Abstract
Pharmacokinetic characteristics of intravascular macromolecular magnetic resonance imaging (MRI) contrast agents with polyamidoamine dendrimer cores smaller than generation‐7 were previously studied in the literature. To evaluate the effects of greater hepatic uptake on the pharmacokinetics of the larger generation dendrimers, the MRI contrast agents GxD‐(1B4M‐Gd) were synthesized with generation‐7, ‐8, and ‐9 polyamidoamine dendrimers and 2‐(p‐isothiocyanatobenzyl)‐6‐methyl‐diethylenetriaminepentaacetic acid (1B4M). Their pharmacokinetic characteristics in mice were compared with that of G6D‐(1B4M‐Gd)~256~. In biodistribution and dynamic micro‐MRI studies, significantly less renal accumulation of G7D‐(1B4M‐Gd)~512~, G8D‐(1B4M‐Gd)~1024~, and G9D‐(1B4M‐Gd)~2048~ was shown compared to G6D‐(1B4M‐Gd)~256~ (P < 0.01). There was a significantly greater accumulation of G8D‐(1B4M‐Gd)~1024~ and G9D‐(1B4M‐Gd)~2048~ in the liver compared to G6D‐(1B4M‐Gd)~256~ and G7D‐(1B4M‐Gd)~512~ (P < 0.01). The highest blood retention of all dendrimer‐based MRI contrast agents was exhibited by G7D‐(1B4M‐Gd)~512~ (P < 0.01). The normal and intratumoral fine vessels of approximately 100 μm diameter were visualized in normal or tumor‐bearing mice by high resolution three‐dimensional‐micro‐MR angiographs with G7D‐(1B4M‐Gd)~512~ and G8D‐(1B4M‐Gd)~1024~ with good vessel‐to‐soft tissue contrast. In summary, increased accumulation in the liver with concomitant decreased uptake in the kidney was caused by increased molecular sizes of the dendrimer‐based MRI contrast agents. J. Magn. Reson. Imaging 2001;14:705–713. © 2001 Wiley‐Liss, Inc.