Connexin 43-targeted T1 contrast agent for MRI diagnosis of glioma
Connexin 43-targeted T1 contrast agent for MRI diagnosis of glioma
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DOI：
10.1002/cmmi.1653
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发表时间：
2016-01-01
影响因子：
--
通讯作者：
Chekhonin, Vladimir
中科院分区：
文献类型：
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作者：
Abakumova, Tatiana;Abakumov, Maxim;Chekhonin, Vladimir
多形性胶质母细胞瘤是最具侵袭性的脑肿瘤。早期准确诊断胶质瘤及其边界是其成功治疗的重要环节。连接蛋白43（Cx43）是胶质瘤及其边缘选择性可视化的一个有前途的靶点，其在反应性星形胶质细胞和迁移性胶质瘤细胞中高度表达。本研究的目的是合成一种基于钆的造影剂与特异性抗体Cx43共轭，以有效地可视化胶质瘤C6在体内。我们已经制备了稳定的Cx43单克隆抗体和与Gd（III）络合的聚赖氨酸-DTPA配体的无毒缀合物，其特征在于比商业试剂Magnevist（R）（3.4 mM（-1）s（-1））更高的T-1弛豫率（在7 T下为6.5 mM（-1）s（-1））。通过流式细胞术和共聚焦分析检测到，胶质瘤C6细胞中Cx43特异性T-1造影剂的细胞摄取比非特异性IgG造影剂高4倍以上。MRI实验表明，所获得的代理人可以显着提高可视化胶质瘤C6在体内静脉给药后。Cx43靶向造影剂在胶质瘤和瘤周区域的显著积聚不仅导致增强的对比度，而且改善了肿瘤周边的检测。荧光成像证实，静脉注射后24小时，与非特异性IgG缀合物相比，Cx43特异性缀合物在瘤周区域中显著蓄积。Cx43靶向造影剂的这些特征可能有助于MRI对胶质瘤及其边界的更准确诊断。版权所有（c）2015约翰威利父子有限公司
Glioblastoma multiforme is the most aggressive form of brain tumor. Early and accurate diagnosis of glioma and its borders is an important step for its successful treatment. One of the promising targets for selective visualization of glioma and its margins is connexin 43 (Cx43), which is highly expressed in reactive astrocytes and migrating glioma cells. The purpose of this study was to synthesize a Gd-based contrast agent conjugated with specific antibodies to Cx43 for efficient visualization of glioma C6 in vivo. We have prepared stable nontoxic conjugates of monoclonal antibody to Cx43 and polylysine-DTPA ligands complexed with Gd(III), which are characterized by higher T-1 relaxivity (6.5 mM(-1) s(-1) at 7 T) than the commercial agent Magnevist (R) (3.4 mM(-1) s(-1)). Cellular uptake of Cx43-specific T-1 contrast agent in glioma C6 cells was more than four times higher than the nonspecific IgG-contrast agent, as detected by flow cytometry and confocal analysis. MRI experiments showed that the obtained agents could markedly enhance visualization of glioma C6 in vivo after their intravenous administration. Significant accumulation of Cx43-targeted contrast agents in glioma and the peritumoral zone led not only to enhanced contrast but also to improved detection of the tumor periphery. Fluorescence imaging confirmed notable accumulation of Cx43-specific conjugates in the peritumoral zone compared with nonspecific IgG conjugates at 24 h after intravenous injection. All these features of Cx43-targeted contrast agents might be useful for more precise diagnosis of glioma and its borders by MRI. Copyright (c) 2015 John Wiley & Sons, Ltd.