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Double-tailed lipid modification as a promising candidate for oligonucleotide delivery in mammalian cells

AuthorsUgarte-Uribe, Begoña; Grijalvo, Santiago CSIC ORCID; Busto, Jon V.; Martín, César; Eritja Casadellà, Ramón CSIC ORCID ; Goñi, Félix Lix M; Alkorta, Itziar
KeywordsCellular uptake and localization
Lipid oligonucleotide conjugates
Model membrane systems
Model membrane systems
Issue Date2013
CitationBiochimica et Biophysica Acta - General Subjects
AbstractBackground The potential use of nucleic acids as therapeutic drugs has triggered the quest for oligonucleotide conjugates with enhanced cellular permeability. To this end, the biophysical aspects of previously reported potential lipid oligodeoxyribonucleotide conjugates were studied including its membrane-binding properties and cellular uptake. Methods These conjugates were fully characterized by MALDI-TOF mass spectrometry and HPLC chromatography. Their ability to insert into lipid model membrane systems was evaluated by Langmuir balance and confocal microscopy followed by the study of the internalization of a lipid oligodeoxyribonucleotide conjugate bearing a double-tail lipid modification (C28) into different cell lines by confocal microscopy and flow cytometry. This compound was also compared with other lipid containing conjugates and with the classical lipoplex formulation using Transfectin as transfection reagent. Results This double-tail lipid modification showed better incorporation into both lipid model membranes and cell systems. Indeed, this lipid conjugation was capable of inserting the oligodeoxyribonucleotide into both liquid-disordered and liquid-ordered domains of model lipid bilayer systems and produced an enhancement of oligodeoxyribonucleotide uptake in cells, even better than the effect caused by lipoplexes. In addition, in β2 integrin (CR3) expressing cells this receptor was directly involved in the enhanced internalization of this compound. Conclusions All these features confirm that the dual lipid modification (C28) is an excellent modification for enhancing nucleic acid delivery without altering their binding properties. General significance Compared to the commercial lipoplex approach, oligodeoxyribonucleotide conjugation with C28 dual lipid modification seems to be promising to improve oligonucleotide delivery in mammalian cells.
Publisher version (URL)DOI: 10.1016/j.bbagen.2013.06.013
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