New enzyme-activated solubility-switchable contrast agent for magnetic resonance imaging: from synthesis to in vivo imaging.
We designed and synthesized a novel contrast agent (CA) to image the activity of matrix metalloproteinase-2 (MMP-2) in a tumor, noninvasively using magnetic resonance imaging (MRI). We exploited the concept of solubility-switchable CAs in the design of a protease-modulated CA (PCA), referred to as PCA2-switch. This PCA contains a paramagnetic gadolinium chelate (Gd-DOTA), which was attached to the N-terminus of a MMP-2 cleavable peptide sequence via a hydrophobic chain. The aqueous solubility of the CA depends on the presence of a polyethylene glycol chain (PEG) on the C-terminus of the peptide. Upon proteolytic cleavage of the peptide by MMP-2, the PEG chain is detached from the CA, which becomes less water soluble. This compound and control compounds were successfully tested in an animal model bearing two tumors with different levels of MMP-2 activity.
Jastrzebska
Beata
B
Centre d'Imagerie Moleculaire de Sherbrooke and Department of Nuclear Medicine and Radiobiology, Universite de Sherbrooke, 3001 12e Avenue Nord, Sherbrooke, Quebec J1H 5N4, Canada.
Lebel
Réjean
R
Therriault
Hélène
H
McIntyre
J Oliver
JO
Escher
Emanuel
E
Guérin
Brigitte
B
Paquette
Benoit
B
Neugebauer
Witold A
WA
Lepage
Martin
M
D000818:Animals; D003287:Contrast Media; D006571:Heterocyclic Compounds; D008279:Magnetic Resonance Imaging; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D009374:Neoplasms, Experimental / Q000201:enzymology; D009942:Organometallic Compounds; D012995:Solubility; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D020778:Matrix Metalloproteinase 2