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. Magn Reson Med 46:781–788, 2001. © 2001 Wiley‐Liss, Inc.