Synthetic Dicer-Substrate siRNAs as Triggers of RNA Interference

Chapter

Abstract

The first synthetic oligonucleotides used to suppress gene expression in mammalian cells via RNA interference were 21-nucleotide (nt) RNA duplexes having symmetric 2-nt 3′-overhangs and were designed to mimic the natural products of Dicer processing of long RNA substrates. Synthetic RNA duplexes which are longer than 23-nt length are substrates for processing by Dicer and can show increased potency as artificial triggers of RNA interference, particularly at a low concentration. Longer duplexes, however, can have variable cleavage patterns following Dicer processing which can adversely affect potency. Optimized synthetic Dicer substrates are asymmetric duplexes having a 25-nt passenger strand and a 27-nt guide strand with a single 2-nt 3′-overhang on the guide strand and modified bases at the 3′-end of the passenger strand. This modified design results in predictable patterns of Dicer processing and shows improved activity. The development of this design strategy and use of Dicer-substrate RNAs to trigger gene suppression in a variety of systems will be reviewed in this chapter.

References

  1. 1.
    Mello CC, Conte D Jr (2004) Revealing the world of RNA interference. Nature 431(7006):338–342PubMedGoogle Scholar
  2. 2.
    Siomi H, Siomi MC (2009) On the road to reading the RNA-interference code. Nature 457(7228):396–404PubMedGoogle Scholar
  3. 3.
    Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136(4):642–655PubMedGoogle Scholar
  4. 4.
    Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–355PubMedGoogle Scholar
  5. 5.
    Meister G, Tuschl T (2004) Mechanisms of gene silencing by double-stranded RNA. Nature 431(7006):343–349PubMedGoogle Scholar
  6. 6.
    Vickers TA, Lima WF, Wu H, Nichols JG, Linsley PS, Crooke ST (2009) Off-target and a portion of target-specific siRNA mediated mRNA degradation is Ago2 ‘Slicer’ independent and can be mediated by Ago1. Nucleic Acids Res 37(20):6927–6941PubMedGoogle Scholar
  7. 7.
    Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409(6818):363–366PubMedGoogle Scholar
  8. 8.
    Zhang H, Kolb FA, Brondani V, Billy E, Filipowicz W (2002) Human Dicer preferentially cleaves dsRNAs at their termini without a requirement for ATP. EMBO J 21(21):5875–5885PubMedGoogle Scholar
  9. 9.
    Okamura K, Lai EC (2008) Endogenous small interfering RNAs in animals. Nat Rev Mol Cell Biol 9(9):673–678PubMedGoogle Scholar
  10. 10.
    Liu Q, Rand TA, Kalidas S, Du F, Kim HE, Smith DP et al (2003) R2D2, a bridge between the initiation and effector steps of the Drosophila RNAi pathway. Science 301(5641): 1921–1925PubMedGoogle Scholar
  11. 11.
    Haase AD, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A et al (2005) TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep 6(10):961–967PubMedGoogle Scholar
  12. 12.
    Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K et al (2005) TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436(7051):740–744PubMedGoogle Scholar
  13. 13.
    MacRae IJ, Zhou K, Li F, Repic A, Brooks AN, Cande WZ et al (2006) Structural basis for double-stranded RNA processing by Dicer. Science 311(5758):195–198PubMedGoogle Scholar
  14. 14.
    MacRae IJ, Zhou K, Doudna JA (2007) Structural determinants of RNA recognition and cleavage by Dicer. Nat Struct Mol Biol 14(10):934–940PubMedGoogle Scholar
  15. 15.
    Maniataki E, Mourelatos Z (2005) A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev 19(24):2979–2990PubMedGoogle Scholar
  16. 16.
    Sontheimer EJ (2005) Assembly and function of RNA silencing complexes. Nat Rev Mol Cell Biol 6(2):127–138PubMedGoogle Scholar
  17. 17.
    Matranga C, Tomari Y, Shin C, Bartel DP, Zamore PD (2005) Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 123(4):607–620PubMedGoogle Scholar
  18. 18.
