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

Mahmoud Razavian,Fabrice Beau,Yunpeng Ye,Jiasheng Zhang,Dimitris Georgiadis,Jakub Toczek,Laurent Devel,Hye-Yeong Kim,Vincent Dive,Thomas Bordenave,Mehran M Sadeghi,Jae-Joon Jung,Jinah Han,Reza Golestani

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.

Highlights

Matrix metalloproteinase (MMP)-12 plays a key role in the development of aneurysm
We describe the development of the first MMP-12-targeted imaging probes and demonstrate their performance in murine models of sterile inflammation and aneurysm
MMP-12 plays an important role in the pathogenesis of aneurysm, atherosclerosis, chronic obstructive pulmonary disease and other pathologies and is under investigations as a therapeutic target[2,3,4,12,13,14,15,19]

Summary

Introduction

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. 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. Given the role of MMP-12 in aneurysm[12,13,14,15], MMP-12 imaging may provide unique information on the pathogenic process in this disease To this end, we developed a novel family of fluorescent probes based on RXP470.1, a highly specific MMP-12 inhibitor[16]. We developed a novel family of fluorescent probes based on RXP470.1, a highly specific MMP-12 inhibitor[16] These probes showed high affinity and selectivity for MMP-12 in vitro. The most promising probe was further evaluated for imaging of the active form of MMP-12 in murine models of sterile inflammation and aneurysm

Methods

Results

Conclusion