In vivo molecular target assessment of matrix metalloproteinase inhibition

A number of different matrix metalloproteinase (MMP) inhibitors have been d eveloped as cytostatic and anti-angiogenic agents and are currently in clin ical 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-infrare d 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 M MP inhibitor, prinomastat (AC3340). The developed probes, together with nov el near-infrared fluorescence imaging technology will enable the detailed a nalysis of a number of proteinases critical for advancing the therapeutic u se of clinical proteinase inhibitors.