Delivery of chemo-sensitizing siRNAs to HER2+-breast cancer cells using RNA aptamersShow others and affiliations
2012 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no 13, p. 6319-6337
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, p. 6319-6337
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-143338DOI: 10.1093/nar/gks294ISI: 000306970700049PubMedID: 22467215Scopus ID: 2-s2.0-84864447484OAI: oai:DiVA.org:liu-143338DiVA, id: diva2:1162518
2017-12-042017-12-042021-12-28Bibliographically approved