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Sci Rep. 2016 Dec 5;6:38345. doi: 10.1038/srep38345.

Optical imaging of MMP-12 active form in inflammation and aneurysm.

Author information

1
Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT USA.
2
Veterans Affairs Connecticut Healthcare System, West Haven, CT USA.
3
Commissariat à l'Energie Atomique, iBiTec-S, Service d'Ingénierie Moléculaire de Protéines, CE-Saclay, 91191 Gif -sur-Yvette cedex, France.
4
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis, Zografou, 15771, Athens, Greece.

Abstract

Matrix metalloproteinase (MMP)-12 plays a key role in the development of aneurysm. Like other members of MMP family, MMP-12 is produced as a proenzyme, mainly by macrophages, and undergoes proteolytic activation to generate an active form. Accordingly, molecular imaging of the MMP-12 active form can inform of the pathogenic process in aneurysm. Here, we developed a novel family of fluorescent probes based on a selective MMP-12 inhibitor, RXP470.1 to target the active form of MMP-12. These probes were stable in complex media and retained the high affinity and selectivity of RXP470.1 for MMP-12. Amongst these, probe 3 containing a zwitterionic fluorophore, ZW800-1, combined a favorable affinity profile toward MMP-12 and faster blood clearance. In vivo binding of probe 3 was observed in murine models of sterile inflammation and carotid aneurysm. Binding specificity was demonstrated using a non-binding homolog. Co-immunostaining localized MMP-12 probe binding to MMP-12 positive areas and F4/80 positive macrophages in aneurysm. In conclusion, the active form of MMP-12 can be detected by optical imaging using RXP470.1-based probes. This is a valuable adjunct for pathophysiology research, drug development, and potentially clinical applications.

PMID:
27917892
PMCID:
PMC5137160
DOI:
10.1038/srep38345
[Indexed for MEDLINE]
Free PMC Article

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