Department of Chemistry, University of California, Berkeley, California 94720, USA.
J Am Chem Soc. 2011 Mar 2;133(8):2390-3. doi: 10.1021/ja110582e. Epub 2011 Feb 4.
One essential requirement for more sensitive gadolinium-based MRI contrast agents is to slow the molecular tumbling of the gadolinium(III) ion, which increases the gadolinium's relaxivity (i.e., its ability to speed up the NMR relaxation of nearby water molecules). One route to this is through conjugation to high-molecular-weight polymers such as dendrimers. In this work, amine-functionalized TREN-bis(1,2-HOPO)-TAM-ethylamine and TREN-bis(1-Me-3,2-HOPO)-TAM-ethylamine ligands have been synthesized and attached to biocompatible 40 kDa esteramide (EA)- and poly-l-lysine (PLL)-based dendrimers capable of binding up to eight gadolinium complexes. These conjugates have T(1) relaxivities of up to 38.14 ± 0.02 mM(-1) s(-1) per gadolinium at 37 °C, corresponding to relaxivities of up to 228 mM(-1) s(-1) per dendrimer molecule. This relaxivity expressed on a "per Gd" basis is several times that of the small-molecule complexes and an order of magnitude higher than that of current commercial agents. Because of their high performance and low toxicity, these macromolecules may constitute an attractive complement to currently available gadolinium(III)-based contrast agents.
对于更灵敏的基于钆的 MRI 造影剂，一个必要的要求是减缓钆（III）离子的分子旋转，这会增加钆的弛豫率（即其加速附近水分子 NMR 弛豫的能力）。实现这一目标的一种方法是通过与高分子量聚合物如树枝状聚合物结合。在这项工作中，合成了伯胺功能化的 TREN-双（1,2-HOPO）-TAM-乙胺和 TREN-双（1-Me-3,2-HOPO）-TAM-乙胺配体，并将其连接到具有生物相容性的 40 kDa 酯酰胺（EA）和聚-L-赖氨酸（PLL）基树枝状聚合物上，这些树枝状聚合物能够结合多达 8 个钆配合物。这些缀合物在 37°C 时的 T(1)弛豫率高达每钆 38.14±0.02 mM(-1) s(-1)，相当于每树枝状聚合物分子高达 228 mM(-1) s(-1)的弛豫率。这种基于“每 Gd”的弛豫率是小分子配合物的数倍，比当前商业制剂的弛豫率高一个数量级。由于其高性能和低毒性，这些大分子可能成为现有基于钆（III）的造影剂的一个有吸引力的补充。
