New concepts in molecular imaging: non-invasive MRI spotting of proteolysis using an Overhauser effect switch.
BACKGROUND
Proteolysis, involved in many processes in living organisms, is tightly regulated in space and time under physiological conditions. However deregulation can occur with local persistent proteolytic activities, e.g. in inflammation, cystic fibrosis, tumors, or pancreatitis. Furthermore, little is known about the role of many proteases, hence there is a need of new imaging methods to visualize specifically normal or disease-related proteolysis in intact bodies.


RESULTS
In this paper, a new concept for non invasive proteolysis imaging is proposed. Overhauser-enhanced Magnetic Resonance Imaging (OMRI) at 0.2 Tesla was used to monitor the enzymatic hydrolysis of a nitroxide-labeled protein. In vitro, image intensity switched from 1 to 25 upon proteolysis due to the associated decrease in the motional correlation time of the substrate. The OMRI experimental device used in this study is consistent with protease imaging in mice at 0.2 T without significant heating. Simulations show that this enzymatic-driven OMRI signal switch can be obtained at lower frequencies suitable for larger animals or humans.


CONCLUSIONS
The method is highly sensitive and makes possible proteolysis imaging in three dimensions with a good spatial resolution. Any protease could be targeted specifically through the use of taylor-made cleavable macromolecules. At short term OMRI of proteolysis may be applied to basic research as well as to evaluate therapeutic treatments in small animal models of experimental diseases.
Mellet
Philippe
P
INSERM IFR 004, and Magnetic Resonance Center CNRS UMR 5536 University Victor Segalen Bordeaux, Bordeaux, France. philippe.mellet@rmsb.u-bordeaux2.fr
Massot
Philippe
P
Madelin
Guillaume
G
Marque
Sylvain R A
SR
Harte
Etienne
E
Franconi
Jean-Michel
JM
Thiaudière
Eric
E
D000818:Animals; D002417:Cattle; D003545:Cysteine / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods; D006868:Hydrolysis; D008279:Magnetic Resonance Imaging / Q000379:methods*; D055641:Mathematical Concepts; D008954:Models, Biological; D009589:Nitrogen Oxides / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism
D009589:Nitrogen Oxides; D011506:Proteins; D012710:Serum Albumin, Bovine; D010447:Peptide Hydrolases; C039900:nitroxyl; D003545:Cysteine