Selected Strategies for the Delivery of siRNA In Vitro and In Vivo

RNA Technologies

Volumn , Issue , 2010, Pages 29-58

  Laufer, Sandra D ^a   Detzer, Anke ^a   Sczakiel, Georg ^a   Restle, Tobias ^a  

^a UNIVERSITY OF LÜBECK   (Germany)

Author keywords

Argonaute 2; Caveosomal endocytosis pathway; Cell penetrating peptides; Cellular uptake; Clinical trials; Delivery; Endocytosis; Endoplasmic reticulum; Endosomal escape; Extracellular RNA; Golgi apparatus; Ilimaquinone; Microinjection; Nanoparticles; Non covalent; Nonviral delivery systems; Oligonucleotide based drugs; Phosphorothioate stimulated uptake; Polycations; Protein transduction domains; RNAi; Signal peptides; siRNA peptide conjugate; siRNAs

Indexed keywords

EID: 85018731688     PISSN: 21979731     EISSN: 21979758     Source Type: Book Series    
DOI: 10.1007/978-3-642-12168-5_2     Document Type: Chapter

References (175)

1. Aigner A (2008) Cellular delivery in vivo of siRNA-based therapeutics. Curr Pharm Des 14:3603–3619
2. Alexis F, Pridgen E, Molnar LK et al (2008) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm 5:505–515
3. Allinquant B, Hantraye P, Mailleux P et al (1995) Downregulation of amyloid precursor protein inhibits neurite outgrowth in vitro. J Cell Biol 128:919–927
4. Anker P, Stroun M (2002) Progress in the knowledge of circulating nucleic acids: plasma RNA is particle-associated. Can it become a general detection marker for a cancer blood test? Clin Chem 48:1210–1211
5. Aouadi M, Tesz GJ, Nicoloro SM et al (2009) Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 458:1180–1184
6. Bayele HK, Sakthivel T, O’Donell M et al (2005) Versatile peptide dendrimers for nucleic acid delivery. J Pharm Sci 94:446–457
7. Bayele HK, Ramaswamy C, Wilderspin AF et al (2006) Protein transduction by lipidic peptide dendrimers. J Pharm Sci 95:1227–1237
8. Berg K, Folini M, Prasmickaite L et al (2007) Photochemical internalization: a new tool for drug delivery. Curr Pharm Biotechnol 8:362–372
9. Bernstein E, Caudy AA, Hammond SM et al (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409:363–366
10. Bitko V, Musiyenko A, Shulyayeva O et al (2005) Inhibition of respiratory viruses by nasally administered siRNA. Nat Med 11:50–55
11. Blackburn WH, Dickerson EB, Smith MH et al (2009) Peptide-functionalized nanogels for targeted siRNA delivery. Bioconjug Chem 20(5):960–968
12. Bøe S, Longva AS, Hovig E (2007) Photochemically induced gene silencing using small interfering RNA molecules in combination with lipid carriers. Oligonucleotides 17:166–173
13. Bonsted A, Wagner E, Prasmickaite L et al (2008) Photochemical enhancement of DNA delivery by EGF receptor targeted polyplexes. Methods Mol Biol 434:171–181
14. Bumcrot D, Manoharan M, Koteliansky V et al (2006) RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2:711–719
15. Castanotto D, Rossi JJ (2009) The promises and pitfalls of RNA-interference-based therapeutics. Nature 457:426–433
16. Check E (2005) Gene therapy put on hold as third child develops cancer. Nature 433:561
17. Chen XQ, Bonnefoi H, Pelte MF et al (2000) Telomerase RNA as a detection marker in the serum of breast cancer patients. Clin Cancer Res 6:3823–3826
18. Chen QR, Zhang L, Stass SA et al (2001) Branched co-polymers of histidine and lysine are efficient carriers of plasmids. Nucleic Acids Res 29:1334–1340
19. Chiu YL, Ali A, Chu CY et al (2004) Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells. Chem Biol 11:1165–1175
20. Console S, Marty C, Garcia-Echeverria C et al (2003) Antennapedia and HIV transactivator of transcription (TAT) “protein transduction domains” promote endocytosis of high molecular weight cargo upon binding to cell surface glycosaminoglycans. J Biol Chem 278:35109–35114
21. Crombez L, Morris MC, Deshayes S et al (2008) Peptide-based nanoparticle for ex vivo and in vivo drug delivery. Curr Pharm Des 14:3656–3665
