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dc.contributor.authorGuo, J.
dc.contributor.authorCheng, W.P.
dc.contributor.authorGu, J.
dc.contributor.authorDing, C.
dc.contributor.authorQu, X.
dc.contributor.authorYang, Z.
dc.contributor.authorO'Driscoll, C.
dc.date.accessioned2012-12-12T10:59:59Z
dc.date.available2012-12-12T10:59:59Z
dc.date.issued2012
dc.identifier.citationGuo , J , Cheng , W P , Gu , J , Ding , C , Qu , X , Yang , Z & O'Driscoll , C 2012 , ' Systemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-l-lysine nanocarrier to suppress prostate cancer growth in mice ' , European Journal of Pharmaceutical Sciences , vol. 45 , no. 5 , pp. 521-532 . https://doi.org/10.1016/j.ejps.2011.11.024
dc.identifier.issn0928-0987
dc.identifier.otherPURE: 662155
dc.identifier.otherPURE UUID: 4b7067df-fb92-433f-8c01-67f89830af87
dc.identifier.otherScopus: 84862777300
dc.identifier.urihttp://hdl.handle.net/2299/9368
dc.descriptionCopyright 2012 Elsevier B.V., All rights reserved.
dc.description.abstractProstate cancer is associated with high mortality and new therapeutic strategies are necessary for improved patient outcome. The utilisation of potent, sequence-specific small interfering RNA (siRNA) to facilitate down-regulation of complementary mRNA sequences in vitro and in vivo has stimulated the development of siRNA-based cancer therapies. However, the lack of an effective siRNA delivery system significantly retards clinical application. Amphiphilic polycations with 'stealth' capacity have previously been synthesised by PEGylation of poly-l-lysine-cholic acid (PLL-CA). The benzoic imine linker between PEG and PLL-CA was designed to be stable at physiological pH but cleavable at lower pHs, consistent with the extracellular environment of tumours and the interior of endosomes/lysosomes. The selective hydrolysis of the PEG linker at these targeted sites should provide enhanced cellular uptake and endosomal escape while simultaneously ensuring prolonged blood circulation times. In this study, physicochemical profiling demonstrated nano-complex formation between the PLL derivatives and siRNA (200-280 nm in diameter). At physiological pH only a slight cationic surface charge (40 mV) were detected upon hydrolysis of the PEG linker at acidic pHs (pH = 6.8 and 5.5, respectively). The PEGylated complexes were stable in serum without significant aggregation or decomplexation of siRNA for up to 48 h. At the cellular level, PEG-PLLs were comparable with the commercial carrier INTERFRin™, in terms of cellular uptake, endosomal escape and in vitro reporter gene knockdown. In vivo, utilising a mouse model grafted with prostate carcinoma, significant tumour suppression was achieved using PEGylated complexes without marked toxicity or undesirable immunological response, this was accompanied by a simultaneous reduction in target mRNA levels. In summary, the advantages of these vectors include: the in vitro and in vivo silencing efficiency, and the low toxicity and immunogenicity.en
dc.language.isoeng
dc.relation.ispartofEuropean Journal of Pharmaceutical Sciences
dc.titleSystemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-l-lysine nanocarrier to suppress prostate cancer growth in miceen
dc.contributor.institutionDepartment of Pharmacy
dc.contributor.institutionHealth & Human Sciences Research Institute
dc.contributor.institutionCentre for Research into Topical Drug Delivery and Toxicology
dc.contributor.institutionPharmaceutics
dc.contributor.institutionNanopharmaceutics
dc.contributor.institutionModified Release Dosage Forms
dc.contributor.institutionPharmaceutical Analysis and Product Characterisation
dc.description.statusPeer reviewed
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=84855506757&partnerID=8YFLogxK
rioxxterms.versionVoR
rioxxterms.versionofrecordhttps://doi.org/10.1016/j.ejps.2011.11.024
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue
herts.rights.accesstypeclosedAccess


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