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Physicochemical and MRI characterization of Gd3+-loaded polyamidoamine and hyperbranched dendrimers

Jászberényi, Zoltán ; Moriggi, Loïck ; Schmidt, Philipp ; Weidensteiner, Claudia ; Kneuer, Rainer ; Merbach, André ; Helm, Lothar ; Tóth, Éva

In: JBIC Journal of Biological Inorganic Chemistry, 2007, vol. 12, no. 3, p. 406-420

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    Titre
    • Physicochemical and MRI characterization of Gd3+-loaded polyamidoamine and hyperbranched dendrimers
    Auteur
    • Jászberényi, Zoltán. Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, ISIC, BCH, 1015, Lausanne, Switzerland
    • Moriggi, Loïck. Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, ISIC, BCH, 1015, Lausanne, Switzerland
    • Schmidt, Philipp. Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland
    • Weidensteiner, Claudia. Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland
    • Kneuer, Rainer. Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland
    • Merbach, André. Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, ISIC, BCH, 1015, Lausanne, Switzerland
    • Helm, Lothar. Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, ISIC, BCH, 1015, Lausanne, Switzerland
    • Tóth, Éva. Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, ISIC, BCH, 1015, Lausanne, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • JBIC Journal of Biological Inorganic Chemistry, 2007, vol. 12, no. 3, p. 406-420. Springer-Verlag
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:316402
    Summary
    Generation 4 polyamidoamine (PAMAM) and, for the first time, hyperbranched poly(ethylene imine) or polyglycerol dendrimers have been loaded with Gd3+ chelates, and the macromolecular adducts have been studied in vitro and in vivo with regard to MRI contrast agent applications. The Gd3+ chelator was either a tetraazatetracarboxylate DOTA-pBn4− or a tetraazatricarboxylate monoamide DO3A-MA3− unit. The water exchange rate was determined from a 17O NMR and 1H Nuclear Magnetic Relaxation Dispersion study for the corresponding monomer analogues [Gd(DO3A-AEM)(H2O)] and [Gd(DOTA-pBn-NH2)(H2O)]− (k ex 298 =3.4 and 6.6×106s−1, respectively), where H3DO3A-AEM is {4-[(2-acetylaminoethylcarbamoyl)methyl]-7,10-bis(carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)}-acetic acid and H4DOTA-pBn-NH2 is 2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. For the macromolecular complexes, variable-field proton relaxivities have been measured and analyzed in terms of local and global motional dynamics by using the Lipari-Szabo approach. At frequencies below 100MHz, the proton relaxivities are twice as high for the dendrimers loaded with the negatively charged Gd(DOTA-pBn)− in comparison with the analogous molecule bearing the neutral Gd(DO3A-MA). We explained this difference by the different rotational dynamics: the much slower motion of Gd(DOTA-pBn)−-loaded dendrimers is likely related to the negative charge of the chelate which creates more rigidity and increases the overall size of the macromolecule compared with dendrimers loaded with the neutral Gd(DO3A-MA). Attachment of poly(ethylene glycol) chains to the dendrimers does not influence relaxivity. Both hyperbranched structures were found to be as good scaffolds as regular PAMAM dendrimers in terms of the proton relaxivity of the Gd3+ complexes. The in vivo MRI studies on tumor-bearing mice at 4.7T proved that all dendrimeric complexes are suitable for angiography and for the study of vasculature parameters like blood volume and permeability of tumor vessels