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

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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)]− (k 298ex  = 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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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

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Acknowledgements

We thank the Swiss National Science Foundation and the Swiss State Secretariat for Education and Research (SER) for financial support. This work was performed in the frame of the EU COST Actions D18 “Lanthanide chemistry for diagnosis and therapy” and D38 “Metal-based systems for molecular imaging applications” and the European-founded EMIL program (LSCH-2004–503569).

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Authors and Affiliations

  1. Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, ISIC, BCH, 1015, Lausanne, Switzerland

    Zoltán Jászberényi, Loïck Moriggi, André E. Merbach, Lothar Helm & Éva Tóth

  2. Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland

    Philipp Schmidt, Claudia Weidensteiner & Rainer Kneuer

  3. Centre de Biophysique Moléculaire, CNRS, rue Charles Sadron, 45071, Orléans, France

    Éva Tóth

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  1. Zoltán Jászberényi
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Correspondence to Éva Tóth.

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Jászberényi, Z., Moriggi, L., Schmidt, P. et al. Physicochemical and MRI characterization of Gd3+-loaded polyamidoamine and hyperbranched dendrimers. J Biol Inorg Chem 12, 406–420 (2007). https://doi.org/10.1007/s00775-006-0197-3

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  • DOI: https://doi.org/10.1007/s00775-006-0197-3

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