molecular imaging agents for imaging protease activity in vivo . Activatable cell penetrating peptides (ACPPs) ha...

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Main Authors: Olson, Emilia S, Whitney, Michael A, Friedman, Beth, Aguilera, Todd A, Crisp, Jessica L, Baik, Fred M, Jiang, Tao, Baird, Stephen M, Tsimikas, Sotirios, Tsien, Roger Y, Nguyen, Quyen T
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creator Olson, Emilia S
Whitney, Michael A
Friedman, Beth
Aguilera, Todd A
Crisp, Jessica L
Baik, Fred M
Jiang, Tao
Baird, Stephen M
Tsimikas, Sotirios
Tsien, Roger Y
Nguyen, Quyen T
description Thrombin and other coagulation enzymes have been shown to be important during atherosclerotic disease development. Study of these proteases is currently limited because of lack of robust molecular imaging agents for imaging protease activity in vivo . Activatable cell penetrating peptides (ACPPs) have been used to monitor MMP activity in tumors and, in principle, can be modified to detect other proteases. We have developed a probe that incorporates the peptide sequence DPRSFL from the proteinase activated receptor 1 (PAR-1) into an ACPP and shown that it is preferentially cleaved by purified thrombin. Active thrombin in serum cleaves DPRSFL-ACPP with >90% inhibition by lepirudin or argatroban. The DPRSFL-ACPP cleavage product accumulated in advanced atherosclerotic lesions in living mice, with 85% reduction in retention upon pre-injection of mice with hirudin. Uptake of the ACPP cleavage product was highest in plaques with histological features associated with more severe disease. Freshly resected human atheromas bathed in DPRSFL-ACPP retained 63% greater cleavage product compared to control ACPP. In conclusion, DPRSFL-ACPP can be used to study thrombin activity in coagulation and atherosclerosis with good spatial and temporal resolution. Thrombin-sensitive ACPPs may be developed into probes for early detection and intraoperative imaging of high risk atherosclerotic plaques. Development of a novel injectable probe for in vivo thrombin detection in advanced atherosclerotic plaques with high spatial resolution. Probe may be further developed for whole body and intraoperative imaging.
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title In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activityElectronic supplementary information (ESI) available. See DOI: 10.1039/c2ib00161f
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