22. Crombez L, Aldrian-Herrada G, Konate K et al (2009a) A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. Mol Ther 17:95–103
23. Crombez L, Morris MC, Dufort S et al (2009b) Targeting cyclin B1 through peptide-based delivery of siRNA prevents tumour growth. Nucleic Acids Res 37(14):4559–4569
24. Davidson TJ, Harel S, Arboleda VA et al (2004) Highly efficient small interfering RNA delivery to primary mammalian neurons induces MicroRNA-like effects before mRNA degradation. J Neurosci 24:10040–10046
25. De Coupade C, Fittipaldi A, Chagnas V et al (2005) Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules. Biochem J 390:407–418
26. de Diesbach P, Berens C, N’Kuli F et al (2000) Identification, purification and partial characterisation of an oligonucleotide receptor in membranes of HepG2 cells. Nucleic Acids Res 28:868–874
27. de Fougerolles A, Vornlocher HP, Maraganore J et al (2007) Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov 6:443–453
28. Derossi D, Joliot AH, Chassaing G et al (1994) The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem 269:10444–10450
29. Derossi D, Calvet S, Trembleau A et al (1996) Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent. J Biol Chem 271:18188–18193
30. Deshayes S, Plenat T, Aldrian-Herrada G et al (2004) Primary amphipathic cell-penetrating peptides: structural requirements and interactions with model membranes. Biochemistry 43:7698–7706
31. Deshayes S, Morris M, Heitz F et al (2008) Delivery of proteins and nucleic acids using a noncovalent peptide-based strategy. Adv Drug Deliv Rev 60:537–547
32. Detzer A, Overhoff M, Mescalchin A et al (2008) Phosphorothioate-stimulated cellular uptake of siRNA: a cell culture model for mechanistic studies. Curr Pharm Des 14:3666–3673
33. Detzer A, Overhoff M, W€unsche W et al (2009) Increased RNAi is related to intracellular release of siRNA via a covalently attached signal peptide. RNA 15:627–636
34. Doerfler W (1995) Uptake of foreign DNA by mammalian cells via the gastrointestinal tract in mice: methylation of foreign DNA – a cellular defense mechanism. Curr Top Microbiol Immunol 197:209–224
35. Doerfler W, Hohlweg U, Muller K et al (2001) Foreign DNA integration – perturbations of the genome – oncogenesis. Ann N Y Acad Sci 945:276–288
36. Edenhofer F (2008) Protein transduction revisited: novel insights into the mechanism underlying intracellular delivery of proteins. Curr Pharm Des 14:3628–3636
37. Eguchi A, Meade BR, Chang YC et al (2009) Efficient siRNA delivery into primary cells by a peptide transduction domain-dsRNA binding domain fusion protein. Nat Biotechnol 27:567–571
38. El-Andaloussi S, Johansson H, Magnusdottir A et al (2005) TP10, a delivery vector for decoy oligonucleotides targeting the Myc protein. J Control Release 110:189–201
39. El-Andaloussi S, Johansson HJ, Holm T et al (2007) A novel cell-penetrating peptide, M918, for efficient delivery of proteins and peptide nucleic acids. Mol Ther 15:1820–1826
40. Elbashir SM, Harborth J, Lendeckel W et al (2001a) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498
41. Elbashir SM, Lendeckel W, Tuschl T (2001b) RNA interference is mediated by 21-and 22-nucleotide RNAs. Genes Dev 15:188–200
42. Ellington AD, Szostak JW (1990) In vitro selection of RNA molecules that bind specific ligands. Nature 346:818–822
43. Endoh T, Sisido M, Ohtsuki T (2007) Photo inducible RNA interference using cell permeable protein carrier. Nucleic Acids Symp Ser (Oxf) 51:127–128
44. Endoh T, Sisido M, Ohtsuki T (2008) Cellular siRNA delivery mediated by a cell-permeant RNA-binding protein and photoinduced RNA interference. Bioconjug Chem 19:1017–1024
45. Endoh T, Ohtsuki T (2009) Cellular siRNA delivery using cell-penetrating peptides modified for endosomal escape. Adv Drug Deliv Rev 61:704–709
46. Epand RM (2003) Fusion peptides and the mechanism of viral fusion. Biochim Biophys Acta 1614:116–121
