In vitro investigations of the efficacy of cyclodextrin-siRNA complexes modified with lipid-PEG-octaarginine: towards a formulation strategy for effective neuronal siRNA delivery
dc.contributor.author | O'Mahony, Aoife M. | |
dc.contributor.author | Desgranges, Stephane | |
dc.contributor.author | Ogier, Julien R. | |
dc.contributor.author | Quinlan, Aoife | |
dc.contributor.author | Devocelle, Marc | |
dc.contributor.author | Darcy, Raphael | |
dc.contributor.author | Cryan, John F. | |
dc.contributor.author | O'Driscoll, Caitríona M. | |
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.date.accessioned | 2013-01-09T11:32:48Z | |
dc.date.available | 2013-01-09T11:32:48Z | |
dc.date.copyright | 2012 | |
dc.date.issued | 2012-11 | |
dc.date.updated | 2013-01-04T15:01:00Z | |
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.description.status | Peer reviewed | en |
dc.description.version | Accepted Version | en |
dc.format.mimetype | application/pdf | en |
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.doi | 10.1007/s11095-012-0945-8 | |
dc.identifier.endpage | 13 | en |
dc.identifier.issn | 0724-8741 | |
dc.identifier.issn | 1573-904X | |
dc.identifier.journaltitle | Pharmaceutical Research | en |
dc.identifier.startpage | 1 | en |
dc.identifier.uri | https://hdl.handle.net/10468/870 | |
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 www.springerlink.com. | 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 |