Wen Xiaoxia, Jackson Edward F, Price Roger E, Kim E Edmund, Wu Qingping, Wallace Sidney, Charnsangavej Chusilp, Gelovani Juri G, Li Chun
Department of Experimental Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Bioconjug Chem. 2004 Nov-Dec;15(6):1408-15. doi: 10.1021/bc049910m.
Most currently evaluated macromolecular contrast agents for magnetic resonance imaging (MRI) are not biodegradable. The goal of this study is to synthesize and characterize poly(l-glutamic acid) (PG) gadolinium chelates as biodegradable blood-pool MRI contrast agents. Two PG chelates of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) were synthesized through the use of difunctional and monofunctional DTPA precursors. The conjugates were characterized with regard to molecular weight and molecular weight distribution, gadolinium content, relaxivity, and degradability. Distributions of the polymeric MRI contrast agents in various organs were determined by intravenous injection of (111)In-labeled polymers into mice bearing murine breast tumors. MRI scans were performed at 1.5 T in mice after bolus injection of the polymeric chelates. PG-Hex-DTPA-Gd, obtained from aminohexyl-substituted PG and DTPA-dianhydride, was partially cross-linked and was undegradable in the presence of cathepsin B. On the other hand, PG-Bz-DTPA-Gd synthesized directly from PG and monofunctional p-aminobenzyl-DTPA(acetic acid-tert-butyl ester) was a linear polymer and was degradable. The relaxivities of the polymers at 1.5 T were 3-8 times as great as that of Gd-DTPA. Both polymers had high blood concentrations and were primarily accumulated in the kidney. However, PG-Bz-DTPA-Gd was gradually cleared from the body and had significantly less retention in the blood, the spleen, and the kidney. MRI with PG-Bz-DTPA-Gd in mice showed enhanced vascular contrast at up to 2 h after the contrast agent injection. The ability of PG-Bz-DTPA-Gd to be degraded and cleared from the body makes it a favorable macromolecular MRI contrast agent.
目前大多数用于磁共振成像（MRI）评估的大分子造影剂都不可生物降解。本研究的目的是合成并表征聚（L-谷氨酸）（PG）钆螯合物，作为可生物降解的血池MRI造影剂。通过使用双功能和单功能二乙三胺五乙酸（DTPA）前体合成了两种钆二乙三胺五乙酸（Gd-DTPA）的PG螯合物。对这些共轭物的分子量和分子量分布、钆含量、弛豫率和可降解性进行了表征。通过将（111）In标记的聚合物静脉注射到患有小鼠乳腺肿瘤的小鼠体内，测定了聚合物MRI造影剂在各个器官中的分布。在静脉注射聚合物螯合物后，对小鼠进行1.5T的MRI扫描。由氨基己基取代的PG和二酐DTPA制得的PG-Hex-DTPA-Gd部分交联，在组织蛋白酶B存在下不可降解。另一方面，直接由PG和单功能对氨基苄基-DTPA（乙酸叔丁酯）合成的PG-Bz-DTPA-Gd是一种线性聚合物，可降解。聚合物在1.5T时的弛豫率是Gd-DTPA的3-8倍。两种聚合物都有较高的血药浓度，主要蓄积在肾脏。然而，PG-Bz-DTPA-Gd从体内逐渐清除，在血液、脾脏和肾脏中的滞留量明显较少。在小鼠中用PG-Bz-DTPA-Gd进行MRI显示，在注射造影剂后长达2小时内血管对比度增强。PG-Bz-DTPA-Gd可降解并从体内清除的特性使其成为一种理想的大分子MRI造影剂。
