Modification of Gd-DTPA cystine copolymers with PEG-1000 optimizes pharmacokinetics and tissue retention for magnetic resonance angiography.

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(III) 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.