Cyclodextrin-siRNA conjugates as versatile gene silencing agents

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dc.contributor.authorMalhotra, Meenakshi
dc.contributor.authorGooding, Matt
dc.contributor.authorEvans, James C.
dc.contributor.authorO'Driscoll, Daniel
dc.contributor.authorDarcy, Raphael
dc.contributor.authorO'Driscoll, Caitríona M.
dc.contributor.funderIrish Research Councilen
dc.contributor.funderFonds de Recherche du Québec - Santéen
dc.contributor.funderIrish Cancer Societyen
dc.date.accessioned2018-01-08T15:45:55Z
dc.date.available2018-01-08T15:45:55Z
dc.date.issued2017-11-27
dc.date.updated2018-01-08T15:38:50Z
dc.description.abstractFunctional siRNAs (luciferase and PLK1) have been conjugated to β-cyclodextrin and the ability of the conjugates to retain gene knockdown activity has been assessed by delivery to cancer cell lines using various formulations. Initially two formulations used complexation with polycations, namely Lipofectamine 2000 and an amphiphilic polycationic cyclodextrin. Gene knockdown results for human glioblastoma cells (U87) and prostate cancer cells (PC3, DU145) showed that conjugation to the cyclodextrin did not reduce gene silencing by the RNA. A third mode of delivery involved formation of targeted nanoparticles in which the conjugate was first complexed with adamantyl-PEG-ligands (targeting ligand RVG peptide or dianisamide) by adamantyl inclusion in the cyclodextrin cavities of the conjugates, followed by charge neutralisation with the cationic polymer chitosan. Enhanced knockdown was achieved by these ligand-targeted formulations. In summary, while this study illustrated the gene silencing efficacy of a simple cyclodextrin-siRNA conjugate it is envisaged that future studies will explore the use of conjugates with a modified cyclodextrin which would be self-delivering. Detailed data such as stability, lysosomal escape etc. will then be reported for each conjugate, since this will be appropriate for conjugates which are intended to exploit, rather than merely demonstrate, the concept. The present paper was intended to demonstrate the viability and generality of this novel concept.en
dc.description.sponsorshipIrish Research Council (GOIPD/2014/151); Fonds de Recherche en Santé du Québec (Postdoctoral fellowship); Irish Cancer Society (CRS12EVA)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMalhotra, M., Gooding, M., Evans, J. C., O'Driscoll, D., Darcy, R. and O'Driscoll, C. M. (2018) 'Cyclodextrin-siRNA conjugates as versatile gene silencing agents', European Journal of Pharmaceutical Sciences, 114, pp. 30-37. doi: 10.1016/j.ejps.2017.11.024en
dc.identifier.doi10.1016/j.ejps.2017.11.024
dc.identifier.endpage37en
dc.identifier.issn0928-0987
dc.identifier.journaltitleEuropean Journal of Pharmaceutical Sciencesen
dc.identifier.startpage30en
dc.identifier.urihttps://hdl.handle.net/10468/5243
dc.identifier.volume114en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urihttps://www.sciencedirect.com/science/article/pii/S092809871730653X
dc.rights© 2017 Elsevier B.V. All rights reserved. This manuscript version is made available under the CC BY-NC-ND 4.0 license.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectSiRNA conjugateen
dc.subjectCyclodextrinsen
dc.subjectGene deliveryen
dc.subjectNanoparticlesen
dc.subjectProstate canceren
dc.subjectGlioblastomaen
dc.titleCyclodextrin-siRNA conjugates as versatile gene silencing agentsen
dc.typeArticle (peer-reviewed)en
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