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Aptamer-Mediated siRNA Targeting

Chapter
Part of the Advances in Delivery Science and Technology book series (ADST)

Abstract

RNA interference (RNAi) is a sequence-specific mechanism for posttranscriptional inhibition of gene expression. As such, it is an attractive approach for the therapeutic treatment of a wide variety of human maladies. Although conceptually elegant, there are key barriers to the widespread clinical application of this process. One of the most formidable impediments to clinical translation of RNAi is safe and effective delivery of the siRNAs to the desired target tissue at therapeutic doses. In this regard, the advent of versatile aptamer technology has prompted the development of aptamer-mediated cell-type-specific delivery for targeted RNAi triggers. In this chapter, we explore the developments of cell-type-specific aptamer applications. We also highlight recent advances of aptamers as functionalized nanocarriers for targeted siRNA delivery.

Keywords

Respiratory Syncytial Virus Anaplastic Large Cell Lymphoma siRNA Delivery Aptamer Selection Nucleic Acid Aptamers 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments and Author Disclosure Statements

This work is supported by grants from the National Institutes of Health AI29329, AI42552, and HL07470 awarded to J.J.R.

J.Z. drafted the article. J.J.R. revised it and gave final approval of the version to be published. All authors read and approved the final article.

The authors declare no competing financial interests.

