Modification of Gd-DTPA cystine copolymers with PEG-1000 optimizes pharmacokinetics and tissue retention for magnetic resonance angiography
Modification of Gd-DTPA cystine copolymers with PEG-1000 optimizes pharmacokinetics and tissue retention for magnetic resonance angiography
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DOI：
10.1002/mrm.21270
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发表时间：
2007-07-01
影响因子：
3.3
通讯作者：
Lu, Zheng-Rong
中科院分区：
文献类型：
--
作者：
Mohs, Aaron M.;Nguyen, Thanh;Lu, Zheng-Rong
本研究的目的是研究新型可生物降解的大分子聚二硫化物Gd（III）配合物，二乙烯三胺五乙酸钆（GdDTPA）胱氨酸共聚物（GDCP）的聚乙二醇化对其药代动力学和Gd（III）长期组织保留的影响，并证明聚乙二醇化GDCP（PEG-GDCP）在MR血管造影（MRA）中的潜在应用。在Sprague-Dawley大鼠中研究了三种不同PEG接枝度的PEG（1000）-GDCP（42.1-52.1 kDa; PEG：MW = 1000 Da）和GDCP（43.3 kDa）的药代动力学、生物分布和代谢排泄。通过开放二室模型分析药代动力学数据。最初，所有三种PEG（1000）-GDCP造影剂（CA）的血浆浓度均高于GDCP，但30分钟后，PEG化造影剂的Gd（III）浓度迅速下降，导致消除半衰期值显著降低。所有生物可降解的大分子CA都表现出较低的长期Gd（III）组织蓄积，而PEG（1000）-GDCP在肝脏中的蓄积显著低于GDCP。在大鼠中，所有CA在长图像采集时间的MRA协议中显示出良好的血管对比度增强。由于PEG（1000-）GDCP在有效的对比增强（CE）-MRA中在可接受的时间内保留在血管内，然后以最小的组织滞留从血管系统中迅速排出，因此PEG（1000-）GDCP显示出作为MRA的血池CA的巨大前景。Magn Reson Med 58：110-118，2007. (c)2007 Wiley-Liss，Inc.
The purpose of this study was to investigate the effect of PEGylation of novel biodegradable macromolecular polydisulfide Gd(III) complexes, gadolinium diethylenetriaminepentaacetate (GdDTPA) cystine copolymers (GDCP), on their pharmacokinetics and long-term Gd(Ill) tissue retention, and to demonstrate the potential application of PEGylated GDCP (PEG-GDCP) for MR angiography (MRA). The pharmacokinetics biodistribution, and metabolic excretion of PEG(1000)-GDCP (42.1-52.1 kDa; PEG: MW = 1000 Da) with three different PEG grafting degrees and GDCP (43.3 kDa) were investigated in Sprague-Dawley rats. Pharmacokinetic data were analyzed by means of an open two-compartment model. Initially all three PEG(1000)-GDCP contrast agents (CAs) had a higher plasma concentration than GDCP, but after 30 min the Gd(III) concentration from the PEGylated agents rapidly decreased, resulting in significantly lower elimination half-life values. All of the biodegradable macromolecular CAs demonstrated low long-term Gd(III) tissue accumulation, while PEG(1000)-GDCP had significantly lower accumulation in the liver than GDCP. In the rats, all CAs showed excellent vascular contrast enhancement in an MRA protocol with a long image acquisition time. Because PEG(1000-)GDCP remained intravascular for an acceptable period for effective contrast-enhanced (CE)-MRA, and then excreted rapidly from the vasculature with minimal tissue retention, PEG(1000-)GDCP shows a great promise as a blood-pool CA for MRA. Magn Reson Med 58:110-118, 2007. (c) 2007 Wiley-Liss, Inc.