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

Show simple item record O'Mahony, Aoife M. Desgranges, Stephane Ogier, Julien R. Quinlan, Aoife Devocelle, Marc Darcy, Raphael Cryan, John F. O'Driscoll, Caitríona M. 2013-01-09T11:32:48Z 2013-01-09T11:32:48Z 2012 2012-11
dc.identifier.citation O'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/s11095-012-0945-8 en
dc.identifier.startpage 1 en
dc.identifier.endpage 13 en
dc.identifier.issn 0724-8741
dc.identifier.issn 1573-904X
dc.identifier.doi 10.1007/s11095-012-0945-8
dc.description.abstract Purpose: 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.sponsorship Science Foundation Ireland (Strategic Research Cluster grant no. 07/SRC/B1154); Irish Research Council for Science Engineering and Technology (Embark initiative) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Springer Science+Business Media en
dc.rights © Springer Science+Business Media New York 2012. The original publication is available at en
dc.subject Cyclodextrin en
dc.subject siRNA en
dc.subject Neuronal delivery en
dc.subject Octa-arganine en
dc.subject.lcsh Cyclodextrins en
dc.title In vitro investigations of the efficacy of cyclodextrin-siRNA complexes modified with lipid-PEG-octaarginine: towards a formulation strategy for effective neuronal siRNA delivery en
dc.type Article (peer-reviewed) en
dc.internal.authorurl en
dc.internal.authorcontactother Caitriona O'Driscoll, School Of Pharmacy, University College Cork, Cork, Ireland. +353-21-490-3000 Email: en
dc.internal.availability Full text available en 2013-01-04T15:01:00Z
dc.description.version Accepted Version en
dc.internal.rssid 181751499
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder Irish Research Council for Science Engineering and Technology en
dc.contributor.funder Irish Drug Delivery Network en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Pharmaceutical Research en
dc.internal.copyrightchecked Yes. CORA - ROMEO. Accepted manuscript and set statement en
dc.internal.licenseacceptance Yes en
dc.internal.placepublication New York en
dc.internal.IRISemailaddress en

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