References

  1. 1.
    Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498PubMedCrossRefGoogle Scholar
  2. 2.
    Zamore PD, Tuschl T, Sharp PA, Bartel DP (2000) RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101:25–33PubMedCrossRefGoogle Scholar
  3. 3.
    Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811PubMedCrossRefGoogle Scholar
  4. 4.
    Davidson BL, McCray PB Jr (2011) Current prospects for RNA interference-based therapies. Nat Rev Genet 12:329–340PubMedCrossRefGoogle Scholar
  5. 5.
    Castanotto D, Rossi JJ (2009) The promises and pitfalls of RNA-interference-based therapeutics. Nature 457:426–433PubMedCrossRefGoogle Scholar
  6. 6.
    Lares MR, Rossi JJ, Ouellet DL (2010) RNAi and small interfering RNAs in human disease therapeutic applications. Trends Biotechnol 28:570–579PubMedCrossRefGoogle Scholar
  7. 7.
    Singerman L (2009) Combination therapy using the small interfering RNA bevasiranib. Retina 29:S49–S50PubMedCrossRefGoogle Scholar
  8. 8.
    DeVincenzo J et al (2008) Evaluation of the safety, tolerability and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed against respiratory syncytial virus (RSV). Antiviral Res 77:225–231PubMedCrossRefGoogle Scholar
  9. 9.
    DeVincenzo J et al (2010) A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad Sci USA 107:8800–8805PubMedCrossRefGoogle Scholar
  10. 10.
    Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345PubMedCrossRefGoogle Scholar
  11. 11.
    Zamora MR et al (2011) RNA interference therapy in lung transplant patients infected with respiratory syncytial virus. Am J Respir Crit Care Med 183:531–538PubMedCrossRefGoogle Scholar
  12. 12.
    Davis ME et al (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464:1067–1070PubMedCrossRefGoogle Scholar
  13. 13.
    Whitehead KA, Langer R, Anderson DG (2009) Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 8:129–138PubMedCrossRefGoogle Scholar
  14. 14.
    Juliano R, Alam MR, Dixit V, Kang H (2008) Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Res 36:4158–4171PubMedCrossRefGoogle Scholar
  15. 15.
    Perez-Martinez FC, Guerra J, Posadas I, Cena V (2011) Barriers to non-viral vector-mediated gene delivery in the nervous system. Pharm Res 28:1843–1858PubMedCrossRefGoogle Scholar
  16. 16.
    Wang J, Lu Z, Wientjes MG, Au JL (2010) Delivery of siRNA therapeutics: barriers and carriers. AAPS J 12:492–503PubMedCrossRefGoogle Scholar
  17. 17.
    Kaiser PK et al (2010) RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027. Am J Ophthalmol 150(33–39):e32Google Scholar
  18. 18.
    Kleinman ME et al (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597PubMedCrossRefGoogle Scholar
  19. 19.
    Shim MS, Kwon YJ (2010) Efficient and targeted delivery of siRNA in vivo. FEBS J 277:4814–4827PubMedCrossRefGoogle Scholar
  20. 20.
    Zhou J, Rossi JJ (2009) The therapeutic potential of cell-internalizing aptamers. Curr Top Med Chem 9:1144–1157PubMedCrossRefGoogle Scholar
  21. 21.
    Zhou J, Rossi JJ (2011) Cell-specific aptamer-mediated targeted drug delivery. Oligonucleotides 21:1–10PubMedCrossRefGoogle Scholar
  22. 22.
    Syed MA, Pervaiz S (2010) Advances in aptamers. Oligonucleotides 20:215–224PubMedCrossRefGoogle Scholar
  23. 23.
    Ellington AD, Szostak JW (1990) In vitro selection of RNA molecules that bind specific ligands. Nature 346:818–822PubMedCrossRefGoogle Scholar
  24. 24.
    Robertson DL, Joyce GF (1990) Selection in vitro of an RNA enzyme that specifically cleaves single-stranded DNA. Nature 344:467–468PubMedCrossRefGoogle Scholar
  25. 25.
    Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505–510PubMedCrossRefGoogle Scholar
  26. 26.
    Mayer G (2009) The chemical biology of aptamers. Angew Chem Int Ed Engl 48:2672–2689PubMedCrossRefGoogle Scholar
  27. 27.
    Famulok M, Hartig JS, Mayer G (2007) Functional aptamers and aptazymes in biotechnology, diagnostics, and therapy. Chem Rev 107:3715–3743PubMedCrossRefGoogle Scholar
  28. 28.
    Keefe AD, Pai S, Ellington A (2010) Aptamers as therapeutics. Nat Rev Drug Discov 9:537–550PubMedCrossRefGoogle Scholar
  29. 29.
