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Nucleic Acids Research, 2000, Vol. 28, No. 2 504-512
© 2000 Oxford University Press

Histidylated oligolysines increase the transmembrane passage and the biological activity of antisense oligonucleotides

Chantal Pichon*, Mahajoub Bello Roufaï, Michel Monsigny and Patrick Midoux

Centre de Biophysique Moléculaire, Glycobiologie, CNRS UPR4301 and University of Orléans, rue Charles-Sadron, F-45071 Orléans Cedex 02, France

We have designed histidylated oligolysines which increase the uptake, the cytosolic delivery and the nuclear accumulation of antisense oligonucleotides (ODN). Flow cytometry analysis showed a 10-fold enhancement of the ODN uptake in the presence of histidylated oligolysines. The intracellular localizations of fluorescein-labeled ODN and of rhodamine-labeled histidylated oligolysines were investigated by confocal microscopy. Histidylated oligolysines favor the cyto­solic delivery of ODN from endosomes and increase their nuclear accumulation. In contrast, in their absence fluorescent ODN were not observed inside the nucleus but were distributed overwhelmingly within the vesicles in the cytosol. In addition, histidylated oligolysines yielded a more than 20-fold enhancement of the biological activity of antisense ODN towards the inhibition of transient as well as constitutive gene expression. Prevention of endosome lumen acidification using bafilomycin A1 abolished the effect of histidylated oligolysines, suggesting that protonation of the histidyl residues was involved in the transmembrane passage of ODN.

* To whom correspondence should be addressed. Tel: +33 2 38 25 55 95; Fax: +33 2 38 69 00 94; Email: pichon@cnrs-orleans.fr


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