    Rand TA, Petersen S, Du F, Wang X (2005) Argonaute2 cleaves the anti-guide strand of siRNA during RISC activation. Cell 123(4):621–629PubMedGoogle Scholar
  19. 19.
    Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R (2005) Human RISC couples MicroRNA biogenesis and posttranscriptional gene silencing. Cell 123(4):631–640PubMedGoogle Scholar
  20. 20.
    Lingel A, Simon B, Izaurralde E, Sattler M (2004) Nucleic acid 3’-end recognition by the Argonaute2 PAZ domain. Nat Struct Mol Biol 11(6):576–577PubMedGoogle Scholar
  21. 21.
    Okamura K, Ishizuka A, Siomi H, Siomi MC (2004) Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. Genes Dev 18(14):1655–1666PubMedGoogle Scholar
  22. 22.
    Peters L, Meister G (2007) Argonaute proteins: mediators of RNA silencing. Mol Cell 26(5):611–623PubMedGoogle Scholar
  23. 23.
    Hutvagner G, Simard MJ (2008) Argonaute proteins: key players in RNA silencing. Nat Rev Mol Cell Biol 9(1):22–32PubMedGoogle Scholar
  24. 24.
    Wang B, Li S, Qi HH, Chowdhury D, Shi Y, Novina CD (2009) Distinct passenger strand and mRNA cleavage activities of human Argonaute proteins. Nat Struct Mol Biol 16(12): 1259–1266PubMedGoogle Scholar
  25. 25.
    Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T (2004) Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell 15(2):185–197PubMedGoogle Scholar
  26. 26.
    Ameres SL, Martinez J, Schroeder R (2007) Molecular basis for target RNA recognition and cleavage by human RISC. Cell 130(1):101–112PubMedGoogle Scholar
  27. 27.
    Wang HW, Noland C, Siridechadilok B, Taylor DW, Ma E, Felderer K et al (2009) Structural insights into RNA processing by the human RISC-loading complex. Nat Struct Mol Biol 16(11):1148–1153PubMedGoogle Scholar
  28. 28.
    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(6836):494–498PubMedGoogle Scholar
  29. 29.
    Chang CI, Kim HA, Dua P, Kim S, Li CJ, Lee DK (2011) Structural diversity repertoire of gene silencing small interfering RNAs. Nucleic Acid Ther 21(3):125–131PubMedGoogle Scholar
  30. 30.
    Kim DH, Behlke MA, Rose SD, Chang MS, Choi S, Rossi JJ (2005) Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat Biotechnol 23(2):222–226PubMedGoogle Scholar
  31. 31.
    Rose SD, Kim DH, Amarzguioui M, Heidel JD, Collingwood MA, Davis ME et al (2005) Functional polarity is introduced by Dicer processing of short substrate RNAs. Nucleic Acids Res 33(13):4140–4156PubMedGoogle Scholar
  32. 32.
    Sano M, Sierant M, Miyagishi M, Nakanishi M, Takagi Y, Sutou S (2008) Effect of asymmetric terminal structures of short RNA duplexes on the RNA interference activity and strand selection. Nucleic Acids Res 36(18):5812–5821PubMedGoogle Scholar
  33. 33.
    Aza-Blanc P, Cooper CL, Wagner K, Batalov S, Deveraux QL, Cooke MP (2003) Identification of modulators of TRAIL-induced apoptosis via RNAi-based phenotypic screening. Mol Cell 12(3):627–637PubMedGoogle Scholar
  34. 34.
    Khvorova A, Reynolds A, Jayasena SD (2003) Functional siRNAs and miRNAs exhibit strand bias. Cell 115(2):209–216PubMedGoogle Scholar
  35. 35.
    Schwarz DS, Hutvagner G, Du T, Xu Z, Aronin N, Zamore PD (2003) Asymmetry in the assembly of the RNAi enzyme complex. Cell 115(2):199–208PubMedGoogle Scholar
  36. 36.
