Folate-targeted amphiphilic cyclodextrin nanoparticles incorporating a fusogenic peptide deliver therapeutic siRNA and inhibit the invasive capacity of 3D prostate cancer tumours

dc.check.date2018-09-13
dc.check.infoAccess to this article is restricted for 12 months after publication by request of the publisher.en
dc.contributor.authorEvans, James C.
dc.contributor.authorMalhotra, Meenakshi
dc.contributor.authorSweeney, Katrina
dc.contributor.authorDarcy, Raphael
dc.contributor.authorNelson, Colleen C.
dc.contributor.authorHollier, Brett G.
dc.contributor.authorO'Driscoll, Caitríona M.
dc.contributor.funderIrish Cancer Societyen
dc.contributor.funderIrish Research Councilen
dc.contributor.funderNational Health and Medical Research Councilen
dc.contributor.funderCancer Australiaen
dc.contributor.funderProstate Cancer Foundation of Australiaen
dc.contributor.funderCure Cancer Australia Foundationen
dc.contributor.funderDepartment of Health, Australian Governmenten
dc.contributor.funderMovember Foundationen
dc.date.accessioned2017-10-05T10:56:05Z
dc.date.available2017-10-05T10:56:05Z
dc.date.issued2017-09-13
dc.date.updated2017-10-05T10:46:47Z
dc.description.abstractThe main barrier to the development of an effective RNA interference (RNAi) therapy is the lack of a suitable delivery vector. Modified cyclodextrins have emerged in recent years for the delivery of siRNA. In the present study, a folate-targeted amphiphilic cyclodextrin was formulated using DSPE-PEG5000-folate to target prostate cancer cells. The fusogenic peptide GALA was included in the formulation to aid in the endosomal release of siRNA. Targeted nanoparticles were less than 200 nm in size with a neutral surface charge. The complexes were able to bind siRNA and protect it from serum nucleases. Incubation with excess free folate resulted in a significant decrease in the uptake of targeted nanoparticles in LNCaP and PC3 cells, both of which have been reported to have differing pathways of folate uptake. There was a significant reduction in the therapeutic targets, ZEB1 and NRP1 at mRNA and protein level following treatment with targeted complexes. In preliminary functional assays using 3D spheroids, treatment of PC3 tumours with targeted complexes with ZEB1 and NRP1 siRNA resulted in more compact colonies relative to the untargeted controls and inhibited infiltration into the Matrigelâ„¢ layer.en
dc.description.sponsorshipIrish Cancer Society ((CRS12EVA), (PCI11ODR)); Irish Research Council (GOIPD/2014/151); National Health and Medical Research Council (NHMRC (APP1100417)); Cure Cancer Australia Foundation(PdCCRS); Prostate Cancer Foundation of Australia and Movember Foundation (Movember Revolutionary Team Award)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationEvans, J. C., Malhotra, M., Sweeney, K., Darcy, R., Nelson, C. C., Hollier, B. G. and O’Driscoll, C. M. (2017) 'Folate-targeted amphiphilic cyclodextrin nanoparticles incorporating a fusogenic peptide deliver therapeutic siRNA and inhibit the invasive capacity of 3D prostate cancer tumours', International Journal of Pharmaceutics, 532(1), pp. 511-518. doi: 10.1016/j.ijpharm.2017.09.013en
dc.identifier.doi10.1016/j.ijpharm.2017.09.013
dc.identifier.endpage518en
dc.identifier.issn0378-5173
dc.identifier.issued1en
dc.identifier.journaltitleInternational Journal of Pharmaceuticsen
dc.identifier.startpage511en
dc.identifier.urihttps://hdl.handle.net/10468/4836
dc.identifier.volume532en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urihttp://www.sciencedirect.com/science/article/pii/S0378517317308682
dc.rights© 2017 Elsevier B.V. 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.subjectRNAien
dc.subjectCyclodextrinen
dc.subjectGALAen
dc.subjectsiRNA deliveryen
dc.subjectProstate canceren
dc.subjectMetastasisen
dc.subjectFolateen
dc.titleFolate-targeted amphiphilic cyclodextrin nanoparticles incorporating a fusogenic peptide deliver therapeutic siRNA and inhibit the invasive capacity of 3D prostate cancer tumoursen
dc.typeArticle (peer-reviewed)en
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