Mechanistic studies on the uptake and intracellular trafficking of novel cyclodextrin transfection complexes by intestinal epithelial cells

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dc.contributor.authorO'Neill, Martin J.
dc.contributor.authorGuo, Jianfeng
dc.contributor.authorByrne, Colin
dc.contributor.authorDarcy, Raphael
dc.contributor.authorO'Driscoll, Caitríona M.
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderEnterprise Irelanden
dc.contributor.funderIrish Research Council for Science Engineering and Technologyen
dc.date.accessioned2013-01-29T10:19:16Z
dc.date.available2013-01-29T10:19:16Z
dc.date.copyright2011
dc.date.issued2011-07
dc.date.updated2013-01-17T15:16:15Z
dc.description.abstractOral delivery of gene therapeutics would facilitate treatment of local intestinal disease, including colon cancer and inflammatory bowel disease, thus avoiding invasive surgery. The aims of this study were to investigate; if the orientation of the lipid tail on the cyclodextrin (CD) influenced the efficacy of a novel poly-6-cationic amphiphilic CD to transfect intestinal enterocytes; the endocytotic uptake pathway(s), and, the intracellular trafficking of the CD.DNA complexes. Inhibitors of clathrin- and caveolae- mediated endocytosis and macropinocytosis were used to determine the mechanism(s) of CD.DNA uptake by both undifferentiated and differentiated Caco-2 cells. Cell surface heparan sulphate proteoglycans were involved in the association of CD.DNA complexes with undifferentiated Caco-2 cells. Complexation of pDNA with CD facilitated significant levels of pDNA uptake and gene expression (comparable to PEI) in both undifferentiated and differentiated Caco-2 cells. Disruption of intracellular vesicular trafficking reduced transfection activity. CD was also capable of transfecting the more physiologically relevant differentiated Caco-2 model. Macropinocytosis was responsible for the uptake of CD.DNA transfection complexes by both undifferentiated and differentiated Caco-2 cells. The ability of this novel CD to transfect differentiated intestinal cells indicates the potential of this vector for oral gene delivery.en
dc.description.sponsorshipScience Foundation Ireland (Strategic Research Cluster and the Irish Drug Delivery Network); Enterprise Ireland (via commercial fund technology development); Irish Research Council for Science, Engineering and Technology (Embark initiative)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMartin J. O'Neill, Jianfeng Guo, Colin Byrne, Raphael Darcy and Caitriona M. O'Driscoll. (2011) 'Mechanistic studies on the uptake and intracellular trafficking of novel cyclodextrin transfection complexes by intestinal epithelial cells'. International Journal of Pharmaceutics, 413 (1-2):174-183.en
dc.identifier.doi10.1016/j.ijpharm.2011.04.021
dc.identifier.endpage183en
dc.identifier.issn0378-5173
dc.identifier.issued1-2en
dc.identifier.journaltitleInternational Journal of Pharmaceuticsen
dc.identifier.startpage174en
dc.identifier.urihttps://hdl.handle.net/10468/935
dc.identifier.volume413en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urihttp://www.sciencedirect.com/science/article/pii/S0378517311003279
dc.rights© 2011, Elsevier. NOTICE: this is the author’s version of a work that was accepted for publication in International Journal of Pharmaceutics . Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in International Journal of Pharmaceutics [413, 1-2, 15 July 2011] DOI: http://dx.doi.org/10.1016/j.ijpharm.2011.04.021en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectNon-viral gene therapyen
dc.subjectCyclodextrinsen
dc.subjectIntestinal deliveryen
dc.subjectUptake pathwaysen
dc.subjectIntracellular traffickingen
dc.subject.lcshGene Therapy--methodsen
dc.titleMechanistic studies on the uptake and intracellular trafficking of novel cyclodextrin transfection complexes by intestinal epithelial cellsen
dc.typeArticle (peer-reviewed)en
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