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RNA Aptamers-Guided Precision Cancer Medicine

  • W. Duan
  • T. Wang
  • S. Shigdar
  • P Tran
Conference paper
Part of the IFMBE Proceedings book series (IFMBE, volume 63)

Abstract

Aptamers, also known as chemical antibodies, are short single-stranded DNA or RNA that fold into complex three-dimensional structures and bind to target molecules with high affinity and specificity. Aptamers have several advantages that offer the possibility of overcoming limitations of antibodies: they have very low immunogenicity and toxicity; they display high stability at room temperature, in extreme pH, or solvent; once selected, they can be chemically synthesized free from cell-culture-derived contaminants, and they can be manufactured at any time, in large amounts, at relatively low cost and reproducibly; they are smaller and thus can diffuse more rapidly into tissues and organs and they have lower molecular weight that can lead to faster body clearance. To improve cancer treatment outcome, the cancer stem cells must be effectively eliminated. However, with a few exceptions, most anticancer drugs currently on the market are incapable of eliminating cancer stem cells. Although the Nobel Prize-winning RNAi holds great potential as a cancer stem cell therapeutic, its translation into clinical medicine is hampered by the lack of an efficient in vivo delivery system. Based on our recently developed the world first RNA aptamers (chemical antibodies) against cancer stem cell surface marker proteins, we have developed a novel strategy using an all-RNA aptamer-siRNA chimera to target cancer stem cells in vivo. Further optimisation of this platform empowered us, for the first time, to achieve cancer stem cell-targeted delivery of siRNA in mouse xenograft tumour models. This strategy can be applied to cell-targeted silencing of any disease genes in vivo. As our system is amenable to good manufacture processes with scale-up ability, the achievement will accelerate the pace of translating RNAi technology to oncology clinics and help to realise the potential of RNAi in diseases where there are currently no drugs available.

Keywords

Cancer stem cells EpCAM Surviving RNAi siRNA 

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References

  1. 1.
    Xia H, Mao Q, Paulson HL, Davidson BL (2002) siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol 20:1006–1010CrossRefGoogle Scholar
  2. 2.
    Schmidt P, Abken H (2011) The beating heart of melanomas: a minor subset of cancer cells sustains tumor growth. Oncotarget 2:313–320CrossRefGoogle Scholar
  3. 3.
    Clevers H (2011) The cancer stem cell: premises, promises and challenges. Nat Med 17:313–319CrossRefGoogle Scholar
  4. 4.
    Vaillant F et al (2013) Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 24:120–129CrossRefGoogle Scholar
  5. 5.
    Gopalan A, Yu W, Sanders BG, Kline K (2013) Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol. Cancer Lett 328:285–296CrossRefGoogle Scholar
  6. 6.
    Han M, Lv Q, Tang XJ, Hu YL, Xu DH, Li FZ, Liang WQ, Gao JQ (2012) Overcoming drug resistance of MCF-7/ADR cells by altering intracellular distribution of doxorubicin via MVP knockdown with a novel siRNA polyamidoamine-hyaluronic acid complex. J Control Release 163:136–144CrossRefGoogle Scholar
  7. 7.
    Wang FW, Dai J, Daum JR, Niedzialkowska E, Banerjee B, Stukenberg PT, Gorbsky GJ, Higgins JMG (2010) Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. Science 330:231–235CrossRefGoogle Scholar
  8. 8.
    Shigdar S, Lin J, Yu Y, Pastuovic M, Wei M, Duan W (2011) RNA aptamer against a cancer stem cell marker epithelial cell adhesion molecule. Cancer Sci 102:991–998CrossRefGoogle Scholar
  9. 9.
    Dudek H et al (2014) Knockdown of beta-catenin with dicer-substrate siRNAs reduces liver tumor burden in vivo. Mol Ther 22:92–101CrossRefGoogle Scholar
  10. 10.
    Scott D, Rose MAB (2013) Synthetic dicer-substrate siRNAs as triggers of RNA interference. Springer, BerlinGoogle Scholar
  11. 11.
    Jackson AL, Linsley PS (2010) Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discov 9:57–67CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.School of MedicineDeakin UniversityGeelongAustralia

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