47. Fattal E, Barratt G (2009) Nanotechnologies and controlled release systems for the delivery of antisense oligonucleotides and small interfering RNA. Br J Pharmacol 157:179–194
48. Fawell S, Seery J, Daikh Y et al (1994) Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci USA 91:664–668
49. Filleur S, Courtin A, Ait-Si-Ali S et al (2003) SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth. Cancer Res 63:3919–3922
50. Fire A, Xu S, Montgomery MK et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811
51. Fittipaldi A, Ferrari A, Zoppe M et al (2003) Cell membrane lipid rafts mediate caveolar endocytosis of HIV-1 Tat fusion proteins. J Biol Chem 278:34141–34149
52. Foged C, Nielsen HM (2008) Cell-penetrating peptides for drug delivery across membrane barriers. Expert Opin Drug Deliv 5:105–117
53. Folini M, Bandiera R, Millo E et al (2007) Photochemically enhanced delivery of a cell-penetrating peptide nucleic acid conjugate targeting human telomerase reverse transcriptase: effects on telomere status and proliferative potential of human prostate cancer cells. Cell Prolif 40:905–920
54. Frankel AD, Pabo CO (1988) Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55:1189–1193
55. Futaki S, Suzuki T, Ohashi W et al (2001) Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J Biol Chem 276:5836–5840
56. Futaki S, Masui Y, Nakase I et al (2005) Unique features of a pH-sensitive fusogenic peptide that improves the transfection efficiency of cationic liposomes. J Gene Med 7:1450–1458
57. Futaki S (2006) Oligoarginine vectors for intracellular delivery: design and cellular-uptake mechanisms. Biopolymers 84:241–249
58. Garcia-Olmo D, Garcia-Olmo DC, Ontanon J et al (2000) Horizontal transfer of DNA and the “genometastasis hypothesis”. Blood 95:724–725
59. Green M, Loewenstein PM (1988) Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 55:1179–1188
60. Grimm D, Streetz KL, Jopling CL et al (2006) Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441:537–541
61. Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419
62. Haley B, Zamore PD (2004) Kinetic analysis of the RNAi enzyme complex. Nat Struct Mol Biol 11:599–606
63. Hammond SM, Boettcher S, Caudy AA et al (2001) Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293:1146–1150
64. Haque ME, Koppaka V, Axelsen PH et al (2005) Properties and structures of the influenza and HIV fusion peptides on lipid membranes: implications for a role in fusion. Biophys J 89:3183–3194
65. Heitz F, Morris MC, Divita G (2009) Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics. Br J Pharmacol 157:195–206
66. Hu Y, Atukorale PU, Lu JJ et al (2009) Cytosolic delivery mediated via electrostatic surface binding of protein, virus, or siRNA cargos to pH-responsive core-shell gel particles. Bioma-cromolecules 10:756–765
67. Hutvagner G, Simard MJ (2008) Argonaute proteins: key players in RNA silencing. Nat Rev Mol Cell Biol 9:22–32
68. Hyndman L, Lemoine JL, Huang L et al (2004) HIV-1 Tat protein transduction domain peptide facilitates gene transfer in combination with cationic liposomes. J Control Release 99:435–444
69. Jeong JH, Mok H, Oh YK et al (2009) siRNA conjugate delivery systems. Bioconjug Chem 20:5–14
70. Jinek M, Doudna JA (2009) A three-dimensional view of the molecular machinery of RNA interference. Nature 457:405–412
71. Johnson LN, Cashman SM, Kumar-Singh R (2008) Cell-penetrating peptide for enhanced delivery of nucleic acids and drugs to ocular tissues including retina and cornea. Mol Ther 16:107–114
72. Joliot AH, Triller A, Volovitch M et al (1991) Alpha-2, 8-Polysialic acid is the neuronal surface receptor of antennapedia homeobox peptide. New Biol 3:1121–1134
73. Kale AA, Torchilin VP (2007a) “Smart” drug carriers: PEGylated TATp-modified pH-sensitive liposomes. J Liposome Res 17:197–203
