Systemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-L-lysine nanocarrier to suppress prostate cancer growth in mice

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dc.contributor.author Guo, Jianfeng
dc.contributor.author Cheng, Woei Ping
dc.contributor.author Gu, Jingxia
dc.contributor.author Ding, Caixia
dc.contributor.author Qu, Xiaozhong
dc.contributor.author Yang, Zhenzhong
dc.contributor.author O'Driscoll, Caitríona M.
dc.date.accessioned 2013-01-29T09:59:45Z
dc.date.available 2013-01-29T09:59:45Z
dc.date.copyright 2012
dc.date.issued 2012-04
dc.identifier.citation GUO, 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, 45, 521-532. http://dx.doi.org/10.1016/j.ejps.2011.11.024 en
dc.identifier.volume 45 en
dc.identifier.startpage 521 en
dc.identifier.endpage 532 en
dc.identifier.issn 0928-0987
dc.identifier.uri http://hdl.handle.net/10468/932
dc.identifier.doi 10.1016/j.ejps.2011.11.024
dc.description.abstract Prostate 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 (200-280nm in diameter). At physiological pH only a slight cationic surface charge (<20mV) was detected, due to the masking effect of the PEG. In contrast, significantly higher positive charges (∼20 to 30mV and >40mV) 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 48h. 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.description.sponsorship Irish Research Council for Science Engineering and Technology (Embark initiative) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Elsevier en
dc.rights Copyright © 2012, Elsevier. NOTICE: this is the author’s version of a work that was accepted for publication in European Journal of Pharmaceutical Sciencess . Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in European Journal of Pharmaceutical Sciences [45, 5, 11 April 2012] DOI: http://dx.doi.org/10.1016/j.ejps.2011.11.024 en
dc.subject siRNA delivery en
dc.subject Prostate cancer en
dc.subject pH-induced endolysosomal escape en
dc.subject Poly-l-lysine nanocarrier en
dc.subject small interfering RNA en
dc.subject.lcsh Cancer--Treatment en
dc.subject.lcsh Drug delivery systems en
dc.title Systemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-L-lysine nanocarrier to suppress prostate cancer growth in mice en
dc.type Article (peer-reviewed) en
dc.internal.authorurl http://publish.ucc.ie/researchprofiles/C019/caitrionaodriscoll en
dc.internal.authorcontactother Caitriona O'Driscoll, School Of Pharmacy, University College Cork, Cork, Ireland. +353-21-490-3000 Email: caitriona.odriscoll@ucc.ie en
dc.internal.availability Full text available en
dc.date.updated 2013-01-17T10:46:56Z
dc.description.version Accepted Version en
dc.internal.rssid 122828452
dc.contributor.funder Irish Research Council for Science Engineering and Technology en
dc.description.status Peer reviewed en
dc.identifier.journaltitle European Journal of Pharmaceutical Sciences en
dc.internal.copyrightchecked Yes. CORA: ROMEO - Elsevier Accepted VErsion and set statement. en
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress caitriona.odriscoll@ucc.ie en


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