In vitro investigations of the efficacy of cyclodextrin-siRNA complexes modified with lipid-PEG-octaarginine: towards a formulation strategy for effective neuronal siRNA delivery

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dc.contributor.authorO'Mahony, Aoife M.
dc.contributor.authorDesgranges, Stephane
dc.contributor.authorOgier, Julien R.
dc.contributor.authorQuinlan, Aoife
dc.contributor.authorDevocelle, Marc
dc.contributor.authorDarcy, Raphael
dc.contributor.authorCryan, John F.
dc.contributor.authorO'Driscoll, Caitríona M.
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderIrish Research Council for Science Engineering and Technologyen
dc.contributor.funderIrish Drug Delivery Networken
dc.date.accessioned2013-01-09T11:32:48Z
dc.date.available2013-01-09T11:32:48Z
dc.date.copyright2012
dc.date.issued2012-11
dc.date.updated2013-01-04T15:01:00Z
dc.description.abstractPurpose: Development of RNA interference based therapeutics for neurological and neurodegenerative diseases is hindered by a lack of non-viral vectors with suitable properties for systemic administration. Amphiphilic and cationic cyclodextrins (CD) offer potential for neuronal siRNA delivery. Here, we aimed to improve our CD-based siRNA formulation through incorporation of a polyethyleneglycol (PEG) shielding layer and a cell penetrating peptide, octaarginine (R8). Methods: CD.siRNA complexes were modified by addition of an R8-PEG-lipid conjugate. Physical properties including size, charge and stability were assessed. Flow cytometry was used to determine uptake levels in a neuronal cell model. Knockdown of an exogenous gene and an endogenous housekeeping gene were used to assess gene silencing abilities. Results: CD.siRNA complexes modified with R8-PEG-lipid exhibited a lower surface charge and greater stability to a salt-containing environment. Neuronal uptake was increased and significant reductions in the levels of two target genes were achieved with the new formulation. However, the PEG layer was not sufficient to protect against serum-induced aggregation. Conclusions: The R8-PEG-lipid-CD.siRNA formulation displayed enhanced salt-stability due to the PEG component, while the R8 component facilitated transfection of neuronal cells and efficient gene silencing. Further improvements will be investigated in the future in order to optimise stability in serum and enhance neuronal specificity.en
dc.description.sponsorshipScience Foundation Ireland (Strategic Research Cluster grant no. 07/SRC/B1154); 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.citationO'Mahony, A.M., Desgranges S., Ogier J.R., Quinlan A., Devocelle M., Darcy, R., Cryan, J.F. and O'Driscoll, C.M. (2012) 'In vitro investigations of the efficacy of Cyclodextrin-siRNA complexes modified with Lipid-PEG-Octaarginine: Towards A Formulation Strategy for Effective Neuronal siRNA Delivery'. Pharmaceutical Research. doi: 10.1007/s11095-012-0945-8en
dc.identifier.doi10.1007/s11095-012-0945-8
dc.identifier.endpage13en
dc.identifier.issn0724-8741
dc.identifier.issn1573-904X
dc.identifier.journaltitlePharmaceutical Researchen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/870
dc.language.isoenen
dc.publisherSpringer Science+Business Mediaen
dc.rights© Springer Science+Business Media New York 2012. The original publication is available at www.springerlink.com.en
dc.subjectCyclodextrinen
dc.subjectsiRNAen
dc.subjectNeuronal deliveryen
dc.subjectOcta-arganineen
dc.subject.lcshCyclodextrinsen
dc.titleIn vitro investigations of the efficacy of cyclodextrin-siRNA complexes modified with lipid-PEG-octaarginine: towards a formulation strategy for effective neuronal siRNA deliveryen
dc.typeArticle (peer-reviewed)en
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