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

Authors
  • Jászberényi, Zoltán1
  • Moriggi, Loïck1
  • Schmidt, Philipp2
  • Weidensteiner, Claudia2
  • Kneuer, Rainer2
  • Merbach, André E.1
  • Helm, Lothar1
  • Tóth, Éva1, 3
  • 1 Ecole Polytechnique Fédérale de Lausanne, ISIC, BCH, Institut des Sciences et Ingénierie Chimiques, Lausanne, 1015, Switzerland , Lausanne (Switzerland)
  • 2 Novartis Pharma AG, Novartis Institutes for Biomedical Research, Basel, 4002, Switzerland , Basel (Switzerland)
  • 3 Centre de Biophysique Moléculaire, CNRS, rue Charles Sadron, Orléans, 45071, France , Orléans (France)
Type
Published Article
Journal
JBIC Journal of Biological Inorganic Chemistry
Publisher
Springer-Verlag
Publication Date
Jan 10, 2007
Volume
12
Issue
3
Pages
406–420
Identifiers
DOI: 10.1007/s00775-006-0197-3
Source
Springer Nature
Keywords
License
Yellow

Abstract

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)]− (kex298 = 3.4 and 6.6 × 106 s−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 100 MHz, 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 4.7 T proved that all dendrimeric complexes are suitable for angiography and for the study of vasculature parameters like blood volume and permeability of tumor vessels.

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