Noninvasive detection of matrix metalloproteinase activity in vivo using a novel magnetic resonance imaging contrast agent with a solubility switch.
We have developed novel proteinase-modulated contrast agents (PCAs) to detect the activity of proteinases in vivo using magnetic resonance imaging. The PCAs are based on the concept of a solubility switch, from hydrophilic to hydrophobic, that significantly modifies the pharmacokinetic properties of the agent as revealed by the slow efflux kinetics from the activity site. Our compound PCA7-switch detects the activity of the secreted matrix-degrading proteinase matrix-metalloproteinase 7 (MMP-7) in living, tumor-bearing mice. Control experiments were performed using an agent that was not cleaved by MMP-7 (PCA7-scrambled), an agent that could be cleaved by MMP-7 but lacked the solubility switch (PCA7-B), and a standard contrast agent (gadolinium-diethylenetriaminepentaacetic acid). PCA7-switch detected a reduction in MMP-7 activity in tumor-bearing mice treated with a synthetic MMP inhibitor, demonstrating its effectiveness in noninvasive functional imaging of proteolytic activity in vivo.
Lepage
Martin
M
Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA. Maritn.Lepage@USherbrooke.ca
Dow
William C
WC
Melchior
Marco
M
You
Ying
Y
Fingleton
Barbara
B
Quarles
C Chad
CC
Pépin
Claude
C
Gore
John C
JC
Matrisian
Lynn M
LM
McIntyre
J Oliver
JO
D000818:Animals; D003287:Contrast Media / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D012995:Solubility; D014407:Tumor Cells, Cultured
D003287:Contrast Media; D020782:Matrix Metalloproteinases; D020783:Matrix Metalloproteinase 7