Positive effects of polyethylene glycol conjugation to generation-4 polyamidoamine dendrimers as macromolecular MR contrast agents.
Macromolecules conjugated with polyethylene glycol (PEG) acquire more hydrophilicity, resulting in a longer half-life in circulation and lower immunogenicity. Two novel conjugates for MRI contrast agents were synthesized from a generation-4 polyamidoamine dendrimer (G4D), 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), and one or two PEG molecules with a molecular weight of 20000 Da (PEG(2)-G4D-(1B4M-Gd)(62) (MW: 96 kD), PEG(1)-G4D-(1B4M-Gd)(63) (MW: 77 kD)). Their pharmacokinetics, excretion, and properties as vascular MRI contrast agents were evaluated and compared with those of G4D-(1B4M-Gd)(64) (MW: 57 kD). PEG(2)-G4D-(1B4M-Gd)(62) remained in the blood significantly longer and accumulated significantly less in the liver and kidney than the other two preparations (P < 0.01). Although the blood clearance was slower, PEG(2)-G4D-(1B4M-Gd)(62) was excreted more readily without renal retention than the other two preparations. In conclusion, the positive effects of PEG conjugation on a macromolecular MRI contrast agent were found to be prolonged retention in the circulation, increased excretion, and decreased accumulation in the organs.
Kobayashi
H
H
Hitachi Medical Co. Chaired Department of Diagnostic and Interventional Imagiology, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto, Japan. hisataka@kuhp.kyoto-u.ac.jp
Kawamoto
S
S
Saga
T
T
Sato
N
N
Hiraga
A
A
Ishimori
T
T
Konishi
J
J
Togashi
K
K
Brechbiel
M W
MW
D000818:Animals; D001672:Biocompatible Materials / Q000493:pharmacokinetics*; D003287:Contrast Media / Q000493:pharmacokinetics*; D050091:Dendrimers; D005079:Excipients / Q000493:pharmacokinetics*; D005682:Gadolinium / Q000493:pharmacokinetics; D046911:Macromolecular Substances; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D011073:Polyamines / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D011868:Radioisotopes / Q000493:pharmacokinetics
D001672:Biocompatible Materials; D003287:Contrast Media; D050091:Dendrimers; D005079:Excipients; D046911:Macromolecular Substances; C104700:PAMAM Starburst; D011073:Polyamines; D011868:Radioisotopes; D011092:Polyethylene Glycols; D005682:Gadolinium