Positive effects of polyethylene glycol conjugation to generation-4 polyamidoamine dendrimers as macromolecular MR contrast agents

Macromolecules conjugated with polyethylene glycol (PEG) acquire more hydro philicity, resulting In a longer half-life in circulation and lower Immunog enicity. 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 mole cules 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, excret ion, and properties as vascular MRI contrast agents were evaluated and comp ared 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 le ss in the liver and kidney than the other two preparations (P < 0.01). Alth ough the blood clearance was slower, PEG(2)-G4D-(1B4M-Gd)(62) was excreted more readily without renal retention than the other two preparations. In co nclusion, the positive effects of PEG conjugation on a macromolecular MRI c ontrast agent were found to be prolonged retention in the circulation, Incr eased excretion, and decreased accumulation in the organs. (C) 2001 Wiley-L iss, Inc.