Synthesis and evaluation of globular Gd-DOTA-monoamide conjugates with precisely controlled nanosizes for magnetic resonance angiography.
Synthesis and evaluation of globular Gd-DOTA-monoamide conjugates with precisely controlled nanosizes for magnetic resonance angiography.
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DOI：
10.1021/bm800486c
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发表时间：
2008-10
影响因子：
6.2
通讯作者：
Lu, Zheng-Rong
中科院分区：
文献类型：
--
作者：
Kaneshiro, Todd Lyle;Jeong, Eun-Kee;Morrell, Glen;Parker, Dennis L.;Lu, Zheng-Rong
本研究的目的是设计和制备具有精确定义的球状结构的刚性造影剂，用于磁共振血管造影和肿瘤血管生成成像。第 1 代至第 3 代（Gd-DOTA-单酰胺）-聚-L-赖氨酸八聚倍半硅氧烷树枝状聚合物被制备为纳米球状 MRI 造影剂。纳米球状 Gd(III) 螯合物具有明确的致密球状结构，并且在其表面具有高负载量的 Gd-DOTA-单酰胺。 G1、G2和G3纳米球状MRI造影剂的尺寸分别约为2.0、2.4和3.2 nm。 G1、G2 和 G3 纳米球 MRI 造影剂的 T1 弛豫率在 3T 时分别约为 6.4、7.2 和 10.0 mM−1sec−1。纳米球状 MRI 造影剂在小鼠脉管系统内显示出尺寸依赖性的对比度增强，在 60 分钟的疗程后逐渐衰减至基线。 0.03 mmol-Gd/kg 的 G3 纳米球造影剂比较小的纳米球造影剂产生更显着和更持久的血管增强。 G3 剂还在低至 0.01 mmol-Gd/kg（常规临床剂量的 1/10）的剂量下对心脏和脉管系统提供显着且持久的对比增强。所有造影剂均观察到肿瘤显着增强。纳米球造影剂通过肾过滤清除并积聚在膀胱中，如动态 MR 图像所示。纳米球状 Gd(III) 螯合物是有效的血管内 MRI 造影剂，且剂量大幅降低。纳米球状 MRI 造影剂有望进一步用于 MR 血管造影和肿瘤血管生成的 MR 成像的临床前开发。
The purpose of this study was to design and prepare rigid contrast agents with a precisely defined globular structure for MR angiography and tumor angiogenesis imaging. Generations 1 through 3 (Gd-DOTA-monoamide)-poly-L-lysine octasilsesquioxane dendrimers were prepared as nanoglobular MRI contrast agents. The nanoglobular Gd(III) chelates had a well-defined compact globular structure and high loading of Gd-DOTA-monoamide at their surface. The size of the G1, G2 and G3 nanoglobular MRI contrast agents was approximately 2.0, 2.4 and 3.2 nm, respectively. The T1 relaxivity of G1, G2 and G3 nanoglobular MRI contrast agents was approximately 6.4, 7.2, and 10.0 mM−1sec−1 at 3T, respectively. The nanoglobular MRI contrast agents showed size-dependent contrast enhancement within the mouse vasculature, which gradually decayed to baseline after a 60-min session. The G3 nanoglobular contrast agent resulted in more significant and prolonged vascular enhancement than the smaller nanoglobular agents at 0.03 mmol-Gd/kg. The G3 agent also provided significant and prolonged contrast enhancement in the heart and vasculature at a dose as low as 0.01 mmol-Gd/kg, 1/10th of the regular clinical dose. Significant enhancement was observed in tumor for all contrast agents. The nanoglobular contrast agents cleared via renal filtration and accumulated in the urinary bladder as shown in the dynamic MR images. The nanoglobular Gd(III) chelates are effective intravascular MRI contrast agents at substantially reduced doses. The nanoglobular MRI contrast agents are promising for further preclinical development for MR angiography and MR imaging of tumor angiogenesis.
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