    Noland CL, Ma E, Doudna JA (2011) siRNA repositioning for guide strand selection by human Dicer complexes. Mol Cell 43(1):110–121PubMedGoogle Scholar
  37. 37.
    Hefner E, Clark K, Whitman C, Behlke MA, Rose SD, Peek AS et al (2008) Increased potency and longevity of gene silencing using validated Dicer substrates. J Biomol Tech 19(4):231–237PubMedGoogle Scholar
  38. 38.
    Eder PS, DeVine RJ, Dagle JM, Walder JA (1991) Substrate specificity and kinetics of degradation of antisense oligonucleotides by a 3’ exonuclease in plasma. Antisense Res Dev 1(2):141–151PubMedGoogle Scholar
  39. 39.
    Kurreck J (2003) Antisense technologies Improvement through novel chemical modifications. Eur J Biochem 270(8):1628–1644PubMedGoogle Scholar
  40. 40.
    Behlke MA (2008) Chemical modification of siRNAs for in vivo use. Oligonucleotides 18(4):305–320PubMedGoogle Scholar
  41. 41.
    Gaglione M, Messere A (2010) Recent progress in chemically modified siRNAs. Mini Rev Med Chem 10(7):578–595PubMedGoogle Scholar
  42. 42.
    Krieg AM, Stein CA (1995) Phosphorothioate oligodeoxynucleotides: antisense or anti-protein? Antisense Res Dev 5(4):241PubMedGoogle Scholar
  43. 43.
    Braasch DA, Jensen S, Liu Y, Kaur K, Arar K, White MA et al (2003) RNA interference in mammalian cells by chemically-modified RNA. Biochemistry 42(26):7967–7975PubMedGoogle Scholar
  44. 44.
    Amarzguioui M, Holen T, Babaie E, Prydz H (2003) Tolerance for mutations and chemical modifications in a siRNA. Nucleic Acids Res 31(2):589–595PubMedGoogle Scholar
  45. 45.
    Chiu YL, Rana TM (2003) siRNA function in RNAi: a chemical modification analysis. RNA 9(9):1034–1048PubMedGoogle Scholar
  46. 46.
    Czauderna F, Fechtner M, Dames S, Aygun H, Klippel A, Pronk GJ et al (2003) Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. Nucleic Acids Res 31(11):2705–2716PubMedGoogle Scholar
  47. 47.
    Harborth J, Elbashir SM, Vandenburgh K, Manninga H, Scaringe SA, Weber K et al (2003) Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. Antisense Nucleic Acid Drug Dev 13(2):83–105PubMedGoogle Scholar
  48. 48.
    Choung S, Kim YJ, Kim S, Park HO, Choi YC (2006) Chemical modification of siRNAs to improve serum stability without loss of efficacy. Biochem Biophys Res Commun 342(3):919–927PubMedGoogle Scholar
  49. 49.
    Allerson CR, Sioufi N, Jarres R, Prakash TP, Naik N, Berdeja A et al (2005) Fully 2’-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. J Med Chem 48(4):901–904PubMedGoogle Scholar
  50. 50.
    Prakash TP, Allerson CR, Dande P, Vickers TA, Sioufi N, Jarres R et al (2005) Positional effect of chemical modifications on short interference RNA activity in mammalian cells. J Med Chem 48(13):4247–4253PubMedGoogle Scholar
  51. 51.
    Kraynack BA, Baker BF (2006) Small interfering RNAs containing full 2’-O-methylribonucleotide-modified sense strands display Argonaute2/eIF2C2-dependent activity. RNA 12(1):163–176PubMedGoogle Scholar
  52. 52.
    Layzer JM, McCaffrey AP, Tanner AK, Huang Z, Kay MA, Sullenger BA (2004) In vivo activity of nuclease-resistant siRNAs. RNA 10(5):766–771PubMedGoogle Scholar
  53. 53.
    Morrissey DV, Blanchard K, Shaw L, Jensen K, Lockridge JA, Dickinson B et al (2005) Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology 41(6):1349–1356PubMedGoogle Scholar
  54. 54.