74. Kale AA, Torchilin VP (2007b) Design, synthesis, and characterization of pH-sensitive PEG-PE conjugates for stimuli-sensitive pharmaceutical nanocarriers: the effect of substitutes at the hydrazone linkage on the ph stability of PEG-PE conjugates. Bioconjug Chem 18:363–370
75. Kang H, Delong R, Fisher MH et al (2005) Tat-conjugated PAMAM dendrimers as delivery agents for antisense and siRNA oligonucleotides. Pharm Res 22:2099–2106
76. Khalil IA, Kogure K, Futaki S et al (2007) Octaarginine-modified multifunctional envelope-type nanoparticles for gene delivery. Gene Ther 14:682–689
77. Kilk K, El-Andaloussi S, J€arver P et al (2005) Evaluation of transportan 10 in PEI mediated plasmid delivery assay. J Control Release 103:511–523
78. Kim WJ, Christensen LV, Jo S et al (2006) Cholesteryl oligoarginine delivering vascular endothelial growth factor siRNA effectively inhibits tumor growth in colon adenocarcinoma. Mol Ther 14:343–350
79. Kleinman ME, Yamada K, Takeda A et al (2008) Sequence-and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597
80. Kogure K, Akita H, Yamada Y et al (2008) Multifunctional envelope-type nano device (MEND) as a non-viral gene delivery system. Adv Drug Deliv Rev 60:559–571
81. Kootstra NA, Verma IM (2003) Gene therapy with viral vectors. Annu Rev Pharmacol Toxicol 43:413–439
82. Kopreski MS, Benko FA, Kwak LW et al (1999) Detection of tumor messenger RNA in the serum of patients with malignant melanoma. Clin Cancer Res 5:1961–1965
83. Kumar P, Wu H, McBride JL et al (2007) Transvascular delivery of small interfering RNA to the central nervous system. Nature 448:39–43
84. Kwon EJ, Bergen JM, Pun SH (2008) Application of an HIV gp41-derived peptide for enhanced intracellular trafficking of synthetic gene and siRNA delivery vehicles. Bioconjug Chem 19:920–927
85. Laktionov PP, Dazard JE, Vives E et al (1999) Characterisation of membrane oligonucleotide-binding proteins and oligonucleotide uptake in keratinocytes. Nucleic Acids Res 27: 2315–2324
86. Langel €U (ed) (2006) Handbook of cell-penetrating peptides. CRC Press, Boca Raton
87. Laufer SD, Restle T (2008) Peptide-mediated cellular delivery of oligonucleotide-based therapeutics in vitro: quantitative evaluation of overall efficacy employing easy to handle reporter systems. Curr Pharm Des 14:3637–3655
88. Lehmann MJ, Sczakiel G (2005) Spontaneous uptake of biologically active recombinant DNA by mammalian cells via a selected DNA segment. Gene Ther 12:446–451
89. Leng Q, Scaria P, Zhu J et al (2005) Highly branched HK peptides are effective carriers of siRNA. J Gene Med 7:977–986
90. Leung RK, Whittaker PA (2005) RNA interference: from gene silencing to gene-specific therapeutics. Pharmacol Ther 107:222–239
91. Lindgren M, H€allbrink M, Prochiantz A et al (2000) Cell-penetrating peptides. Trends Pharmacol Sci 21:99–103
92. Liu Z, Li M, Cui D et al (2005) Macro-branched cell-penetrating peptide design for gene delivery. J Control Release 102:699–710
93. Lundberg M, Johansson M (2001) Is VP22 nuclear homing an artifact? Nat Biotechnol 19:713–714
94. Lundberg M, Johansson M (2002) Positively charged DNA-binding proteins cause apparent cell membrane translocation. Biochem Biophys Res Commun 291:367–371
95. Lundberg P, El-Andaloussi S, Sutlu T et al (2007) Delivery of short interfering RNA using endosomolytic cell-penetrating peptides. FASEB J 21:2664–2671
96. Maiolo JR, Ferrer M, Ottinger EA (2005) Effects of cargo molecules on the cellular uptake of arginine-rich cell-penetrating peptides. Biochim Biophys Acta 1712:161–172
97. Mano M, Teodosio C, Paiva A et al (2005) On the mechanisms of the internalization of S4(13)-PV cell-penetrating peptide. Biochem J 390:603–612
98. McCaffrey AP, Meuse L, Pham TT et al (2002) RNA interference in adult mice. Nature 418:38–39
99. McNamara JO, Andrechek ER, Wang Y et al (2006) Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol 24:1005–1015
