title: Physical, chemical and biological evaluations of CMD-A2-Gd-DOTA. A new paramagnetic dextran polymer.
abstract: OBJECTIVE
  We investigated the synthesis and physical, chemical and biological characterisation of a carboxymethyl-dextran polymer substituted with the paramagnetic macrocyclic complex Gd-DOTA using an amino spacer.
  
  
  METHODS
  The product was synthesised in 4 steps. Using rigorous purification conditions in each step, a polymer was obtained, 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 carboxyl groups. The paramagnetic efficacy of the polymer was 3 times higher than Gd-DOTA alone, which suggests that the injected doses of Gd(III) can be reduced. The vascular residence time of the polymer was measured in rats and rabbits, showing that the pharmacokinetics of the product is similar whatever the dose. Forty-five percent of the product was excreted in urine after 24 h and 1.64% was found in the liver. No acute toxicity was observed at the maximum dose injected (> 5 mmol Gd/kg) and the general biocompatibility of the product tested in vitro was comparable to that of Gd-DOTA.
  
  
  CONCLUSIONS
  These results show the advantages of using paramagnetic macrocyclic complexes in the synthesis of macromolecules to preserve biological stability, in contrast with linear chelates. Additional studies will be carried out to demonstrate the benefits of this type of product, particularly in functional imaging.
authors.affiliation: Groupe Guerbet, Roissy Charles-de-Gaulle, France.
authors.forename: C
authors.initials: C
authors.lastname: Corot
authors.forename: M
authors.initials: M
authors.lastname: Schaefer
authors.forename: S
authors.initials: S
authors.lastname: Beauté
authors.forename: P
authors.initials: P
authors.lastname: Bourrinet
authors.forename: S
authors.initials: S
authors.lastname: Zehaf
authors.forename: V
authors.initials: V
authors.lastname: Bénizé
authors.forename: M
authors.initials: M
authors.lastname: Sabatou
authors.forename: D
authors.initials: D
authors.lastname: Meyer
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D003911:Dextrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D005682:Gadolinium / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D007928:Lethal Dose 50; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008970:Molecular Weight; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D003911:Dextrans; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C107329:carboxymethyl-dextran-A2-gadolinium-DOTA; C014392:carboxymethyl dextran; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D005682:Gadolinium