    Bunka DH, Platonova O, Stockley PG (2010) Development of aptamer therapeutics. Curr Opin Pharmacol 10:557–562PubMedCrossRefGoogle Scholar
  30. 30.
    Phillips JA, Lopez-Colon D, Zhu Z, Xu Y, Tan W (2008) Applications of aptamers in cancer cell biology. Anal Chim Acta 621:101–108PubMedCrossRefGoogle Scholar
  31. 31.
    Guo KT, Paul A, Schichor C, Ziemer G, Wendel HP (2008) CELL-SELEX: novel perspectives of aptamer-based therapeutics. Int J Mol Sci 9:668–678PubMedCrossRefGoogle Scholar
  32. 32.
    Cerchia L, Giangrande PH, McNamara JO, de Franciscis V (2009) Cell-specific aptamers for targeted therapies. Methods Mol Biol 535:59–78PubMedCrossRefGoogle Scholar
  33. 33.
    Hicke BJ et al (2001) Tenascin-C aptamers are generated using tumor cells and purified protein. J Biol Chem 276:48644–48654PubMedCrossRefGoogle Scholar
  34. 34.
    Kulbachinskiy AV (2007) Methods for selection of aptamers to protein targets. Biochemistry (Mosc) 72:1505–1518CrossRefGoogle Scholar
  35. 35.
    Berezovski M et al (2005) Nonequilibrium capillary electrophoresis of equilibrium mixtures: a universal tool for development of aptamers. J Am Chem Soc 127:3165–3171PubMedCrossRefGoogle Scholar
  36. 36.
    Berezovski M, Musheev M, Drabovich A, Krylov SN (2006) Non-SELEX selection of aptamers. J Am Chem Soc 128:1410–1411PubMedCrossRefGoogle Scholar
  37. 37.
    Mallikaratchy P, Stahelin RV, Cao Z, Cho W, Tan W (2006) Selection of DNA ligands for protein kinase C-delta. Chem Commun (Camb)30: 3229–3231Google Scholar
  38. 38.
    Farokhzad OC et al (2005) Microfluidic system for studying the interaction of nanoparticles and microparticles with cells. Anal Chem 77:5453–5459PubMedCrossRefGoogle Scholar
  39. 39.
    Xu Y, Phillips JA, Yan J, Li Q, Fan ZH, Tan W (2009) Aptamer-based microfluidic device for enrichment, sorting, and detection of multiple cancer cells. Anal Chem 81:7436–7442PubMedCrossRefGoogle Scholar
  40. 40.
    Zhou J 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(9):3094–3109PubMedCrossRefGoogle Scholar
  41. 41.
    Li N, Larson T, Nguyen HH, Sokolov KV, Ellington AD (2010) Directed evolution of gold nanoparticle delivery to cells. Chem Commun (Camb) 46:392–394CrossRefGoogle Scholar
  42. 42.
    Chen CH et al (2008) Aptamer-based endocytosis of a lysosomal enzyme. Proc Natl Acad Sci U S A 105:15908–15913PubMedCrossRefGoogle Scholar
  43. 43.
    Kraus E, James W, Barclay AN (1998) Cutting edge: novel RNA ligands able to bind CD4 antigen and inhibit CD4+ T lymphocyte function. J Immunol 160:5209–5212PubMedGoogle Scholar
  44. 44.
    Lupold SE, Hicke BJ, Lin Y, Coffey DS (2002) Identification and characterization of nuclease-stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. Cancer Res 62:4029–4033PubMedGoogle Scholar
  45. 45.
    Cerchia L, de Franciscis V (2010) Targeting cancer cells with nucleic acid aptamers. Trends Biotechnol 28:517–525PubMedCrossRefGoogle Scholar
  46. 46.
    Cerchia L et al (2005) Neutralizing aptamers from whole-cell SELEX inhibit the RET receptor tyrosine kinase. PLoS Biol 3:e123PubMedCrossRefGoogle Scholar
  47. 47.
    Pestourie C et al (2006) Comparison of different strategies to select aptamers against a transmembrane protein target. Oligonucleotides 16:323–335PubMedCrossRefGoogle Scholar
  48. 48.
    Liu Y et al (2009) Aptamers selected against the unglycosylated EGFRvIII ectodomain and delivered intracellularly reduce membrane-bound EGFRvIII and induce apoptosis. Biol Chem 390:137–144PubMedGoogle Scholar
  49. 49.
    Fang X, Tan W (2009) Aptamers generated from cell-SELEX for molecular medicine: a chemical biology approach. Acc Chem Res 43(1):48–57CrossRefGoogle Scholar
  50. 50.
    Shangguan D et al (2008) Cell-specific aptamer probes for membrane protein elucidation in cancer cells. J Proteome Res 7:2133–2139PubMedCrossRefGoogle Scholar
  51. 51.
    Shangguan D, Cao ZC, Li Y, Tan W (2007) Aptamers evolved from cultured cancer cells reveal molecular differences of cancer cells in patient samples. Clin Chem 53:1153–1155PubMedCrossRefGoogle Scholar
  52. 52.