    Morrissey DV, Lockridge JA, Shaw L, Blanchard K, Jensen K, Breen W et al (2005) Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 23(8):1002–1007PubMedGoogle Scholar
  55. 55.
    Swayze EE, Siwkowski AM, Wancewicz EV, Migawa MT, Wyrzykiewicz TK, Hung G et al (2007) Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals. Nucleic Acids Res 35(2):687–700PubMedGoogle Scholar
  56. 56.
    Elmen J, Thonberg H, Ljungberg K, Frieden M, Westergaard M, Xu Y et al (2005) Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality. Nucleic Acids Res 33(1):439–447PubMedGoogle Scholar
  57. 57.
    Elmen J, Lindow M, Silahtaroglu A, Bak M, Christensen M, Lind-Thomsen A et al (2008) Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res 36(4):1153–1162PubMedGoogle Scholar
  58. 58.
    Elmen J, Lindow M, Schutz S, Lawrence M, Petri A, Obad S et al (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452(7189):896–899PubMedGoogle Scholar
  59. 59.
    Kubo T, Zhelev Z, Ohba H, Bakalova R (2007) Modified 27-nt dsRNAs with dramatically enhanced stability in serum and long-term RNAi activity. Oligonucleotides 17(4): 445–464PubMedGoogle Scholar
  60. 60.
    Kubo T, Zhelev Z, Ohba H, Bakalova R (2008) Chemically modified symmetric and asymmetric duplex RNAs: an enhanced stability to nuclease degradation and gene silencing effect. Biochem Biophys Res Commun 365(1):54–61PubMedGoogle Scholar
  61. 61.
    Turner JJ, Jones SW, Moschos SA, Lindsay MA, Gait MJ (2007) MALDI-TOF mass spectral analysis of siRNA degradation in serum confirms an RNAse A-like activity. Mol Biosyst 3(1):43–50PubMedGoogle Scholar
  62. 62.
    Collingwood MA, Rose SD, Huang L, Hillier C, Amarzguioui M, Wiiger MT et al (2008) Chemical modification patterns compatible with high potency dicer-substrate small interfering RNAs. Oligonucleotides 18(2):187–200PubMedGoogle Scholar
  63. 63.
    Nishina K, Unno T, Uno Y, Kubodera T, Kanouchi T, Mizusawa H et al (2008) Efficient in vivo delivery of siRNA to the liver by conjugation of alpha-tocopherol. Mol Ther 16(4):734–740PubMedGoogle Scholar
  64. 64.
    Rigotti A (2007) Absorption, transport, and tissue delivery of vitamin E. Mol Aspects Med 28(5–6):423–436PubMedGoogle Scholar
  65. 65.
    Kubo T, Takei Y, Mihara K, Yanagihara K, Seyama T (2012) Amino-modified and lipid-conjugated dicer-substrate siRNA enhances RNAi efficacy. Bioconjug Chem 23(2):164–173PubMedGoogle Scholar
  66. 66.
    Kariko K, Buckstein M, Ni H, Weissman D (2005) Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23(2):165–175PubMedGoogle Scholar
  67. 67.
    Robbins M, Judge A, Liang L, McClintock K, Yaworski E, Maclachlan I (2007) 2’-O-methyl-modified RNAs Act as TLR7 Antagonists. Mol Ther 15(9):1663–1669PubMedGoogle Scholar
  68. 68.
    Gantier MP, Williams BR (2007) The response of mammalian cells to double-stranded RNA. Cytokine Growth Factor Rev 18(5–6):363–371PubMedGoogle Scholar
  69. 69.
    Robbins M, Judge A, MacLachlan I (2009) siRNA and innate immunity. Oligonucleotides 19(2):89–102PubMedGoogle Scholar
  70. 70.
    Reynolds A, Anderson EM, Vermeulen A, Fedorov Y, Robinson K, Leake D et al (2006) Induction of the interferon response by siRNA is cell type- and duplex length-dependent. RNA 12(6):988–993PubMedGoogle Scholar
  71. 71.
