Micro-MR angiography of normal and intratumoral vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: reference to pharmacokinetic properties of dendrimer-based MR contrast agents.
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)(2(x+2)) 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 microm 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.
Kobayashi
H
H
Department of Diagnostic and Interventional Imagiology, Kyoto University, Kyoto, Japan. hisataka@kuhp.kyoto-u.ac.jp
Kawamoto
S
S
Saga
T
T
Sato
N
N
Hiraga
A
A
Konishi
J
J
Togashi
K
K
Brechbiel
M W
MW
D000704:Analysis of Variance; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000493:pharmacokinetics; D001808:Blood Vessels / Q000033:anatomy & histology*; D002460:Cell Line; D003287:Contrast Media / Q000737:chemistry* / Q000493:pharmacokinetics*; D050091:Dendrimers; D019786:Gadolinium DTPA / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D018810:Magnetic Resonance Angiography; D051379:Mice; D023421:Models, Animal; D008970:Molecular Weight; D011073:Polyamines / Q000737:chemistry* / Q000493:pharmacokinetics*
D001672:Biocompatible Materials; D003287:Contrast Media; D050091:Dendrimers; C117777:Gd(DTPA-BBA); C104700:PAMAM Starburst; D011073:Polyamines; D019786:Gadolinium DTPA