Polymeric Conjugates of Gd3+−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters

Macromolecular conjugates of dextran 40 (Mn = 38 kg/mol, Mw = 43 kg/mol) and diethylenetriaminepentaacetic acid (DTPA), capable of complexing Gd3+, were synthesized in order to obtain contrast agents for nuclear magnetic resonance imaging, with long intravascular persistence. As already reported, relaxivity of these macromolecular complexes was greater than that of molecular complexes (2-2.5 times). On the other hand, as relaxivity of paramagnetic agents partially depends on their rotation speed, the influence of the length of the spacer arm inserted between DTPA and dextran was investigated. Various conjugates with spacer arms comprised of methylenic chains (-(CH2)n-) with varying lengths (2 < or = n < or = 6) were prepared. The result was that, whatever the distance between DTPA and dextran, all of the Gd(3+)-complexed polymeric conjugates with similar DTPA content (0.6-0.8 mmol/g) exhibited, at 20 MHz, about the same relaxivity values. On the other hand, in the same way, no significant effect of the molecular masses (Mn between 166 and 224 kg/mol and Mw between 332 and 865 kg/mol) of the polymeric conjugates on relaxivity were observed. Toxicity studies carried out on mice, showed very similar LD50 values whatever the spacer arm and molecular mass of the macromolecular conjugates. Finally the urinary excretion studied on rats (after 4 h) and on rabbits (after 24 h) was relatively low (15-20% of the administered dose), and, as expected, the lower values were obtained with the higher molecular mass conjugates.