100. Meade BR, Dowdy SF (2008) Enhancing the cellular uptake of siRNA duplexes following noncovalent packaging with protein transduction domain peptides. Adv Drug Deliv Rev 60:530–536
101. Mescalchin A, Detzer A, Wecke M et al (2007) Cellular uptake and intracellular release are major obstacles to the therapeutic application of siRNA: novel options by phosphorothioate-stimulated delivery. Expert Opin Biol Ther 7:1531–1538
102. Meyer M, Philipp A, Oskuee R et al (2008) Breathing life into polycations: functionalization with pH-responsive endosomolytic peptides and polyethylene glycol enables siRNA delivery. J Am Chem Soc 130:3272–3273
103. Meyer M, Dohmen C, Philipp A et al (2009) Synthesis and biological evaluation of a bioresponsive and endosomolytic siRNA-polymer conjugate. Mol Pharm 6:752–762
104. Michiue H, Tomizawa K, Wei FY et al (2005) The NH2 terminus of influenza virus hemaggluti-nin-2 subunit peptides enhances the antitumor potency of polyarginine-mediated p53 protein transduction. J Biol Chem 280:8285–8289
105. Midoux P, Monsigny M (1999) Efficient gene transfer by histidylated polylysine/pDNA complexes. Bioconjug Chem 10:406–411
106. Morris MC, Vidal P, Chaloin L et al (1997) A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. Nucleic Acids Res 25:2730–2736
107. Morris MC, Deshayes S, Heitz F et al (2008) Cell-penetrating peptides: from molecular mechanisms to therapeutics. Biol Cell 100:201–217
108. Moschos SA, Jones SW, Perry MM et al (2007) Lung delivery studies using siRNA conjugated to TAT(48–60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjug Chem 18:1450–1459
109. Muratovska A, Eccles MR (2004) Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells. FEBS Lett 558:63–68
110. Nakamura Y, Kogure K, Futaki S et al (2007) Octaarginine-modified multifunctional envelope-type nano device for siRNA. J Control Release 119:360–367
111. Ng EK, Tsui NB, Lam NY et al (2002) Presence of filterable and nonfilterable mRNA in the plasma of cancer patients and healthy individuals. Clin Chem 48:1212–1217
112. Oehlke J, Scheller A, Wiesner B et al (1998) Cellular uptake of an alpha-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically. Biochim Biophys Acta 1414:127–139
113. Ogris M, Carlisle RC, Bettinger T et al (2001) Melittin enables efficient vesicular escape and enhanced nuclear access of nonviral gene delivery vectors. J Biol Chem 276: 47550–47555
114. Oliveira S, Fretz MM, Hogset A et al (2007a) Photochemical internalization enhances silencing of epidermal growth factor receptor through improved endosomal escape of siRNA. Biochim Biophys Acta 1768:1211–1217
115. Oliveira S, van Rooy I, Kranenburg O et al (2007b) Fusogenic peptides enhance endosomal escape improving siRNA-induced silencing of oncogenes. Int J Pharm 331:211–214
116. Oliveira S, Hogset A, Storm G et al (2008) Delivery of siRNA to the target cell cytoplasm: photochemical internalization facilitates endosomal escape and improves silencing efficiency, in vitro and in vivo. Curr Pharm Des 14:3686–3697
117. Overhoff M, W€unsche W, Sczakiel G (2004) Quantitative detection of siRNA and single-stranded oligonucleotides: relationship between uptake and biological activity of siRNA. Nucleic Acids Res 32:e170
118. Overhoff M, Sczakiel G (2005) Phosphorothioate-stimulated uptake of short interfering RNA by human cells. EMBO Rep 6:1176–1181
119. Paddison PJ, Caudy AA, Bernstein E et al (2002) Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev 16:948–958
120. Patel LN, Zaro JL, Shen WC (2007) Cell penetrating peptides: intracellular pathways and pharmaceutical perspectives. Pharm Res 24:1977–1992
121. Peer D, Zhu P, Carman CV et al (2007) Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1. Proc Natl Acad Sci USA 104:4095–4100
