Abstract
BackgroundFibrosis, which is characterized by the pathological accumulation of collagen, is recognized as an important feature of many chronic diseases, and as such, constitutes an enormous health burden. We need non-invasive specific methods for the early diagnosis and follow-up of fibrosis in various disorders. Collagen targeting molecules are therefore of interest for potential in vivo imaging of fibrosis. In this study, we developed a collagen-specific probe using a new approach that takes advantage of the inherent specificity of Glycoprotein VI (GPVI), the main platelet receptor for collagens I and III.Methodology/Principal FindingsAn anti-GPVI antibody that neutralizes collagen-binding was used to screen a bacterial random peptide library. A cyclic motif was identified, and the corresponding peptide (designated collagelin) was synthesized. Solid-phase binding assays and histochemical analysis showed that collagelin specifically bound to collagen (Kd 10−7 M) in vitro, and labelled collagen fibers ex vivo on sections of rat aorta and rat tail. Collagelin is therefore a new specific probe for collagen. The suitability of collagelin as an in vivo probe was tested in a rat model of healed myocardial infarctions (MI). Injecting Tc-99m-labelled collagelin and scintigraphic imaging showed that uptake of the probe occurred in the cardiac area of rats with MI, but not in controls. Post mortem autoradiography and histological analysis of heart sections showed that the labeled areas coincided with fibrosis. Scintigraphic molecular imaging with collagelin provides high resolution, and good contrast between the fibrotic scars and healthy tissues. The capacity of collagelin to image fibrosis in vivo was confirmed in a mouse model of lung fibrosis.Conclusion/SignificanceCollagelin is a new collagen-targeting agent which may be useful for non-invasive detection of fibrosis in a broad spectrum of diseases.
Highlights
Collagen, a major component of the extracellular matrix (ECM), is one of the determinants of tissue structure
Fibrosis is characterized by the pathological accumulation of collagen, and is increasingly recognized as an important feature of many chronic diseases, and as such, represents an enormous health burden [1]
B–collagelin bound to collagen-coated plates, and this binding was completely inhibited in the presence of Glycoprotein VI (GPVI)-Fc or of 9O12.2 IgGs (Figure 2C), whereas the anti-GPVI monoclonal antibody 3J24.2, which binds to an epitope distinct from 9O12.2 [15], did not inhibit B-collagelin interaction with collagen. These results demonstrate that collagelin and GPVI bind to sites on collagen that must overlap or be identical
Summary
A major component of the extracellular matrix (ECM), is one of the determinants of tissue structure. Functional tests are currently used to assess the degree to which organs are affected, but functional impairment only occurs in the presence of a relatively high degree of fibrosis This means that we still need non-invasive specific methods for the early diagnosis and follow-up of fibrosis in many disorders in which fibrosis is of major prognostic interest. Molecular imaging of cardiac fibrosis was reported using radiotracers specific for targets co-expressed or co-located with fibrosis in patients and mice with post-infarction cardiomyopathy: 18F-fluorobenzoyl-lisinopril specific for angiotensin-converting enzyme [5], Tc-99m losartan specific for angiotensinII receptors [6], 99mTc-Cy5.5 RGD imaging peptide targeting proliferating myofibroblats [7,8] Such indirect tracers are not adapted to all clinical situations involving fibrosis, because of different physiopathology and the need to detect fibrosis as well as fibrogenesis. We developed a collagen-specific probe using a new approach that takes advantage of the inherent specificity of Glycoprotein VI (GPVI), the main platelet receptor for collagens I and III
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