Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
Bioconjug Chem. 2011 May 18;22(5):931-7. doi: 10.1021/bc100573t. Epub 2011 Apr 19.
Because of the recent observation of the toxic side effects of Gd(III) based MRI contrast agents in patients with impaired renal function, there is strong interest on developing alternative contrast agents for MRI. In this study, macrocyclic Mn(II) chelates were conjugated to nanoglobular carriers, lysine dendrimers with a silsesquioxane core, to synthesize non-Gd(III) based MRI contrast agents. A generation 3 nanoglobular conjugate of Mn(II)-1,4,7-triaazacyclononane-1,4,7-triacetate-GA amide (G3-NOTA-Mn) was also synthesized and evaluated. The per ion T(1) and T(2) relaxivities of G2, G3, G4 nanoglobular Mn(II)-DOTA monoamide conjugates decreased with increasing generation of the carriers. The T(1) relaxivities of G2, G3, and G4 nanoglobular Mn(II)-DOTA conjugates were 3.3, 2.8, and 2.4 mM(-1) s(-1) per Mn(II) chelate at 3 T, respectively. The T(1) relaxivity of G3-NOTA-Mn was 3.80 mM(-1) s(-1) per Mn(II) chelate at 3 T. The nanoglobular macrocyclic Mn(II) chelate conjugates showed good in vivo stability and were readily excreted via renal filtration. The conjugates resulted in much less nonspecific liver enhancement than MnCl(2) and were effective for contrast-enhanced tumor imaging in nude mice bearing MDA-MB-231 breast tumor xenografts at a dose of 0.03 mmol Mn/kg. The nanoglobular macrocyclic Mn(II) chelate conjugates are promising nongadolinium based MRI contrast agents.
由于最近观察到肾功能受损患者的 Gd(III) 型磁共振成像对比剂的毒副作用，因此人们强烈希望开发替代磁共振成像的对比剂。在这项研究中，将大环锰(II)螯合物与纳米球蛋白载体（具有硅倍半氧烷核的赖氨酸树枝状大分子）连接起来，以合成非 Gd(III) 型磁共振成像对比剂。还合成并评价了 Mn(II)-1,4,7-三氮杂环壬烷-1,4,7-三乙酸-GA 酰胺（G3-NOTA-Mn）的第三代纳米球蛋白轭合物。随着载体代数的增加，G2、G3、G4 纳米球蛋白 Mn(II)-DOTA 单酰胺轭合物的每个离子的 T(1)和 T(2)弛豫率降低。G2、G3 和 G4 纳米球蛋白 Mn(II)-DOTA 轭合物在 3 T 时的 T(1)弛豫率分别为 3.3、2.8 和 2.4 mM(-1) s(-1) per Mn(II)螯合物。在 3 T 时，G3-NOTA-Mn 的 T(1)弛豫率为 3.80 mM(-1) s(-1) per Mn(II)螯合物。纳米球蛋白大环锰(II)螯合物轭合物在体内显示出良好的稳定性，并且易于通过肾脏过滤排泄。与 MnCl(2)相比，这些轭合物引起的非特异性肝增强作用要小得多，并且在剂量为 0.03 mmol Mn/kg 时，对荷 MDA-MB-231 乳腺癌异种移植瘤的裸鼠的肿瘤增强成像有效。纳米球蛋白大环锰(II)螯合物轭合物是很有前途的非钆基磁共振成像对比剂。
