Method for Enhancing Cell Penetration of Gd3+-based MRI Contrast Agents by Conjugation with Hydrophobic Fluorescent Dyes
Method for Enhancing Cell Penetration of Gd3+-based MRI Contrast Agents by Conjugation with Hydrophobic Fluorescent Dyes
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DOI：
10.1021/bc200127t
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发表时间：
2011-11-01
影响因子：
4.7
通讯作者：
Nagano, Tetsuo
中科院分区：
文献类型：
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作者：
Yamane, Takehiro;Hanaoka, Kenjiro;Nagano, Tetsuo
钆离子 (Gd3+) 复合物通常用作磁共振成像 (MRI) 造影剂，以增强 T-1 加权 MR 图像中的信号。最近，已经报道了几种实现 Gd3+ 复合物细胞渗透的方法，但需要更通用和有效的方法。在本报告中，我们描述了一种通过使用疏水性荧光染料作为细胞渗透性增强单元来实现 Gd3+ 复合物细胞渗透的新方法。我们合成了与二吡咯亚甲基硼 (BDP-Gd) 和 Cy7 染料 (Cy7-Gd) 缀合的 Gd3+ 复合物，并表明这些缀合物可以有效地引入细胞中。为了研究细胞通透性与染料结构之间的关系，我们进一步合成了一系列Cy7-Gd衍生物。根据对装载 Cy7-Gd 衍生物的细胞进行 MR 成像、流式细胞术和 ICP-MS 分析，高度疏水性和非阴离子染料可有效增强 Gd3+ 复合物的细胞渗透。此外，还在小鼠中检查了这些 Cy7-Gd 衍生物的行为。因此，疏水性荧光染料的缀合似乎是提高 Gd3+ 复合物细胞渗透性的有效方法，并且应该适用于基于 Gd3+ 的 MRI 造影剂的进一步开发。
Gadolinium ion (Gd3+) complexes are commonly used as magnetic resonance imaging (MRI) contrast agents to enhance signals in T-1-weighted MR images. Recently, several methods to achieve cell-permeation of Gd3+ complexes have been reported, but more general and efficient methodology is needed. In this report, we describe a novel method to achieve cell permeation of Gd3+ complexes by using hydrophobic fluorescent dyes as a cell-permeability-enhancing unit. We synthesized Gd3+ complexes conjugated with boron dipyrromethene (BDP-Gd) and Cy7 dye (Cy7-Gd), and showed that these conjugates can be introduced efficiently into cells. To examine the relationship between cell permeability and dye structure, we further synthesized a series of Cy7-Gd derivatives. On the basis of MR imaging, flow cytometry, and ICP-MS analysis of cells loaded with Cy7-Gd derivatives, highly hydrophobic and nonanionic dyes were effective for enhancing cell permeation of Gd3+ complexes. Furthermore, the behavior of these Cy7-Gd derivatives was examined in mice. Thus, conjugation of hydrophobic fluorescent dyes appears to be an effective approach to improve the cell permeability of Gd3+ complexes, and should be applicable for further development of Gd3+-based MRI contrast agents.