Novel Gd(III)-based probes for MR molecular imaging of matrix metalloproteinases

Concetta V. Gringeri, Valeria Menchise, Silvia Rizzitelli, Evelina Cittadino, Valeria Catanzaro, Gabriele Dati, Linda Chaabane, Giuseppe Digilio, Silvio Aime

Research output: Contribution to journalArticlepeer-review


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 670μ m respectively) and for serum albumin (K D 350 and 90μ 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.

Original languageEnglish
Pages (from-to)175-184
Number of pages10
JournalContrast Media and Molecular Imaging
Issue number2
Publication statusPublished - Mar 2012


  • Contrast agent
  • Gadolinium
  • Matrix metalloproteinase
  • Mouse melanoma
  • MRI
  • Tumor

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging


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