title: Imaging of MMP activity in postischemic cardiac remodeling using radiolabeled MMP-2/9 activatable peptide probes.
abstract: The noninvasive imaging of matrix metalloproteinases (MMPs) activity in postischemic myocardial tissue holds great promise to predict cardiac function post-myocardial infarction. Consequently, development of MMP specific molecular imaging probes for noninvasive visualization and quantification of MMP activity is of great interest. A novel MMP imaging strategy is based on activatable cell-penetrating peptide probes (ACPP) that are sensitive to the proteolytic activity of MMP-2 and -9. The MMP-mediated activation of these ACPPs drives probe accumulation at the target site. The aim of this study was the development and characterization of radiolabeled MMP-2/9 sensitive ACPPs to assess MMP activity in myocardial remodeling in vivo. Specifically, a short and long-circulating MMP activatable cell-penetrating imaging probe (ACPP and Alb-ACPP, respectively; the latter is an ACPP modified with an albumin binding ligand that prolongs blood clearance) were successfully synthesized and radiolabeled. Subsequently, their biodistributions were determined in vivo in a Swiss mouse model of myocardial infarction. Both peptide probes showed a significantly higher uptake in infarcted myocardium compared to remote myocardium. The biodistribution for dual-isotope radiolabeled probes, which allowed us to discriminate between uncleaved ACPP and activated ACPP, showed increased retention of activated ACPP and activated Alb-ACPP in infarcted myocardium compared to remote myocardium. The enhanced retention correlated to gelatinase levels determined by gelatin zymography, whereas no correlation was found for the negative control: an MMP-2/9 insensitive non-ACPP. In conclusion, radiolabeled MMP sensitive ACPP probes enable to assess MMP activity in the course of remodeling post-myocardial infarction in vivo. Future research should evaluate the feasibility and the predictive value of the ACPP strategy for assessing MMP activity as a main player in postinfarction myocardial remodeling in vivo.
authors.affiliation: Department of Biomedical Engineering, Eindhoven University of Technology , 5656 Eindhoven, The Netherlands.
authors.forename: Sander M J
authors.initials: SM
authors.lastname: van Duijnhoven
authors.forename: Marc S
authors.initials: MS
authors.lastname: Robillard
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.forename: Michael T
authors.initials: MT
authors.lastname: Kuhlmann
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Klaas
authors.initials: K
authors.lastname: Nicolay
authors.forename: Holger
authors.initials: H
authors.lastname: Grüll
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry* / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry* / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D015335:Molecular Probes / Q000737:chemistry; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010455:Peptides / Q000737:chemistry
chemical_list: D015335:Molecular Probes; D010455:Peptides; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9