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Delivery of chemo-sensitizing siRNAs to HER2+-breast cancer cells using RNA aptamers
Department of Internal Medicine, University of of Iowa, Iowa City, IA 52242, United States.
Department of Internal Medicine, University of of Iowa, Iowa City, IA 52242, United States.
Department of Internal Medicine, University of of Iowa, Iowa City, IA 52242, United States; Department of Molecular and Cellular Biology Program, University of of Iowa, Iowa City, IA 52242, United States.
Department of Internal Medicine, University of of Iowa, Iowa City, IA 52242, United States.
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2012 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no 13, 6319-6337 p.Article in journal (Refereed) Published
Abstract [en]

Human epidermal growth factor receptor 2 (HER2) expression in breast cancer is associated with an aggressive phenotype and poor prognosis, making it an appealing therapeutic target. Trastuzumab, an HER2 antibody-based inhibitor, is currently the leading targeted treatment for HER2+-breast cancers. Unfortunately, many patients inevitably develop resistance to the therapy, highlighting the need for alternative targeted therapeutic options. In this study, we used a novel, cell-based selection approach for isolating cell-type specific, cell-internalizing RNA ligands (aptamers) capable of delivering therapeutic small interfering RNAs (siRNAs) to HER2-expressing breast cancer cells. RNA aptamers with the greatest specificity and internalization potential were covalently linked to siRNAs targeting the anti-apoptotic gene, Bcl-2. We demonstrate that, when applied to cells, the HER2 aptamer-Bcl-2 siRNA conjugates selectively internalize into HER2+-cells and silence Bcl-2 gene expression. Importantly, Bcl-2 silencing sensitizes these cells to chemotherapy (cisplatin) suggesting a potential new therapeutic approach for treating breast cancers with HER2+-status. In summary, we describe a novel cell-based selection methodology that enables the identification of cell-internalizing RNA aptamers for targeting therapeutic siRNAs to HER2-expressing breast cancer cells. The future refinement of this technology may promote the widespread use of RNA-based reagents for targeted therapeutic applications. © 2012 The Author(s).

Place, publisher, year, edition, pages
Oxford University Press, 2012. Vol. 40, no 13, 6319-6337 p.
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Cell and Molecular Biology
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URN: urn:nbn:se:liu:diva-143338DOI: 10.1093/nar/gks294ISI: 000306970700049PubMedID: 22467215Scopus ID: 2-s2.0-84864447484OAI: oai:DiVA.org:liu-143338DiVA: diva2:1162518
Available from: 2017-12-04 Created: 2017-12-04 Last updated: 2017-12-13Bibliographically approved

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Hernandez, Luiza I.Hernandez, Frank J

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