In vivo molecular target assessment of matrix metalloproteinase inhibition

Abstract

A number of different matrix metalloproteinase (MMP) inhibitors have been developed as cytostatic and anti-angiogenic agents and are currently in clinical testing. One major hurdle in assessing the efficacy of such drugs has been the inability to sense or image anti-proteinase activity directly and non-invasively in vivo. We show here that novel, biocompatible near-infrared fluorogenic MMP substrates can be used as activatable reporter probes to sense MMP activity in intact tumors in nude mice. Moreover, we show for the first time that the effect of MMP inhibition can be directly imaged using this approach within hours after initiation of treatment using the potent MMP inhibitor, prinomastat (AG3340). The developed probes, together with novel near-infrared fluorescence imaging technology will enable the detailed analysis of a number of proteinases critical for advancing the therapeutic use of clinical proteinase inhibitors.

In Vivo Near-Infrared Fluorescence Imaging of Matrix Metalloproteinase Activity after Cerebral Ischemia

“…Quenched NIRF probes were developed that become fluorescent through proteolytic cleavage by MMPs (Weissleder et al, 1999;Tung, 2004). Such MMP-activatable probes have the advantage of exhibiting low background fluorescence, and have been applied thus far in a variety of experimental disease models including cancer (Bremer et al, 2001) and cardiovascular diseases (Chen et al, 2005;Deguchi et al, 2006;Aikawa et al, 2007).…”

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

“…This approach has been used to monitor the inhibition of matrix metalloproteinase activity by activatable MRI probes that are cleaved by this enzyme. 35 Few ligands have been validated for imaging target inhibition in this way. Also, radiolabeling of drugs frequently does not provide useful imaging probes for monitoring target inhibition because uptake of the drug in the tumor can be dominated by nonspecific binding to the cell membrane or other cellular components.…”

Molecular imaging of gene therapy for cancer

“…Recent developments allow NIRF-MMP substrates to be used as activatable NIRF reporter probes to monitor MMP activity in intact tumors. 69 These probes have the advantage of directly imaging MMP activity within hours after treatment with potent MMP inhibitors.…”