122. Pichon C, Monsigny M, Roche AC (1999) Intracellular localization of oligonucleotides: influence of fixative protocols. Antisense Nucleic Acid Drug Dev 9:89–93
123. Plank C, Zauner W, Wagner E (1998) Application of membrane-active peptides for drug and gene delivery across cellular membranes. Adv Drug Deliv Rev 34:21–35
124. Pooga M, H€allbrink M, Zorko M et al (1998) Cell penetration by transportan. FASEB J 12:67–77
125. Preuss M, Tecle M, Shah I et al (2003) Comparison between the interactions of adenovirus-derived peptides with plasmid DNA and their role in gene delivery mediated by liposome-peptide-DNA virus-like nanoparticles. Org Biomol Chem 1:2430–2438
126. Rahbek UL, Howard KA, Oupický D et al (2008) Intracellular siRNA and precursor miRNA trafficking using bioresponsive copolypeptides. J Gene Med 10:81–93
127. Rana TM (2007) Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 8:23–36
128. Rao DD, Vorhies JS, Senzer N et al (2009) siRNA vs. shRNA: similarities and differences. Adv Drug Deliv Rev 61:746–759
129. Raper SE, Yudkoff M, Chirmule N et al (2002) A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther 13:163–175
130. Raper SE, Chirmule N, Lee FS et al (2003) Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 80:148–158
131. Read ML, Bremner KH, Oupicky D et al (2003) Vectors based on reducible polycations facilitate intracellular release of nucleic acids. J Gene Med 5:232–245
132. Read ML, Singh S, Ahmed Z et al (2005) A versatile reducible polycation-based system for efficient delivery of a broad range of nucleic acids. Nucleic Acids Res 33:e86
133. Reddi KK, Holland JF (1976) Elevated serum ribonuclease in patients with pancreatic cancer. Proc Natl Acad Sci USA 73:2308–2310
134. Richard JP, Melikov K, Vives E et al (2003) Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. J Biol Chem 278:585–590
135. Richard JP, Melikov K, Brooks H et al (2005) Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors. J Biol Chem 280:15300–15306
136. Ritter W, Plank C, Lausier J et al (2003) A novel transfecting peptide comprising a tetrameric nuclear localization sequence. J Mol Med 81:708–717
137. Robertson DL, Joyce GF (1990) Selection in vitro of an RNA enzyme that specifically cleaves single-stranded DNA. Nature 344:467–468
138. Rothbard JB, Jessop TC, Lewis RS et al (2004) Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cells. J Am Chem Soc 126:9506–9507
139. Sakurai Y, Hatakeyama H, Akita H et al (2009) Efficient short interference RNA delivery to tumor cells using a combination of octaarginine, GALA and tumor-specific, cleavable polyethylene glycol system. Biol Pharm Bull 32:928–932
140. Schubbert R, Lettmann C, Doerfler W (1994) Ingested foreign (phage M13) DNA survives transiently in the gastrointestinal tract and enters the bloodstream of mice. Mol Gen Genet 242:495–504
141. Schubbert R, Renz D, Schmitz B et al (1997) Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen, and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc Natl Acad Sci USA 94:961–966
142. Schwarze SR, Ho A, Vocero-Akbani A et al (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285:1569–1572
143. Schwarze SR, Dowdy SF (2000) In vivo protein transduction: intracellular delivery of biologically active proteins, compounds and DNA. Trends Pharmacol Sci 21:45–48
144. Simeoni F, Morris MC, Heitz F et al (2003) Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells. Nucleic Acids Res 31:2717–2724
145. Snøve O Jr, Rossi JJ (2006) Toxicity in mice expressing short hairpin RNAs gives new insight into RNAi. Genome Biol 7:231
146. Song E, Lee SK, Wang J et al (2003) RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 9:347–351
147. Song E, Zhu P, Lee SK et al (2005) Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol 23:709–717
148. Song JJ, Smith SK, Hannon GJ et al (2004) Crystal structure of Argonaute and its implications for RISC slicer activity. Science 305:1434–1437
