In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV-driven tumours View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2014-02

AUTHORS

Norliana Khairuddin, Stephen J Blake, Farah Firdaus, Raymond J Steptoe, Mark A Behlke, Paul J Hertzog, Nigel AJ McMillan

ABSTRACT

Small interfering RNAs (siRNAs) to inhibit oncogene expression and also to activate innate immune responses via Toll-like receptor (TLR) recognition have been shown to be beneficial as anti-cancer therapy in certain cancer models. In this study, we investigated the effects of local versus systemic delivery of such immune-stimulating Dicer-substrate siRNAs (IS-DsiRNAs) on a human papillomavirus (HPV)-driven tumour model. Localized siRNA delivery using intratumour injection of siRNA was able to increase siRNA delivery to the tumour compared with intravenous (IV) delivery and potently activated innate immune responses. However, IV injection remained the more effective delivery route for reducing tumour growth. Although IS-DsiRNAs activated innate immune cells and required interferon-α (IFNα) for full effect on tumour growth, we found that potent silencing siRNA acting independently of IFNα were overall more effective at inhibiting TC-1 tumour growth. Other published work utilising IS-siRNAs have been carried out on tumour models with low levels of major histocompatibility complex (MHC)-class 1, a target of natural killer cells that are potently activated by IS-siRNA. As TC-1 cells used in our study express high levels of MHC-class I, the addition of the immunostimulatory motifs may not be as beneficial in this particular tumour model. Our data suggest that selection of siRNA profile and delivery method based on tumour environment is crucial to developing siRNA-based therapies. More... »

PAGES

156

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/icb.2013.75

    DOI

    http://dx.doi.org/10.1038/icb.2013.75

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1031996145

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/24217808


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