Non-invasive molecular imaging of fibrosis using a collagen-targeted peptidomimetic of the platelet collagen receptor glycoprotein VI.
BACKGROUND
Fibrosis, 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.


RESULTS
An 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.


CONCLUSIONS
Collagelin is a new collagen-targeting agent which may be useful for non-invasive detection of fibrosis in a broad spectrum of diseases.
Muzard
Julien
J
INSERM, U698, Hôpital Bichat, Paris, France.
Sarda-Mantel
Laure
L
Loyau
Stéphane
S
Meulemans
Alain
A
Louedec
Liliane
L
Bantsimba-Malanda
Claudie
C
Hervatin
Florence
F
Marchal-Somme
Joëlle
J
Michel
Jean Baptiste
JB
Le Guludec
Dominique
D
Billiald
Philippe
P
Jandrot-Perrus
Martine
M
D000818:Animals; D001011:Aorta / Q000378:metabolism; D015153:Blotting, Western; D003952:Diagnostic Imaging / Q000379:methods*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D066298:In Vitro Techniques; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000737:chemistry*; D011877:Radionuclide Imaging / Q000379:methods*; D051381:Rats; D013623:Tail / Q000378:metabolism
D010455:Peptides; D010980:Platelet Membrane Glycoproteins