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首页> 外文期刊>Chemistry: A European journal >Target visualization by MRI using the avidin/biotin amplification route: Synthesis and testing of a biotin-Gd-DOTA monoamide trimer
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Target visualization by MRI using the avidin/biotin amplification route: Synthesis and testing of a biotin-Gd-DOTA monoamide trimer

机译：使用抗生物素蛋白/生物素扩增途径通过MRI进行靶标可视化：生物素-Gd-DOTA单酰胺三聚体的合成和测试

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摘要

To design efficient targeting strategies in magnetic resonance (MR) molecular imaging applications, the formation of supramolecular adducts between (strept)avidin ((S)Av) and tribiotinylated Gd-DOTA-monoamide complexes (DOTA = 1,4,7,10-tetraazacyclododecane-N, N', N", N"'-tetraacetic acid) was explored. Two compounds based on the trivalent core of tris(2aminoethyl)amine each containing three biotin molecules and one (Ll) or three (L2) DOTA-monoamide (DOTAMA) ligands were synthesized. In these tribiotinylated derivatives the biotins are spaced far enough apart to allow the formation of the supramolecular adduct with the protein and to host the chelating units in between the (S)Av layers. Size exclusion HPLC analyses indicated complete formation of very high molecular weight polymers (>2MDa) with (S)Av in solution. A ~1H NMR spectroscopy relaxometric study on the obtained polymeric adducts showed a marked increase of the relaxivity at 35-40 MHz as a consequence of the lengthening of the tumbling time due to the formation of Gdchelates/(S)Av polymers. The most effi-cient Gd_3L2/(S)Av polymeric system was used for a test in cell cultures. The target is represented by a neural cell adhesion molecule (NCAM), which is overexpressed in Kaposi's sarcoma cells and tumor endothelial cells (TEC) and that is efficiently recognized by a biotinylated tetrameric peptide (C3dBio). In vitro experiments showed that only cells incubated with both C3d-Bio and Gd_3L2/SAv polymer were hyperintense with respect to the control. Relaxation rates of cell pellets incubated with Gd_3L2/SAv alone were not significantly different from the untreated cells demonstrating the absence of a specific binding.
机译：为了设计磁共振（MR）分子成像应用中的有效靶向策略，在（链）亲和素（（S）Av）和三生物素化的Gd-DOTA-单酰胺复合物（DOTA = 1,4,7,10-探索了四氮杂环十二烷-N，N'，N”，N”'-四乙酸。合成了基于三（2氨基乙基）胺的三价核心的两种化合物，每种化合物包含三个生物素分子和一个（L1）或三个（L2）DOTA-单酰胺（DOTAMA）配体。在这些三生物素化的衍生物中，生物素之间的间隔足够远，可以与蛋白质形成超分子加合物，并在（S）Av层之间容纳螯合单元。尺寸排阻HPLC分析表明在溶液中具有（S）Av的非常高分子量的聚合物（> 2MDa）的完全形成。对获得的聚合物加合物进行的〜1H NMR光谱弛豫研究显示，由于形成Gdchelates /（S）Av聚合物而延长了翻滚时间，因此在35-40 MHz处弛豫度显着增加。最有效的Gd_3L2 /（S）Av聚合物系统用于细胞培养。靶标由神经细胞粘附分子（NCAM）表示，该分子在卡波西氏肉瘤细胞和肿瘤内皮细胞（TEC）中过表达，并被生物素化的四聚体肽（C3dBio）有效识别。体外实验表明，仅与C3d-Bio和Gd_3L2 / SAv聚合物一起孵育的细胞相对于对照而言是超强的。单独与Gd_3L2 / SAv一起孵育的细胞沉淀的弛豫率与未处理的细胞无显着差异，表明不存在特异性结合。

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