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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aneurysm / diagnostic imaging*
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Aneurysm / immunology
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Aneurysm / metabolism
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Aneurysm / pathology
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism
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Carotid Arteries / diagnostic imaging*
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Carotid Arteries / immunology
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Carotid Arteries / metabolism
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Carotid Arteries / pathology
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Disease Models, Animal
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Fluorescent Dyes / chemistry
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Fluorescent Dyes / metabolism
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Gene Expression
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Humans
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Inflammation
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages / pathology
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Matrix Metalloproteinase 12 / genetics
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Matrix Metalloproteinase 12 / metabolism*
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Matrix Metalloproteinase Inhibitors / chemical synthesis
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Matrix Metalloproteinase Inhibitors / metabolism*
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Mice
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Mice, Inbred C57BL
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Optical Imaging / methods*
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Peptides / chemistry
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Peptides / metabolism
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Protein Binding
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Quaternary Ammonium Compounds / chemistry
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Quaternary Ammonium Compounds / metabolism
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Sulfonic Acids / chemistry
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Sulfonic Acids / metabolism
Substances
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Antigens, Differentiation
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Fluorescent Dyes
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Matrix Metalloproteinase Inhibitors
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Peptides
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Quaternary Ammonium Compounds
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RXP470.1 peptide
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Sulfonic Acids
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ZW800-1 compound
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monocyte-macrophage differentiation antigen
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MMP12 protein, human
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Matrix Metalloproteinase 12