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

dc.contributor.authorGuo, Jianfeng
dc.contributor.authorCheng, Woei Ping
dc.contributor.authorGu, Jingxia
dc.contributor.authorDing, Caixia
dc.contributor.authorQu, Xiaozhong
dc.contributor.authorYang, Zhenzhong
dc.contributor.authorO'Driscoll, Caitríona M.
dc.contributor.funderIrish Research Council for Science Engineering and Technologyen
dc.date.accessioned2013-01-29T09:59:45Z
dc.date.available2013-01-29T09:59:45Z
dc.date.copyright2012
dc.date.issued2012-04
dc.date.updated2013-01-17T10:46:56Z
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 (200-280nm 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.sponsorshipIrish Research Council for Science Engineering and Technology (Embark initiative)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
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, 45, 521-532. http://dx.doi.org/10.1016/j.ejps.2011.11.024en
dc.identifier.doi10.1016/j.ejps.2011.11.024
dc.identifier.endpage532en
dc.identifier.issn0928-0987
dc.identifier.journaltitleEuropean Journal of Pharmaceutical Sciencesen
dc.identifier.startpage521en
dc.identifier.urihttps://hdl.handle.net/10468/932
dc.identifier.volume45en
dc.language.isoenen
dc.publisherElsevieren
dc.rightsCopyright © 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.2011.11.024en
dc.subjectsiRNA deliveryen
dc.subjectProstate canceren
dc.subjectpH-induced endolysosomal escapeen
dc.subjectPoly-l-lysine nanocarrieren
dc.subjectsmall interfering RNAen
dc.subject.lcshCancer--Treatmenten
dc.subject.lcshDrug delivery systemsen
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.typeArticle (peer-reviewed)en
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