    Fedorov Y, King A, Anderson E, Karpilow J, Ilsley D, Marshall W et al (2005) Different delivery methods-different expression profiles. Nat Methods 2(4):241PubMedGoogle Scholar
  72. 72.
    Marques JT, Devosse T, Wang D, Zamanian-Daryoush M, Serbinowski P, Hartmann R et al (2006) A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat Biotechnol 24(5):559–565PubMedGoogle Scholar
  73. 73.
    Behlke MA (2006) Progress towards in vivo use of siRNAs. Mol Ther 13(4):644–670PubMedGoogle Scholar
  74. 74.
    Rettig GR, Behlke MA (2012) Progress towards in vivo use of siRNAs-II. Mol Ther 20:483–512PubMedGoogle Scholar
  75. 75.
    Lundberg P, Welander PV, Edwards CK 3rd, van Rooijen N, Cantin E (2007) Tumor necrosis factor (TNF) protects resistant C57BL/6 mice against herpes simplex virus-induced encephalitis independently of signaling via TNF receptor 1 or 2. J Virol 81(3):1451–1460PubMedGoogle Scholar
  76. 76.
    Lundberg P, Yang H-J, Jung S-J, Behlke MA, Rose SD, Cantin EM (2012) Protection against TNFα-dependent liver toxicity by intraperitoneal liposome delivered DsiRNA targeting TNFα in vivo. J Control Release 160:194–199PubMedGoogle Scholar
  77. 77.
    Howard KA, Paludan SR, Behlke MA, Besenbacher F, Deleuran B, Kjems J (2008) Chitosan/siRNA nanoparticle-mediated TNF-alpha knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model. Mol Ther 17(1):162–168PubMedGoogle Scholar
  78. 78.
    Nawroth I, Alsner J, Behlke MA, Besenbacher F, Overgaard J, Howard KA et al (2010) Intraperitoneal administration of chitosan/DsiRNA nanoparticles targeting TNFalpha prevents radiation-induced fibrosis. Radiother Oncol 97(1):143–148PubMedGoogle Scholar
  79. 79.
    Dore-Savard L, Roussy G, Dansereau MA, Collingwood MA, Lennox KA, Rose SD et al (2008) Central delivery of Dicer-substrate siRNA: a direct application for pain research. Mol Ther 16(7):1331–1339PubMedGoogle Scholar
  80. 80.
    LaCroix-Fralish ML, Mo G, Smith SB, Sotocinal SG, Ritchie J, Austin JS et al (2009) The beta3 subunit of the Na+, K  +  -ATPase mediates variable nociceptive sensitivity in the formalin test. Pain 144(3):294–302PubMedGoogle Scholar
  81. 81.
    Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y et al (2008) Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol 26(4):431–442PubMedGoogle Scholar
  82. 82.
    Kortylewski M, Swiderski P, Herrmann A, Wang L, Kowolik C, Kujawski M et al (2009) In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol 27(10):925–932PubMedGoogle Scholar
  83. 83.
    Neff CP, Zhou J, Remling L, Kuruvilla J, Zhang J, Li H 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(66):66ra6PubMedGoogle Scholar
  84. 84.
    Zhou J, Neff CP, Liu X, Zhang J, Li H, Smith DD et al (2011) Systemic administration of combinatorial dsiRNAs via nanoparticles efficiently suppresses HIV-1 infection in humanized mice. Mol Ther 19(12):2228–2238PubMedGoogle Scholar
  85. 85.
    Amarzguioui M, Lundberg P, Cantin E, Hagstrom JE, Behlke MA, Rossi JJ (2006) Rational design and in vitro and in vivo delivery of Dicer substrate siRNA. Nat Protoc 1(2):508–517PubMedGoogle Scholar
  86. 86.
    Howard KA, Rahbek UL, Liu X, Damgaard CK, Glud SZ, Andersen MO et al (2006) RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system. Mol Ther 14(4):476–484PubMedGoogle Scholar
  87. 87.
    Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R et al (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374(6522):546–549PubMedGoogle Scholar
  88. 88.
