Burtea Carmen, Laurent Sophie, Murariu Oltea, Rattat Dirk, Toubeau Gérard, Verbruggen Alfons, Vansthertem David, Vander Elst Luce, Muller Robert N
Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons-Hainaut, 24, Avenue du Champ de Mars, B-7000 Mons, Belgium.
Cardiovasc Res. 2008 Apr 1;78(1):148-57. doi: 10.1093/cvr/cvm115. Epub 2008 Jan 3.
The integrin alpha v beta3 is highly expressed in atherosclerotic plaques by medial and intimal smooth muscle cells and by endothelial cells of angiogenic microvessels. In this study, we have assessed non-invasive molecular magnetic resonance imaging (MRI) of plaque-associated alpha v beta3 integrin expression on transgenic ApoE-/- mice with a low molecular weight peptidomimetic of Arg-Gly-Asp (mimRGD) grafted to gadolinium diethylenetriaminepentaacetate (Gd-DTPA-g-mimRGD). The analogous compound Eu-DTPA-g-mimRGD was employed for an in vivo competition experiment and to confirm the molecular targeting. The specific interaction of mimRGD conjugated to Gd-DTPA or to 99mTc-DTPA with alpha v beta3 integrin was furthermore confirmed on Jurkat T lymphocytes.
The mimRGD was synthesized and conjugated to DTPA. DTPA-g-mimRGD was complexed with GdCl3.6H2O, EuCl3.6H2O, or with [99mTc(CO)3(H2O)3]+. MRI evaluation was performed on a 4.7 T Bruker imaging system. Blood pharmacokinetics of Gd-DTPA-g-mimRGD were assessed in Wistar rats and in c57bl/6j mice. The presence of angiogenic blood vessels and the expression of alpha v beta3 integrin were confirmed in aorta specimens by immunohistochemistry. Gd-DTPA-g-mimRGD produced a strong enhancement of the external structures of the aortic wall and of the more profound layers (possibly tunica media and intima). The aortic lumen seemed to be restrained and distorted. Pre-injection of Eu-DTPA-g-mimRGD diminished the Gd-DTPA-g-mimRGD binding to atherosclerotic plaque and confirmed the specific molecular targeting. A slower blood clearance was observed for Gd-DTPA-g-mimRGD, as indicated by a prolonged elimination half-life and a diminished total clearance.
The new compound is potentially useful for the diagnosis of vulnerable atherosclerotic plaques and of other pathologies characterized by alpha v beta3 integrin expression, such as cancer and inflammation. The delayed blood clearance, the significant enhancement of the signal-to-noise ratio, and the low immunogenicity of the mimetic molecule highlight its potential for an industrial and clinical implementation.
整合素αvβ3在动脉粥样硬化斑块中的中膜和内膜平滑肌细胞以及新生微血管的内皮细胞中高表达。在本研究中，我们使用接枝到钆二乙三胺五乙酸（钆喷酸葡胺 - g - mimRGD）上的低分子量精氨酸 - 甘氨酸 - 天冬氨酸（mimRGD）肽模拟物，对转基因ApoE - / - 小鼠斑块相关的αvβ3整合素表达进行了非侵入性分子磁共振成像（MRI）评估。类似化合物铕 - DTPA - g - mimRGD用于体内竞争实验并确认分子靶向。此外，在Jurkat T淋巴细胞上证实了与钆喷酸葡胺或99m锝 - DTPA缀合的mimRGD与αvβ3整合素的特异性相互作用。
合成mimRGD并将其与DTPA缀合。DTPA - g - mimRGD与六水合氯化钆、六水合氯化铕或[99m锝（CO）3（H2O）3]+络合。在4.7 T布鲁克成像系统上进行MRI评估。在Wistar大鼠和c57bl / 6j小鼠中评估钆喷酸葡胺 - g - mimRGD的血液药代动力学。通过免疫组织化学在主动脉标本中证实新生血管的存在和αvβ3整合素的表达。钆喷酸葡胺 - g - mimRGD使主动脉壁的外部结构和更深层（可能是中膜和内膜）产生强烈增强。主动脉腔似乎受到限制和扭曲。预先注射铕 - DTPA - g - mimRGD减少了钆喷酸葡胺 - g - mimRGD与动脉粥样硬化斑块的结合，并证实了特异性分子靶向。如消除半衰期延长和总清除率降低所示，观察到钆喷酸葡胺 - g - mimRGD的血液清除较慢。
这种新化合物可能对诊断易损动脉粥样硬化斑块以及其他以αvβ3整合素表达为特征的病理状况（如癌症和炎症）有用。模拟分子的血液清除延迟、信噪比显著提高以及低免疫原性突出了其在工业和临床应用中的潜力。