    Blank M, Weinschenk T, Priemer M, Schluesener H (2001) Systematic evolution of a DNA aptamer binding to rat brain tumor microvessels. Selective targeting of endothelial regulatory protein pigpen. J Biol Chem 276:16464–16468PubMedCrossRefGoogle Scholar
  53. 53.
    Shangguan D et al (2006) Aptamers evolved from live cells as effective molecular probes for cancer study. Proc Natl Acad Sci U S A 103:11838–11843PubMedCrossRefGoogle Scholar
  54. 54.
    Avci-Adali M, Metzger M, Perle N, Ziemer G, Wendel HP (2010) Pitfalls of cell-systematic evolution of ligands by exponential enrichment (SELEX): existing dead cells during in vitro selection anticipate the enrichment of specific aptamers. Oligonucleotides 20:317–323PubMedCrossRefGoogle Scholar
  55. 55.
    Levy-Nissenbaum E, Radovic-Moreno AF, Wang AZ, Langer R, Farokhzad OC (2008) Nanotechnology and aptamers: applications in drug delivery. Trends Biotechnol 26:442–449PubMedCrossRefGoogle Scholar
  56. 56.
    Bagalkot V, Farokhzad OC, Langer R, Jon S (2006) An aptamer-doxorubicin physical conjugate as a novel targeted drug-delivery platform. Angew Chem Int Ed Engl 45:8149–8152PubMedCrossRefGoogle Scholar
  57. 57.
    Cheng J et al (2007) Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. Biomaterials 28:869–876PubMedCrossRefGoogle Scholar
  58. 58.
    Dhar S, Gu FX, Langer R, Farokhzad OC, Lippard SJ (2008) Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc Natl Acad Sci USA 105:17356–17361PubMedCrossRefGoogle Scholar
  59. 59.
    Farokhzad OC et al (2006) Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci USA 103:6315–6320PubMedCrossRefGoogle Scholar
  60. 60.
    Gu F et al (2008) Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc Natl Acad Sci USA 105:2586–2591PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang L et al (2007) Co-delivery of hydrophobic and hydrophilic drugs from nanoparticle-aptamer bioconjugates. ChemMedChem 2:1268–1271PubMedCrossRefGoogle Scholar
  62. 62.
    Engels FK, Mathot RA, Verweij J (2007) Alternative drug formulations of docetaxel: a review. Anticancer Drugs 18:95–103PubMedCrossRefGoogle Scholar
  63. 63.
    Cao Z et al (2009) Reversible cell-specific drug delivery with aptamer-functionalized liposomes. Angew Chem Int Ed Engl 48:6494–6498PubMedCrossRefGoogle Scholar
  64. 64.
    Ferreira CS, Cheung MC, Missailidis S, Bisland S, Gariepy J (2009) Phototoxic aptamers selectively enter and kill epithelial cancer cells. Nucleic Acids Res 37:866–876PubMedCrossRefGoogle Scholar
  65. 65.
    Chu TC et al (2006) Aptamer:toxin conjugates that specifically target prostate tumor cells. Cancer Res 66:5989–5992PubMedCrossRefGoogle Scholar
  66. 66.
    Hicke BJ et al (2006) Tumor targeting by an aptamer. J Nucl Med 47:668–678PubMedGoogle Scholar
  67. 67.
    Tong GJ, Hsiao SC, Carrico ZM, Francis MB (2009) Viral capsid DNA aptamer conjugates as multivalent cell-targeting vehicles. J Am Chem Soc 131:11174–11178PubMedCrossRefGoogle Scholar
  68. 68.
    Zhou J, Rossi JJ (2010) Aptamer-targeted cell-specific RNA interference. Silence 1:4PubMedCrossRefGoogle Scholar
  69. 69.
    Chu TC, Twu KY, Ellington AD, Levy M (2006) Aptamer mediated siRNA delivery. Nucleic Acids Res 34:e73PubMedCrossRefGoogle Scholar
  70. 70.
    McNamara JO 2nd et al (2006) Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol 24:1005–1015PubMedCrossRefGoogle Scholar
  71. 71.
    Dassie JP et al (2009) Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat Biotechnol 27:839–849PubMedCrossRefGoogle Scholar
  72. 72.
    Pastor F, Kolonias D, Giangrande PH, Gilboa E (2010) Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. Nature 465:227–230PubMedCrossRefGoogle Scholar
  73. 73.
    Zhou J, Li H, Li S, Zaia J, Rossi JJ (2008) Novel dual inhibitory function aptamer-siRNA delivery system for HIV-1 therapy. Mol Ther 16:1481–1489PubMedCrossRefGoogle Scholar
  74. 74.
    Neff CP et al (2011) An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice. Sci Transl Med 3:66ra66CrossRefGoogle Scholar
  75. 75.
    Wheeler LA et al (2011) Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras. J Clin Invest 121:2401–2412PubMedCrossRefGoogle Scholar
  76. 76.
