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

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

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aneurysm / diagnostic imaging*
  • Aneurysm / immunology
  • Aneurysm / metabolism
  • Aneurysm / pathology
  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism
  • Carotid Arteries / diagnostic imaging*
  • Carotid Arteries / immunology
  • Carotid Arteries / metabolism
  • Carotid Arteries / pathology
  • Disease Models, Animal
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / metabolism
  • Gene Expression
  • Humans
  • Inflammation
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Matrix Metalloproteinase 12 / genetics
  • Matrix Metalloproteinase 12 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Optical Imaging / methods*
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Binding
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / metabolism
  • Sulfonic Acids / chemistry
  • Sulfonic Acids / metabolism

Substances

  • Antigens, Differentiation
  • Fluorescent Dyes
  • Matrix Metalloproteinase Inhibitors
  • Peptides
  • Quaternary Ammonium Compounds
  • RXP470.1 peptide
  • Sulfonic Acids
  • ZW800-1 compound
  • monocyte-macrophage differentiation antigen
  • MMP12 protein, human
  • Matrix Metalloproteinase 12