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Nucleic Acids Research 2004 32(20):e159; doi:10.1093/nar/gnh153
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Published online 16 November 2004

Nucleic Acids Research, Vol. 32 No. 20 © Oxford University Press 2004; all rights reserved

Negatively charged self-assembling DNA/poloxamine nanospheres for in vivo gene transfer

Bruno Pitard*, Mahajoub Bello-Roufaï, Olivier Lambert1, Peggy Richard, Léa Desigaux, Sarah Fernandes, Caroline Lanctin, Hélène Pollard, Mehdi Zeghal2, Pierre-Yves Rescan3 and Denis Escande

L'institut du Thorax, Inserm U533, Faculté de Médecine, 44035 Nantes, France, 1 IECB-UBS UMR CNRS 5471 CNRS, Université Bordeaux 1, avenue des Facultés, 33405 Talence, France, 2 Université Paris XI, 91400 Orsay, France and 3 INRA-SCRIBE, Campus Beaulieu, 35042 Rennes, France

* To whom correspondence should be addressed. Tel: +33 2 40 41 29 74; Fax: +33 2 40 41 29 50; Email: bruno.pitard{at}nantes.inserm.fr

Received August 25, 2004; Revised and Accepted October 19, 2004

Over the past decade, numerous nonviral cationic vectors have been synthesized. They share a high density of positive charges and efficiency for gene transfer in vitro. However, their positively charged surface causes instability in body fluids and cytotoxicity, thereby limiting their efficacy in vivo. Therefore, there is a need for developing alternative molecular structures. We have examined tetrabranched amphiphilic block copolymers consisting of four polyethyleneoxide/polypropyleneoxide blocks centered on an ethylenediamine moiety. Cryo-electron microscopy, ethidium bromide fluorescence and light and X-ray scattering experiments performed on vector–DNA complexes showed that the dense core of the nanosphere consisted of condensed DNA interacting with poloxamine molecules through electrostatic, hydrogen bonding and hydrophobic interactions, with DNA molecules also being exposed at the surface. The supramolecular organization of block copolymer/DNA nanospheres induced the formation of negatively charged particles. These particles were stable in a solution that had a physiological ionic composition and were resistant to decomplexation by heparin. The new nanostructured material, the structure of which clearly contrasted with that of lipoplexes and polyplexes, efficiently transferred reporter and therapeutic genes in skeletal and heart muscle in vivo. Negatively charged supramolecular assemblies hold promise as therapeutic gene carriers for skeletal and heart muscle-related diseases and expression of therapeutic proteins for local or systemic uses.


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