Skip to main content

Aptamer-MiRNA Conjugates for Cancer Cell-Targeted Delivery

  • Protocol
SiRNA Delivery Methods

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1364))

Abstract

microRNAs (miRNAs) are short noncoding RNAs that effectively regulate the expression of a wide variety of genes. Increasing evidences have shown a fundamental role of miRNAs in cancer initiation and progression, thus indicating these molecules among the most promising for new approaches in cancer therapy. However, several hurdles limit the translation of miRNAs into the clinic. One of the most critical aspects is represented by the lack of a safe and reliable way to selectively target organs and tissues. Therefore, the development of cell-specific delivery means has become an essential step for the translation of miRNA-based therapeutics to clinic for cancer management. To this end aptamer-based approaches may provide efficient delivery tools for the selective accumulation of miRNA to target tumors, their intracellular uptake, processing, and functional silencing of target genes. In this chapter, we discuss the direct conjugation of miRNAs to aptamers against transmembrane receptors as innovative experimental approach for their selective delivery to cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  2. Elbashir SM, Lendeckel W, Tuschl T (2001) RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev 15:188–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Rand TA, Petersen S, Du F et al (2005) Argonaute2 cleaves the anti-guide strand of siRNA during RISC activation. Cell 123:621–629

    Article  CAS  PubMed  Google Scholar 

  4. Li Z, Rana TM (2014) Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov 13:622–638

    Article  CAS  PubMed  Google Scholar 

  5. Di Leva G, Garofalo M, Croce CM (2013) MicroRNAs in cancer. Annu Rev Pathol 14:287–314

    Google Scholar 

  6. Garofalo M, Condorelli GL, Croce CM et al (2010) MicroRNAs as regulators of death receptors signaling. Cell Death Differ 17:200–208

    Article  CAS  PubMed  Google Scholar 

  7. Boyerinas B, Park SM, Hau A et al (2010) The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer 17:F19–F36

    Article  CAS  PubMed  Google Scholar 

  8. Johnson SM, Grosshans H, Shingara J et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647

    Article  CAS  PubMed  Google Scholar 

  9. Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21:1025–1030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Calin GA, Cimmino A, Fabbri M et al (2008) MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A 105:5166–5171

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Bartels CL, Tsongalis GJ (2009) MicroRNAs: novel biomarkers for human cancer. Clin Chem 55:623–631

    Article  CAS  PubMed  Google Scholar 

  12. Rothschild SI (2014) microRNA therapies in cancer. Mol Cell Ther 2:7

    Article  PubMed Central  PubMed  Google Scholar 

  13. Wu SY, Lopez-Berestein G, Calin GA et al (2014) RNAi therapies: drugging the undruggable. Sci Transl Med 6:240ps7

    Article  PubMed Central  PubMed  Google Scholar 

  14. Esposito CL, Cerchia L, Catuogno S et al (2014) Multifunctional aptamer-miRNA conjugates for targeted cancer therapy. Mol Ther 22:1151–1163

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Kota J, Chivukula RR, O’Donnell KA et al (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancermodel. Cell 137:1005–1017

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Kay MA (2011) State-of-the-art gene-based therapies: the road ahead. Nat Rev Genet 12:316–328

    Article  CAS  PubMed  Google Scholar 

  17. Zhou J, Shum KT, Burnett JC et al (2013) Nanoparticle-based delivery of RNAi therapeutics: progress and challenges. Pharmaceuticals (Basel) 6:85–107

    Article  CAS  Google Scholar 

  18. Bouchie A (2013) First microRNA mimic enters clinic. Nat Biotechnol 31:577

    Article  CAS  PubMed  Google Scholar 

  19. Cedervall T, Lynch I, Lindman S et al (2007) Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci U S A 104:2050–2055

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Tuek C, Gold L (1990) Systematic evolution of ligands by exponential enrichment RNA ligands to bacteriophage T4 polymerase. Science 249:505–510

    Article  Google Scholar 

  21. Esposito CL, Catuogno S, de Franciscis V et al (2011) New insight into clinical development of nucleic acid aptamers. Discov Med 11:487–496

    PubMed  Google Scholar 

  22. Cerchia L, de Franciscis V (2010) Targeting cancer cells with nucleic acid aptamers. Trends Biotechnol 28:517–525

    Article  CAS  PubMed  Google Scholar 

  23. Wang J, Sefah K, Altman MB et al (2013) Aptamer-conjugated nanorods for targeted photothermal therapy of prostate cancer stem cells. Chem Asian J 8:2417–2422

    Article  CAS  PubMed  Google Scholar 

  24. Farokhzad OC, Cheng J, Teply BA et al (2006) Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A 103:6315–6320

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Bagalkot V, Farokhzad OC, Langer R et al (2006) Anaptamer doxorubicin physical conjugateas a novel targeted drug-delivery platform. Angew Chem Int Ed Engl 45:8149–8152