149. Soomets U, Lindgren M, Gallet X et al (2000) Deletion analogues of transportan. Biochim Biophys Acta 1467:165–176
150. Sorensen DR, Leirdal M, Sioud M (2003) Gene silencing by systemic delivery of synthetic siRNAs in adult mice. J Mol Biol 327:761–766
151. Soundara Manickam D, Oupický D (2006) Multiblock reducible copolypeptides containing histidine-rich and nuclear localization sequences for gene delivery. Bioconjug Chem 17: 1395–1403
152. Soutschek J, Akinc A, Bramlage B et al (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432:173–178
153. Takizawa PA, Yucel JK, Veit B et al (1993) Complete vesiculation of Golgi membranes and inhibition of protein transport by a novel sea sponge metabolite, ilimaquinone. Cell 73:1079–1090
154. Tönges L, Lingor P, Egle R et al (2006) Stearylated octaarginine and artificial virus-like particles for transfection of siRNA into primary rat neurons. RNA 12:1431–1438
155. Torchilin VP, Rammohan R, Weissig V et al (2001) TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proc Natl Acad Sci USA 98:8786–8791
156. Torchilin VP, Levchenko TS, Rammohan R et al (2003) Cell transfection in vitro and in vivo with nontoxic TAT peptide-liposome-DNA complexes. Proc Natl Acad Sci USA 100:1972–1977
157. Tu Y, Kim JS (2008) A fusogenic segment of glycoprotein H from herpes simplex virus enhances transfection efficiency of cationic liposomes. J Gene Med 10:646–654
158. Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505–510
159. Turner JJ, Arzumanov AA, Gait MJ (2005) Synthesis, cellular uptake and HIV-1 Tat-dependent trans-activation inhibition activity of oligonucleotide analogues disulphide-conjugated to cell-penetrating peptides. Nucleic Acids Res 33:27–42
160. Tyagi M, Rusnati M, Presta M et al (2001) Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans. J Biol Chem 276:3254–3261
161. Veldhoen S, Laufer SD, Trampe A et al (2006) Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effect. Nucleic Acids Res 34:6561–6573
162. Veldhoen S, Laufer SD, Restle T (2008) Recent developments in peptide-based nucleic acid delivery. Int J Mol Sci 9:1276–1320
163. Verma IM, Weitzman MD (2005) Gene therapy: twenty-first century medicine. Annu Rev Biochem 74:711–738
164. Vives E, Brodin P, Lebleu B (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem 272:16010–16017
165. Wadia JS, Stan RV, Dowdy SF (2004) Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nat Med 10:310–315
166. Wang HJ, Benlimame N, Nabi I (1997) The AMF-R tubule is a smooth ilimaquinone-sensitive subdomain of the endoplasmic reticulum. J Cell Sci 110(Pt 24):3043–3053
167. Wang Y, Sheng G, Juranek S et al (2008a) Structure of the guide-strand-containing argonaute silencing complex. Nature 456:209–213
168. Wang Y, Juranek S, Li H et al (2008b) Structure of an argonaute silencing complex with a seed-containing guide DNA and target RNA duplex. Nature 456:921–926
169. Wesche-Soldato DE, Chung CS, Lomas-Neira J et al (2005) In vivo delivery of caspase-8 or Fas siRNA improves the survival of septic mice. Blood 106:2295–2301
170. Whitehead KA, Langer R, Anderson DG (2009) Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 8:129–138
171. Xie FY, Woodle MC, Lu PY (2006) Harnessing in vivo siRNA delivery for drug discovery and therapeutic development. Drug Discov Today 11:67–73
172. Yu JY, DeRuiter SL, Turner DL (2002) RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc Natl Acad Sci USA 99:6047–6052
173. Zatsepin TS, Turner JJ, Oretskaya TS et al (2005) Conjugates of oligonucleotides and analogues with cell penetrating peptides as gene silencing agents. Curr Pharm Des 11:3639–3654
174. Zimmermann TS, Lee AC, Akinc A et al (2006) RNAi-mediated gene silencing in non-human primates. Nature 441:111–114
175. Zorko M, Langel €U (2005) Cell-penetrating peptides: mechanism and kinetics of cargo delivery. Adv Drug Deliv Rev 57:529–545