JBIC Journal of Biological Inorganic Chemistry

, Volume 12, Issue 3, pp 406–420

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

  • Zoltán Jászberényi
  • Loïck Moriggi
  • Philipp Schmidt
  • Claudia Weidensteiner
  • Rainer Kneuer
  • André E. Merbach
  • Lothar Helm
  • Éva Tóth
Original Paper

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.

Keywords

MRI contrast agents Dendrimers Hyperbranched Gadolinium Rotational dynamics 

Abbreviations

CA

Contrast agent

DCE

Dynamic contrast enhanced

DTPA

Diethylenetriaminpentaacetic acid

EPR

Electron paramagnetic resonance

FLASH

Fast low-angle shot

FOV

Field of view

G4

Generation 4

H3DO3A-AEM

{4-[(2-Acetylaminoethylcarbamoyl)methyl]-7,10-bis(carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)}-acetic acid

H4DOTA-pBn-NH2

2-(4-Aminobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

H4DOTA-pBn-SCN is

2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

H4DOTA-NHS

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(N-hydroxysuccinimide ester)

HB

Hyperbranched

HEPES

N-(2-Hydroxyethyl)piperazine-N′-ethanesulfonic acid

ICP

Inductively coupled plasma

IR

Inversion recovery

MA

Monoamide

mPEG-SPA

Methoxypoly(ethylene glycol)–succinimidyl propionate

MRI

Magnetic resonance imaging

NMRD

Nuclear Magnetic Relaxation Dispersion

PAMAM

Polyamidoamine

PEG

Poly(ethylene glycol)

PEI

Poly(ethylene imine)

PG

Polyglycerol

RARE

Rapid acquisition and relaxation enhancement, fast spin echo MRI method

ROI

Region of interest

TE

Echo time

TR

Repetition time

ZFS

Zero-field splitting

Supplementary material

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Copyright information

© SBIC 2007

Authors and Affiliations

  • Zoltán Jászberényi
    • 1
  • Loïck Moriggi
    • 1
  • Philipp Schmidt
    • 2
  • Claudia Weidensteiner
    • 2
  • Rainer Kneuer
    • 2
  • André E. Merbach
    • 1
  • Lothar Helm
    • 1
  • Éva Tóth
    • 1
    • 3
  1. 1.Institut des Sciences et Ingénierie ChimiquesEcole Polytechnique Fédérale de Lausanne, ISIC, BCHLausanneSwitzerland
  2. 2.Novartis Institutes for Biomedical ResearchNovartis Pharma AGBaselSwitzerland
  3. 3.Centre de Biophysique Moléculaire, CNRSOrléansFrance

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