    Shi H, Hoffman BE, Lis JT (1999) RNA aptamers as effective protein antagonists in a multicellular organism. Proc Natl Acad Sci USA 96:10033–10038PubMedCrossRefGoogle Scholar
  77. 77.
    Santulli-Marotto S, Nair SK, Rusconi C, Sullenger B, Gilboa E (2003) Multivalent RNA aptamers that inhibit CTLA-4 and enhance tumor immunity. Cancer Res 63:7483–7489PubMedGoogle Scholar
  78. 78.
    McNamara JO et al (2008) Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice. J Clin Invest 118:376–386PubMedCrossRefGoogle Scholar
  79. 79.
    Dollins CM et al (2008) Assembling OX40 aptamers on a molecular scaffold to create a receptor-activating aptamer. Chem Biol 15:675–682PubMedCrossRefGoogle Scholar
  80. 80.
    Wullner U, Neef I, Eller A, Kleines M, Tur MK, Barth S (2008) Cell-specific induction of apoptosis by rationally designed bivalent aptamer-siRNA transcripts silencing eukaryotic elongation factor 2. Curr Cancer Drug Targets 8:554–565PubMedCrossRefGoogle Scholar
  81. 81.
    Guo P (2010) The emerging field of RNA nanotechnology. Nat Nanotechnol 5:833–842PubMedCrossRefGoogle Scholar
  82. 82.
    De Rosa G, La Rotonda MI (2009) Nano and microtechnologies for the delivery of oligonucleotides with gene silencing properties. Molecules 14:2801–2823PubMedCrossRefGoogle Scholar
  83. 83.
    Kim S, Kim JH, Jeon O, Kwon IC, Park K (2009) Engineered polymers for advanced drug delivery. Eur J Pharm Biopharm 71:420–430PubMedCrossRefGoogle Scholar
  84. 84.
    Tan W et al (2011) Molecular aptamers for drug delivery. Trends Biotechnol 29:634–640PubMedCrossRefGoogle Scholar
  85. 85.
    Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392PubMedGoogle Scholar
  86. 86.
    Greish K (2007) Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J Drug Target 15:457–464PubMedCrossRefGoogle Scholar
  87. 87.
    Guo P (2005) RNA nanotechnology: engineering, assembly and applications in detection, gene delivery and therapy. J Nanosci Nanotechnol 5:1964–1982PubMedCrossRefGoogle Scholar
  88. 88.
    Shu D, Huang LP, Hoeprich S, Guo P (2003) Construction of phi29 DNA-packaging RNA monomers, dimers, and trimers with variable sizes and shapes as potential parts for nanodevices. J Nanosci Nanotechnol 3:295–302PubMedCrossRefGoogle Scholar
  89. 89.
    Guo P et al (2010) Engineering RNA for targeted siRNA delivery and medical application. Adv Drug Deliv Rev 62:650–666PubMedCrossRefGoogle Scholar
  90. 90.
    Shu Y, Cinier M, Shu D, Guo P (2011) Assembly of multifunctional phi29 pRNA nanoparticles for specific delivery of siRNA and other therapeutics to targeted cells. Methods 54(2):204–214PubMedCrossRefGoogle Scholar
  91. 91.
    Guo S, Tschammer N, Mohammed S, Guo P (2005) Specific delivery of therapeutic RNAs to cancer cells via the dimerization mechanism of phi29 motor pRNA. Hum Gene Ther 16:1097–1109PubMedCrossRefGoogle Scholar
  92. 92.
    Hoeprich S, Guo P (2002) Computer modeling of three-dimensional structure of DNA-packaging RNA (pRNA) monomer, dimer, and hexamer of Phi29 DNA packaging motor. J Biol Chem 277:20794–20803PubMedCrossRefGoogle Scholar
  93. 93.
    Kim E et al (2010) Prostate cancer cell death produced by the co-delivery of Bcl-xL shRNA and doxorubicin using an aptamer-conjugated polyplex. Biomaterials 31:4592–4599PubMedCrossRefGoogle Scholar
  94. 94.
    Zhao N, Bagaria HG, Wong MS, Zu Y (2011) A nanocomplex that is both tumor cell-selective and cancer gene-specific for anaplastic large cell lymphoma. J Nanobiotechnology 9:2PubMedCrossRefGoogle Scholar
  95. 95.
    Zhang P et al (2009) Using an RNA aptamer probe for flow cytometry detection of CD30-expressing lymphoma cells. Lab Invest 89:1423–1432PubMedCrossRefGoogle Scholar
  96. 96.
    Duyster J, Bai RY, Morris SW (2001) Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20:5623–5637PubMedCrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2013

Authors and Affiliations

  1. 1.Division of Molecular and Cellular BiologyBeckman Research Institute of City of Hope, City of HopeDuarteUSA
  2. 2.Irell and Manella Graduate School of Biological Sciences, Division of Molecular and Cellular BiologyBeckman Research Institute of City of Hope, City of HopeDuarteUSA

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