Delivery of chemo-sensitizing siRNAs to HER2+-breast cancer cells using RNA aptamers

Nucleic Acids Res. 2012 Jul;40(13):6319-37. doi: 10.1093/nar/gks294. Epub 2012 Mar 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Aptamers, Nucleotide / analysis
  • Aptamers, Nucleotide / chemistry*
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Female
  • Humans
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / metabolism
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Interference*
  • RNA, Small Interfering / administration & dosage*
  • Receptor, ErbB-2 / metabolism*
  • SELEX Aptamer Technique


  • Antineoplastic Agents
  • Aptamers, Nucleotide
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Receptor, ErbB-2
  • Cisplatin