In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity

Emilia S. Olson, Michael A. Whitney, Beth Friedman, Todd A. Aguilera, Jessica L. Crisp, Fred M. Baik, Tao Jiang, Stephen M. Baird, Sotirios Tsimikas, Roger Y. Tsien, Quyen T. Nguyen

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)595-605
Number of pages11
JournalIntegrative Biology (United Kingdom)
Volume4
Issue number6
DOIs
StatePublished - Dec 1 2012

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Cell-Penetrating Peptides
Optical Imaging
Atherosclerotic Plaques
Thrombin
Fluorescence
Imaging techniques
Peptide Hydrolases
Coagulation
PAR-1 Receptor
Hirudins
Molecular imaging
Molecular Imaging
Matrix Metalloproteinases
Tumors
Atherosclerosis

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

Cite this

In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity. / 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.

In: Integrative Biology (United Kingdom), Vol. 4, No. 6, 01.12.2012, p. 595-605.

Research output: Contribution to journalArticle

Olson, ES, Whitney, MA, Friedman, B, Aguilera, TA, Crisp, JL, Baik, FM, Jiang, T, Baird, SM, Tsimikas, S, Tsien, RY & Nguyen, QT 2012, 'In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity', Integrative Biology (United Kingdom), vol. 4, no. 6, pp. 595-605. https://doi.org/10.1039/c2ib00161f
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. / In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity. In: Integrative Biology (United Kingdom). 2012 ; Vol. 4, No. 6. pp. 595-605.
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