Novel solubility‐switchable MRI agent allows the noninvasive detection of matrix metalloproteinase‐2 activity in vivo in a mouse model

作者：Réjean Lebel, Beata Jastrzębska, Hélène Therriault, Marie‐Michèle Cournoyer, J. Oliver McIntyre, Emanuel Escher, Witold A. Neugebauer, Benoît Paquette, Martin D. Lepage · 发表于：Magnetic Resonance in Medicine · 年份：2008 · DOI：10.1002/mrm.21741 · 被引用次数：51 · 研究领域：Protease and Inhibitor Mechanisms、Peptidase Inhibition and Analysis、Cell Adhesion Molecules Research

A novel MRI proteinase-modulated contrast agent (PCA) was developed to detect the activity of the proinvasive enzyme matrix metalloproteinase-2 (MMP-2) in vivo. The PCA2-switch agent incorporates a solubility switch, where cleavage of a peptide substrate by MMP-2 decreases the water solubility of the agent. Evidence suggests that this leads to an accumulation of cleaved PCA2-switch in an MMP-2-positive, wild-type, MC7-L1 mammary carcinoma tumor in a Balb/c mouse model compared to a MC7-L1 MMP-2-knockdown tumor. When a scrambled peptide sequence is inserted into the agent (PCA2-scrambled), the in vitro cleavage efficiency of MMP-2 is markedly reduced. In vivo, PCA2-scrambled does not accumulate in the wild-type tumor and the pharmacokinetics is similar in both tumors. In conclusion, in vivo cleavage of PCA2-switch by MMP-2 results in a significant accumulation of the cleaved PCA2-switch in an MMP-2-positive tumor.