In vivo molecular target assessment of matrix metalloproteinase inhibition.
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.
Bremer
C
C
Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
Tung
C H
CH
Weissleder
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D003952:Diagnostic Imaging; D005354:Fibrosarcoma / Q000188:drug therapy / Q000503:physiopathology; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000503:physiopathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009930:Organic Chemicals; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019265:Spectroscopy, Near-Infrared / Q000379:methods*
D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010455:Peptides; D011480:Protease Inhibitors; C113282:prinomastat; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2