    Thiel KW, Giangrande PH (2009) Therapeutic applications of DNA and RNA aptamers. Oligonucleotides 19(3):209–222PubMedGoogle Scholar
  89. 89.
    Zhou J, Rossi JJ (2010) Aptamer-targeted cell-specific RNA interference. Silence 1(1):4PubMedGoogle Scholar
  90. 90.
    Syed MA, Pervaiz S (2010) Advances in aptamers. Oligonucleotides 20(5):215–224PubMedGoogle Scholar
  91. 91.
    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(8):1481–1489PubMedGoogle Scholar
  92. 92.
    Zhou J, Swiderski P, Li H, Zhang J, Neff CP, Akkina R 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):3094–3109PubMedGoogle Scholar
  93. 93.
    Davidson BL, McCray PB Jr (2011) Current prospects for RNA interference-based therapies. Nat Rev Genet 12(5):329–340PubMedGoogle Scholar
  94. 94.
    Burnett JC, Rossi JJ, Tiemann K (2011) Current progress of siRNA/shRNA therapeutics in clinical trials. Biotechnol J 6(9):1130–1146PubMedGoogle Scholar
  95. 95.
    De Paula D, Bentley MV, Mahato RI (2007) Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting. RNA 13(4):431–456PubMedGoogle Scholar
  96. 96.
    de Fougerolles AR (2008) Delivery vehicles for small interfering RNA in vivo. Hum Gene Ther 19(2):125–132PubMedGoogle Scholar
  97. 97.
    Howard KA, Kjems J (2007) Polycation-based nanoparticle delivery for improved RNA interference therapeutics. Expert Opin Biol Ther 7(12):1811–1822PubMedGoogle Scholar
  98. 98.
    Howard KA (2009) Delivery of RNA interference therapeutics using polycation-based nanoparticles. Adv Drug Deliv Rev 61(9):710–720PubMedGoogle Scholar
  99. 99.
    Tseng YC, Mozumdar S, Huang L (2009) Lipid-based systemic delivery of siRNA. Adv Drug Deliv Rev 61(9):721–731PubMedGoogle Scholar
  100. 100.
    Davis ME (2009) The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. Mol Pharm 6(3):659–668PubMedGoogle Scholar
  101. 101.
    Eguchi A, Dowdy SF (2009) siRNA delivery using peptide transduction domains. Trends Pharmacol Sci 30(7):341–345PubMedGoogle Scholar
  102. 102.
    Jarver P, Mager I, Langel U (2010) In vivo biodistribution and efficacy of peptide mediated delivery. Trends Pharmacol Sci 31(11):528–535PubMedGoogle Scholar
  103. 103.
    Giljohann DA, Seferos DS, Daniel WL, Massich MD, Patel PC, Mirkin CA (2010) Gold nanoparticles for biology and medicine. Angew Chem Int Ed Engl 49(19):3280–3294PubMedGoogle Scholar
  104. 104.
    Serda RE, Godin B, Blanco E, Chiappini C, Ferrari M (2011) Multi-stage delivery nano-particle systems for therapeutic applications. Biochim Biophys Acta 1810(3):317–329, Epub 2010/05/25PubMedGoogle Scholar
  105. 105.
    Peer D, Lieberman J (2011) Special delivery: targeted therapy with small RNAs. Gene Ther 18(12):1127–1133PubMedGoogle Scholar
  106. 106.
    Sanghvi YS, Schulte M (2004) Therapeutic oligonucleotides: the state-of-the-art in purification technologies. Curr Opin Drug Discov Devel 7(6):765–776PubMedGoogle Scholar
  107. 107.
    Tedebark U, Scozzari A, Werbitzky O, Capaldi D, Holmberg L (2011) Industrial-scale manufacturing of a possible oligonucleotide cargo CPP-based drug. Methods Mol Biol 683:505–524, Epub 2010/11/06PubMedGoogle Scholar

Copyright information

© Controlled Release Society 2013

Authors and Affiliations

  1. 1.Integrated DNA Technologies, Inc.CoralvilleUSA

Personalised recommendations