GADOLINIUM(III) DO3A MACROCYCLES AND POLYETHYLENE-GLYCOL COUPLED TO DENDRIMERS - EFFECT OF MOLECULAR-WEIGHT ON PHYSICAL AND BIOLOGICAL PROPERTIES OF MACROMOLECULAR MAGNETIC-RESONANCE-IMAGING CONTRAST AGENTS

The macrocycle 1-(4-isothiocyanatobenzyl)amido-4,7,10-triacetic acid-t etraazacyclododecane (DO3A-bz-NCS) was synthesized and coupled to the terminal amine sites of a series of different generations (G(n)) of po lyamidoamine or starburst dendrimers (n-SBDs) creating macromolecular polychelates. Gadolinium ion was added to the dendrimer polychelates f or evaluating the parameters needed to create magnetic resonance imagi ng (MRI) contrast agents that have long blood circulation times. The r esulting water soluble n-SBD-GdDO3As were mono-disperse and ranged fro m 11 Gd3+ ions per G(3) dendrimer (MW 18.4 kDalton (kDa)) to 57 Gd3+ i ons per G(3) dendrimer (MW 61.8 kDa). Nuclear Magnetic Resonance Dispe rsion (NMRD) profiles revealed peak relaxivities up to 18.8 mM(-1) s(- 1) at 25 MHz, with the magnitude increasing linearly as a function of molecular weight. Blood elimination half-life in rats increased with m olecular weight ranging from 11(+/-5) min for 3-SBD-(GdDO3A)(24) (22 k Da) to 115(+/-8) min for the 5-SBD-(GdDO3A)(57) (61.8 kDa). Seven-day liver retention increased from 1 to over 40% over the same molecular w eight range. The effects of grafting polyethylene glycol (PEG) onto n- SBD-GdDO3A polychelates were also studied. Relaxivities ranged from 11 to 14.9 mM(-1) s(-1), blood elimination half-lives increased signific antly (range 33-1219 min) and the seven-day liver uptake dropped to 1- 8% of the injected dose. However, no correlations between these measur ements and molecular weight were found over the range studied (20.5-69 .3 kDa). These results suggest that both the molecular weight and type of terminal group on the n-SBD-GdDO3A polychelates control the pharma cokinetics and biodistribution of the macromolecular contrast agent. T he addition of covalently bound PEG to the n-SBD-GdDO3A surface signif icantly improved the biological performance of the contrast agents.