title: Novel Gd(III)-based probes for MR molecular imaging of matrix metalloproteinases.
abstract: Two novel Gd-based contrast agents (CAs) for the molecular imaging of matrix metalloproteinases (MMPs) were synthetized and characterized in vitro and in vivo. These probes were based on the PLG*LWAR peptide sequence, known to be hydrolyzed between Gly and Leu by a broad panel of MMPs. A Gd-DOTA chelate was conjugated to the N-terminal position through an amide bond, either directly to proline (compd Gd-K11) or through a hydrophilic spacer (compd Gd-K11N). Both CA were made strongly amphiphilic by conjugating an alkyl chain at the C-terminus of the peptide sequence. Gd-K11 and Gd-K11N have a good affinity for β-cyclodextrins (K(D) 310 and 670 µ m respectively) and for serum albumin (K(D) 350 and 90 µ m respectively), and can be efficiently cleaved in vitro at the expected site by MMP-2 and MMP-12. Upon MMP-dependent cleavage, the CAs lose the C-terminal tetrapeptide and the alkyl chain, thus undergoing to an amphiphilic-to-hydrophilic transformation that is expected to alter tissue pharmacokinetics. To prove this, Gd-K11 was systemically administered to mice bearing a subcutaneous B16.F10 melanoma, either pre-treated or not with the broad spectrum MMP inhibitor GM6001 (Ilomastat). The washout of the Gd-contrast enhancement in MR images was significantly faster for untreated subjects (displaying MMP activity) with respect to treated ones (MMP activity inhibited). The washout kinetics of Gd-contrast enhancement from the tumor microenvironment could be then interpreted in terms of the local activity of MMPs.
authors.affiliation: Department of Environmental and Life Sciences, Università del Piemonte Orientale A. Avogadro, Viale T. Michel 11, 15121, Alessandria, Italy.
authors.forename: Concetta V
authors.initials: CV
authors.lastname: Gringeri
authors.forename: Valeria
authors.initials: V
authors.lastname: Menchise
authors.forename: Silvia
authors.initials: S
authors.lastname: Rizzitelli
authors.forename: Evelina
authors.initials: E
authors.lastname: Cittadino
authors.forename: Valeria
authors.initials: V
authors.lastname: Catanzaro
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dati
authors.forename: Linda
authors.initials: L
authors.lastname: Chaabane
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Digilio
authors.forename: Silvio
authors.initials: S
authors.lastname: Aime
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D004195:Disease Models, Animal; D005682:Gadolinium / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D057054:Molecular Imaging / Q000379:methods*; D015335:Molecular Probes / Q000378:metabolism*; D060327:Solid-Phase Synthesis Techniques
chemical_list: D015335:Molecular Probes; D005682:Gadolinium; D020782:Matrix Metalloproteinases