PHYSICAL, CHEMICAL AND BIOLOGICAL EVALUATIONS OF CMD-A2-GD-DOTA - A NEW PARAMAGNETIC DEXTRAN POLYMER

Purpose: We investigated the synthesis and physical, chemical and biol ogical characterisation of a carboxymethyl-dextran polymer substituted with the paramagnetic macrocyclic complex Gd-DOTA using an amino spac er. Material and Methods: The product was synthesised in 4 steps. Usin g rigorous purification conditions in each step, a polymer was obtaine d, i.e. CMD-A2-Gd-DOTA, whose polydispersity profile was comparable to the initial dextran (I = 1.66 - Mw = 50.5 kDa). Approximately 22% of the glucose groups were replaced by Gd-DOTA and 39% were replaced by c arboxyl groups. The paramagnetic efficacy of the polymer was 3 times h igher than Gd-DOTA alone, which suggests that the injected doses of Gd (III) can be reduced. The vascular residence time of the polymer was m easured in rats and rabbits, showing that the pharmacokinetics of the product is similar whatever the dose. Forty-five percent of the produc t was excreted in urine after 24 h and 1.64% was found in the liver. N o acute toxicity was observed at the maximum dose injected (>5 mmol Gd /kg) and the general biocompatibility of the product tested in vitro w as comparable to that of Gd-DOTA. Results and Conclusion: These result s show the advantages of using paramagnetic macrocyclic complexes in t he synthesis of macromolecules to preserve biological stability, in co ntrast with linear chelates. Additional studies will be carried out to demonstrate the benefits of this type of product, particularly in fun ctional imaging.