    Article  CAS  PubMed  Google Scholar 

  26. Chu TC, Marks JW 3rd, Lavery LA et al (2006) Aptamer:toxin conjugates that specifically target prostate tumor cells. Cancer Res 66:5989–5992

    Article  CAS  PubMed  Google Scholar 

  27. Chen CH, Dellamaggiore KR, Ouellette CP et al (2008) Aptamer-based endocytosis of a lysosomal enzyme. Proc Natl Acad Sci U S A 105:15908–15913

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Hicke BJ, Stephens AW, Gould T et al (2006) Tumor targeting by an aptamer. J Nucl Med 47:668–678

    CAS  PubMed  Google Scholar 

  29. Tong GJ, Hsiao SC, Carrico ZM et al (2009) Viral capsid DNA aptamer conjugates as multivalent cell targeting vehicles. J Am Chem Soc 131:11174–11178

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. McNamara JO II, Andrechek ER, Wang Y et al (2006) Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol 24:1005–1015

    Article  CAS  PubMed  Google Scholar 

  31. Wullner U, Neef I, Eller A et al (2008) Cell-specific induction of apoptosis by rationally designed bivalent aptamer-siRNA transcripts silencing eukaryotic elongation factor 2. Curr Cancer Drug Targets 8:554–565

    Article  CAS  PubMed  Google Scholar 

  32. Dassie JP, Liu XY, Thomas GS et al (2009) Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat Biotechnol 27:839–849

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Neff CP, Zhou J, Remling L et al (2011) An aptamer-siRNA conjugate suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice. Sci Transl Med 3:66ra6

    Article  PubMed Central  PubMed  Google Scholar 

  34. Ni X, Zhang Y, Ribas J et al (2011) Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts. J Clin Invest 121:2383–2390

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Wheeler LA, Trifonova R, Vrbanac V et al (2011) Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras. J Clin Invest 121:2401–2424

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Thiel KW, Hernandez LI, Dassie JP et al (2012) Delivery of chemo-sensitizing siRNAs to HER2+-breast cancer cells using RNA aptamers. Nucleic Acids Res 40:6319–6337

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Zhu Q, Shibata T, Kabashima T et al (2012) Inhibition of HIV-1 protease expression in T cells owing to DNA aptamer-mediated specific delivery of siRNA. Eur J Med Chem 56:396–399

    Article  CAS  PubMed  Google Scholar 

  38. Zhou J, Swiderski P, Li H et al (2009) Selection, characterization and application of new RNA HIV gp 120 aptamers for facile delivery of Dicer substrate siRNAs into HIV infected cells. Nucleic Acids Res 37:3094–3109

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Zhou J, Neff CP, Swiderski P et al (2013) Functional in vivo delivery of multiplexed anti-HIV-1 siRNAs via a chemically synthesized aptamer with a sticky bridge. Mol Ther 21:192–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Liu N, Zhou C, Zhao J et al (2012) Reversal of paclitaxel resistance in epithelial ovarian carcinoma cells by a MUC1 aptamerlet-7i chimera. Cancer Invest 30:577–582

    Article  CAS  PubMed  Google Scholar 

  41. Dai F, Zhang Y, Zhu X et al (2012) Anticancer role of MUC1 aptamer-miR-29b chimera in epithelial ovarian carcinoma cells through regulation of PTEN methylation. Target Oncol 7:217–225

    Article  PubMed  Google Scholar 

  42. Cerchia L, Esposito CL, Camorani S et al (2012) Targeting Axl with an high-affinity inhibitory aptamer. Mol Ther 20:2291–303

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Camorani S, Esposito CL, Rienzo A et al (2014) Inhibition of receptor signaling and of glioblastoma-derived tumor growth by a novel PDGFRβ aptamer. Mol Ther 22:828–841

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Amarzguioui M, Rossi JJ (2008) Principles of Dicer substrate (D-siRNA) design and function. Methods Mol Biol 442:3–10

    Article  CAS  PubMed  Google Scholar 

  45. Robbins M, Judge A, MacLachlan I (2009) siRNA and innate immunity. Oligonucleotides 19:89–102

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This work was supported by funds from: MIUR grant, MERIT RBNE08YFN3_001 (VdF), AIRC # 13345 (VdF); from the Italian Ministry of Economy and Finance to the CNR for the Project FaReBio di Qualità (VdF); Grant CNR “Medicina Personalizzata” (VdF); Compagnia San Paolo # 2011.1172 (VdF); CNR Flagship Project NanoMax (DESIRED) 2012–2014 (VdF).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Vittorio de Franciscis .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this protocol

Cite this protocol

Esposito, C.L., Catuogno, S., de Franciscis, V. (2016). Aptamer-MiRNA Conjugates for Cancer Cell-Targeted Delivery. In: Shum, K., Rossi, J. (eds) SiRNA Delivery Methods. Methods in Molecular Biology, vol 1364. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3112-5_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3112-5_16

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3111-8

  • Online ISBN: 978-1-4939-3112-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics