RNA Interference for Cancer Therapy

  • Kun Cheng
  • Bin Qin

Evolved as a defense mechanism against RNA virus, RNA interference (RNAi) is the phenomenon in which small interfering RNA (siRNA) of 21–23 nucleotides in length silences the target gene by binding to its complementary mRNA and triggering the degradation of target mRNA [1]. It was first found in Caenorhabditis elegans that introduction of foreign small double-stranded RNA (dsRNA) can lead to potent degradation of the complementary mRNA [2]. This finding generated huge interest in the application of siRNA for the biomedical research community. Potent knockdown of the target gene with high sequence specificity makes RNAi a powerful tool to uncover gene functions, understand the effects of selective gene silencing, and explore potential therapeutics for complex diseases [3]. The discovery of RNAi is one of the most dramatic findings over the past decade in the field of molecular biology [4]. As illustrated by the histogram in Fig. 1, the number of publications related to “RNAi” increased dramatically from 5 in 1998 to over 2000 in 2007.


Vascular Endothelial Growth Factor Enhance Green Fluorescent Protein Antibody Fragment Cationic Lipid Cationic Liposome 
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.


  1. 1.
    Cheng K, Mahato RI. Gene modulation for treating liver fibrosis. Crit Rev Ther Drug Carrier Syst 2007; 24: 93–146.PubMedGoogle Scholar
  2. 2.
    Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004; 10: 789–799.PubMedGoogle Scholar
  3. 3.
    Masiero M, Nardo G, Indraccolo S, Favaro E. RNA interference: implications for cancer treatment. Mol Aspects Med 2007; 28: 143–166.PubMedGoogle Scholar
  4. 4.
    Takeshita F, Ochiya T. Therapeutic potential of RNA interference against cancer. Cancer Sci 2006; 97: 689–696.PubMedGoogle Scholar
  5. 5.
    Cejka D, Losert D, Wacheck V. Short interfering RNA (siRNA): tool or therapeutic? Clin Sci (Lond) 2006; 110: 47–58.Google Scholar
  6. 6.
    Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2007 – an update. J Gene Med 2007; 9: 833–842.PubMedGoogle Scholar
  7. 7.
    Fuchs U, Borkhardt A. The application of siRNA technology to cancer biology discovery. Adv Cancer Res 2007; 96: 75–102.PubMedGoogle Scholar
  8. 8.
    Nykanen A, Haley B, Zamore PD. ATP requirements and small interfering RNA structure in the RNA interference pathway. Cell 2001; 107: 309–321.PubMedGoogle Scholar
  9. 9.
    Dykxhoorn DM, Novina CD, Sharp PA. Killing the messenger: short RNAs that silence gene expression. Nat Rev Mol Cell Biol 2003; 4: 457–467.PubMedGoogle Scholar
  10. 10.
    Schwarz DS, Hutvagner G, Du T, Xu Z, Aronin N, Zamore PD. Asymmetry in the assembly of the RNAi enzyme complex. Cell 2003; 115: 199–208.PubMedGoogle Scholar
  11. 11.
    Mahato RI, Cheng K, Guntaka RV. Modulation of gene expression by antisense and antigene oligodeoxynucleotides and small interfering RNA. Expert Opin Drug Deliv 2005; 2: 3–28.PubMedGoogle Scholar
  12. 12.
    Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A. Rational siRNA design for RNA interference. Nat Biotechnol 2004; 22: 326–330.PubMedGoogle Scholar
  13. 13.
    Ui-Tei K, Naito Y, Takahashi F, Haraguchi T, Ohki-Hamazaki H, Juni A, et al. Guidelines for the selection of highly effective siRNA sequences for mammalian and chick RNA interference. Nucleic Acids Res 2004; 32: 936–948.PubMedGoogle Scholar
  14. 14.
    Milhavet O, Gary DS, Mattson MP. RNA interference in biology and medicine. Pharmacol Rev 2003; 55: 629–648.PubMedGoogle Scholar
  15. 15.
    Naito Y, Yamada T, Ui-Tei K, Morishita S, Saigo K. siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference. Nucleic Acids Res 2004; 32: W124–W129.PubMedGoogle Scholar
  16. 16.
    Amarzguioui M, Lundberg P, Cantin E, Hagstrom J, Behlke MA, Rossi JJ. Rational design and in vitro and in vivo delivery of Dicer substrate siRNA. Nat Protoc 2006; 1: 508–517.PubMedGoogle Scholar
  17. 17.
    Sanguino A, Lopez-Berestein G, Sood AK. Strategies for in vivo siRNA delivery in cancer. Mini Rev Med Chem 2008; 8: 248–255.PubMedGoogle Scholar
  18. 18.
    Matveeva O, Nechipurenko Y, Rossi L, Moore B, Saetrom P, Ogurtsov AY, et al. Comparison of approaches for rational siRNA design leading to a new efficient and transparent method. Nucleic Acids Res 2007; 35: e63.PubMedGoogle Scholar
  19. 19.
    Tafer H, Ameres SL, Obernosterer G, Gebeshuber CA, Schroeder R, Martinez J, et al. The impact of target site accessibility on the design of effective siRNAs. Nat Biotechnol 2008; 26: 578–583.PubMedGoogle Scholar
  20. 20.
    Zeng Y, Cullen BR. RNA interference in human cells is restricted to the cytoplasm. RNA 2002; 8: 855–860.PubMedGoogle Scholar
  21. 21.
    Aagaard L, Rossi JJ. RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev 2007; 59: 75–86.PubMedGoogle Scholar
  22. 22.
    Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296: 550–553.PubMedGoogle Scholar
  23. 23.
    Makinen PI, Koponen JK, Karkkainen AM, Malm TM, Pulkkinen KH, Koistinaho J, et al. Stable RNA interference: comparison of U6 and H1 promoters in endothelial cells and in mouse brain. J Gene Med 2006; 8: 433–441.PubMedGoogle Scholar
  24. 24.
    Tomar RS, Matta H, Chaudhary PM. Use of adeno-associated viral vector for delivery of small interfering RNA. Oncogene 2003; 22: 5712–5715.PubMedGoogle Scholar
  25. 25.
    Henriksen JR, Lokke C, Hammero M, Geerts D, Versteeg R, Flaegstad T, et al. Comparison of RNAi efficiency mediated by tetracycline-responsive H1 and U6 promoter variants in mammalian cell lines. Nucleic Acids Res 2007; 35: e67.PubMedGoogle Scholar
  26. 26.
    Lin X, Yang J, Chen J, Gunasekera A, Fesik SW, Shen Y. Development of a tightly regulated U6 promoter for shRNA expression. FEBS Lett 2004; 577: 376–380.PubMedGoogle Scholar
  27. 27.
    Wang S, Shi Z, Liu W, Jules J, Feng X. Development and validation of vectors containing multiple siRNA expression cassettes for maximizing the efficiency of gene silencing. BMC Biotechnol 2006; 6: 50.PubMedGoogle Scholar
  28. 28.
    Jazag A, Kanai F, Ijichi H, Tateishi K, Ikenoue T, Tanaka Y, et al. Single small-interfering RNA expression vector for silencing multiple transforming growth factor-beta pathway components. Nucleic Acids Res 2005; 33: e131.PubMedGoogle Scholar
  29. 29.
    Chen SM, Wang Y, Xiao BK, Tao ZZ. Effect of blocking VEGF, hTERT and Bcl-xl by multiple shRNA expression vectors on the human laryngeal squamous carcinoma xenograft in nude mice. Cancer Biol Ther 2007; 7.Google Scholar
  30. 30.
    De Paula D, Bentley MV, Mahato RI. Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting. RNA 2007; 13: 431–456.PubMedGoogle Scholar
  31. 31.
    Cho-Rok J, Yoo J, Jang YJ, Kim S, Chu IS, Yeom YI, et al. Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo. Hepatology 2006; 43: 1042–1052.PubMedGoogle Scholar
  32. 32.
    McCaffrey AP, Meuse L, Pham TT, Conklin DS, Hannon GJ, Kay MA. RNA interference in adult mice. Nature 2002; 418: 38–39.PubMedGoogle Scholar
  33. 33.
    Song E, Lee SK, Wang J, Ince N, Ouyang N, Min J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 2003; 9: 347–351.PubMedGoogle Scholar
  34. 34.
    Shackel NA, Rockey DC. Intrahepatic gene silencing by RNA interference. Gastroenterology 2004; 126: 356–358; discussion 358–359.PubMedGoogle Scholar
  35. 35.
    Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 2004; 432: 173–178.PubMedGoogle Scholar
  36. 36.
    Meyer M, Wagner E. Recent developments in the application of plasmid DNA-based vectors and small interfering RNA therapeutics for cancer. Hum Gene Ther 2006; 17: 1062–1076.PubMedGoogle Scholar
  37. 37.
    Chu TC, Twu KY, Ellington AD, Levy M. Aptamer mediated siRNA delivery. Nucleic Acids Res 2006; 34: e73.PubMedGoogle Scholar
  38. 38.
    Moschos SA, Jones SW, Perry MM, Williams AE, Erjefalt JS, Turner JJ, et al. 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 2007; 18: 1450–1459.PubMedGoogle Scholar
  39. 39.
    Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol 2005; 23: 709–717.PubMedGoogle Scholar
  40. 40.
    Nawrot B, Sipa K. Chemical and structural diversity of siRNA molecules. Curr Top Med Chem 2006; 6: 913–925.PubMedGoogle Scholar
  41. 41.
    Chiu YL, Rana TM. siRNA function in RNAi: a chemical modification analysis. RNA 2003; 9: 1034–1048.PubMedGoogle Scholar
  42. 42.
    Manoharan M. RNA interference and chemically modified small interfering RNAs. Curr Opin Chem Biol 2004; 8: 570–579.PubMedGoogle Scholar
  43. 43.
    Czauderna F, Fechtner M, Dames S, Aygun H, Klippel A, Pronk GJ, et al. Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. Nucleic Acids Res 2003; 31: 2705–2716.PubMedGoogle Scholar
  44. 44.
    Chiu YL, Ali A, Chu CY, Cao H, Rana TM. Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells. Chem Biol 2004; 11: 1165–1175.PubMedGoogle Scholar
  45. 45.
    Elbashir SM, Martinez J, Patkaniowska A, Lendeckel W, Tuschl T. Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. Embo J 2001; 20: 6877–6888.PubMedGoogle Scholar
  46. 46.
    Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, et al. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol 2003; 21: 635–637.PubMedGoogle Scholar
  47. 47.
    Scacheri PC, Rozenblatt-Rosen O, Caplen NJ, Wolfsberg TG, Umayam L, Lee JC, et al. Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells. Proc Natl Acad Sci USA 2004; 101: 1892–1897.PubMedGoogle Scholar
  48. 48.
    Birmingham A, Anderson EM, Reynolds A, Ilsley-Tyree D, Leake D, Fedorov Y, et al. 3′ UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat Methods 2006; 3: 199–204.PubMedGoogle Scholar
  49. 49.
    Fedorov Y, Anderson EM, Birmingham A, Reynolds A, Karpilow J, Robinson K, et al. Off-target effects by siRNA can induce toxic phenotype. RNA 2006; 12: 1188–1196.PubMedGoogle Scholar
  50. 50.
    Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M, Lim L, et al. Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA 2006; 12: 1179–1187.PubMedGoogle Scholar
  51. 51.
    Jackson AL, Burchard J, Leake D, Reynolds A, Schelter J, Guo J, et al. Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. RNA 2006; 12: 1197–1205.PubMedGoogle Scholar
  52. 52.
    Naito Y, Yamada T, Matsumiya T, Ui-Tei K, Saigo K, Morishita S. dsCheck: highly sensitive off-target search software for double-stranded RNA-mediated RNA interference. Nucleic Acids Res 2005; 33: W589–W591.PubMedGoogle Scholar
  53. 53.
    Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem 1998; 67: 227–264.PubMedGoogle Scholar
  54. 54.
    Kim JY, Choung S, Lee EJ, Kim YJ, Choi YC. Immune activation by siRNA/liposome complexes in mice is sequence- independent: lack of a role for Toll-like receptor 3 signaling. Mol Cells 2007; 24: 247–254.PubMedGoogle Scholar
  55. 55.
    Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001; 411: 494–498.PubMedGoogle Scholar
  56. 56.
    Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR. Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 2003; 5: 834–839.PubMedGoogle Scholar
  57. 57.
    Judge AD, Bola G, Lee AC, MacLachlan I. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther 2006; 13: 494–505.PubMedGoogle Scholar
  58. 58.
    Iorns E, Lord CJ, Turner N, Ashworth A. Utilizing RNA interference to enhance cancer drug discovery. Nat Rev Drug Discov 2007; 6: 556–568.PubMedGoogle Scholar
  59. 59.
    Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A, et al. BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell 2002; 111: 393–405.PubMedGoogle Scholar
  60. 60.
    Shin SH, Kim HS, Jung SH, Xu HD, Jeong YB, Chung YJ. Implication of leucyl-tRNA synthetase 1 (LARS1) over-expression in growth and migration of lung cancer cells detected by siRNA targeted knock-down analysis. Exp Mol Med 2008; 40: 229–236.PubMedGoogle Scholar
  61. 61.
    Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002; 2: 243–247.PubMedGoogle Scholar
  62. 62.
    Silva JM, Mizuno H, Brady A, Lucito R, Hannon GJ. RNA interference microarrays: high-throughput loss-of-function genetics in mammalian cells. Proc Natl Acad Sci USA 2004; 101: 6548–6552.PubMedGoogle Scholar
  63. 63.
    Silva J, Chang K, Hannon GJ, Rivas FV. RNA-interference-based functional genomics in mammalian cells: reverse genetics coming of age. Oncogene 2004; 23: 8401–8409.PubMedGoogle Scholar
  64. 64.
    Micklem DR, Lorens JB. RNAi screening for therapeutic targets in human malignancies. Curr Pharm Biotechnol 2007; 8: 337–343.PubMedGoogle Scholar
  65. 65.
    Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Velds A, Heimerikx M, et al. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 2004; 428: 431–437.PubMedGoogle Scholar
  66. 66.
    Sachse C, Echeverri CJ. Oncology studies using siRNA libraries: the dawn of RNAi-based genomics. Oncogene 2004; 23: 8384–8391.PubMedGoogle Scholar
  67. 67.
    Hunt KK, Vorburger SA, Swisher SG. Gene Therapy for Cancer. Humana Press: Totowa, 2007.Google Scholar
  68. 68.
    Pai SI, Lin YY, Macaes B, Meneshian A, Hung CF, Wu TC. Prospects of RNA interference therapy for cancer. Gene Ther 2006; 13: 464–477.PubMedGoogle Scholar
  69. 69.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182–1186.PubMedGoogle Scholar
  70. 70.
    Hadj-Slimane R, Lepelletier Y, Lopez N, Garbay C, Raynaud F. Short interfering RNA (siRNA), a novel therapeutic tool acting on angiogenesis. Biochimie 2007; 89: 1234–1244.PubMedGoogle Scholar
  71. 71.
    de Fougerolles A, Vornlocher HP, Maraganore J, Lieberman J. Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov 2007; 6: 443–453.PubMedGoogle Scholar
  72. 72.
    Spagnou S, Miller AD, Keller M. Lipidic carriers of siRNA: differences in the formulation, cellular uptake, and delivery with plasmid DNA. Biochemistry 2004; 43: 13348–13356.PubMedGoogle Scholar
  73. 73.
    Heidel JD. Linear cyclodextrin-containing polymers and their use as delivery agents. Expert Opin Drug Deliv 2006; 3: 641–646.PubMedGoogle Scholar
  74. 74.
    Boussif O, Lezoualc'h F, Zanta MA, Mergny MD, Scherman D, Demeneix B, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci USA 1995; 92: 7297–7301.PubMedGoogle Scholar
  75. 75.
    Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA 1987; 84: 7413–7417.PubMedGoogle Scholar
  76. 76.
    Morille M, Passirani C, Vonarbourg A, Clavreul A, Benoit JP. Progress in developing cationic vectors for non-viral systemic gene therapy against cancer. Biomaterials 2008; 29: 3477–3496.Google Scholar
  77. 77.
    Mevel M, Breuzard G, Yaouanc JJ, Clement JC, Lehn P, Pichon C, et al. Synthesis and Transfection Activity of New Cationic Phosphoramidate Lipids: High Efficiency of an Imidazolium Derivative. Chembiochem 2008; 9: 1462–1471.Google Scholar
  78. 78.
    Akhtar S, Benter IF. Nonviral delivery of synthetic siRNAs in vivo. J Clin Invest 2007; 117: 3623–3632.PubMedGoogle Scholar
  79. 79.
    Zhang S, Zhao B, Jiang H, Wang B, Ma B. Cationic lipids and polymers mediated vectors for delivery of siRNA. J Control Release 2007; 123: 1–10.PubMedGoogle Scholar
  80. 80.
    Hobel S, Prinz R, Malek A, Urban-Klein B, Sitterberg J, Bakowsky U, et al. Polyethylenimine PEI F25-LMW allows the long-term storage of frozen complexes as fully active reagents in siRNA-mediated gene targeting and DNA delivery. Eur J Pharm Biopharm 2008; 70: 29–41.Google Scholar
  81. 81.
    Werth S, Urban-Klein B, Dai L, Hobel S, Grzelinski M, Bakowsky U, et al. A low molecular weight fraction of polyethylenimine (PEI) displays increased transfection efficiency of DNA and siRNA in fresh or lyophilized complexes. J Control Release 2006; 112: 257–270.PubMedGoogle Scholar
  82. 82.
    Malek A, Czubayko F, Aigner A. PEG grafting of polyethylenimine (PEI) exerts different effects on DNA transfection and siRNA-induced gene targeting efficacy. J Drug Target 2008; 16: 124–139.PubMedGoogle Scholar
  83. 83.
    Mao S, Neu M, Germershaus O, Merkel O, Sitterberg J, Bakowsky U, et al. Influence of polyethylene glycol chain length on the physicochemical and biological properties of poly(ethylene imine)-graft-poly(ethylene glycol) block copolymer/SiRNA polyplexes. Bioconjug Chem 2006; 17: 1209–1218.PubMedGoogle Scholar
  84. 84.
    Shim MS, Kwon YJ. Controlled delivery of plasmid DNA and siRNA to intracellular targets using ketalized polyethylenimine. Biomacromolecules 2008; 9: 444–455.PubMedGoogle Scholar
  85. 85.
    de Wolf HK, Snel CJ, Verbaan FJ, Schiffelers RM, Hennink WE, Storm G. Effect of cationic carriers on the pharmacokinetics and tumor localization of nucleic acids after intravenous administration. Int J Pharm 2007; 331: 167–175.PubMedGoogle Scholar
  86. 86.
    Kim SH, Mok H, Jeong JH, Kim SW, Park TG. Comparative evaluation of target-specific GFP gene silencing efficiencies for antisense ODN, synthetic siRNA, and siRNA plasmid complexed with PEI-PEG-FOL conjugate. Bioconjug Chem 2006; 17: 241–244.PubMedGoogle Scholar
  87. 87.
    Katas H, Alpar HO. Development and characterisation of chitosan nanoparticles for siRNA delivery. J Control Release 2006; 115: 216–225.PubMedGoogle Scholar
  88. 88.
    Liu X, Howard KA, Dong M, Andersen MO, Rahbek UL, Johnsen MG, et al. The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing. Biomaterials 2007; 28: 1280–1288.PubMedGoogle Scholar
  89. 89.
    de Martimprey H, Bertrand JR, Fusco A, Santoro M, Couvreur P, Vauthier C, et al. siRNA nanoformulation against the ret/PTC1 junction oncogene is efficient in an in vivo model of papillary thyroid carcinoma. Nucleic Acids Res 2008; 36: e2.PubMedGoogle Scholar
  90. 90.
    Howard KA, Rahbek UL, Liu X, Damgaard CK, Glud SZ, Andersen MO, et al. RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system. Mol Ther 2006; 14: 476–484.PubMedGoogle Scholar
  91. 91.
    Dufes C, Uchegbu IF, Schatzlein AG. Dendrimers in gene delivery. Adv Drug Deliv Rev 2005; 57: 2177–2202.PubMedGoogle Scholar
  92. 92.
    Tsutsumi T, Hirayama F, Uekama K, Arima H. Evaluation of polyamidoamine dendrimer/alpha-cyclodextrin conjugate (generation 3, G3) as a novel carrier for small interfering RNA (siRNA). J Control Release 2007; 119: 349–359.PubMedGoogle Scholar
  93. 93.
    Patil ML, Zhang M, Betigeri S, Taratula O, He H, Minko T. Surface-Modified and Internally Cationic Polyamidoamine Dendrimers for Efficient siRNA Delivery. Bioconjug Chem 2008; 19: 1396–1403.Google Scholar
  94. 94.
    Kang H, DeLong R, Fisher MH, Juliano RL. Tat-conjugated PAMAM dendrimers as delivery agents for antisense and siRNA oligonucleotides. Pharm Res 2005; 22: 2099–2106.PubMedGoogle Scholar
  95. 95.
    Gupta B, Levchenko TS, Torchilin VP. Intracellular delivery of large molecules and small particles by cell-penetrating proteins and peptides. Adv Drug Deliv Rev 2005; 57: 637–651.PubMedGoogle Scholar
  96. 96.
    Muratovska A, Eccles MR. Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells. FEBS Lett 2004; 558: 63–68.PubMedGoogle Scholar
  97. 97.
    Crombez L, Charnet A, Morris MC, Aldrian-Herrada G, Heitz F, Divita G. A non-covalent peptide-based strategy for siRNA delivery. Biochem Soc Trans 2007; 35: 44–46.PubMedGoogle Scholar
  98. 98.
    Zeineddine D, Papadimou E, Chebli K, Gineste M, Liu J, Grey C, et al. Oct-3/4 dose dependently regulates specification of embryonic stem cells toward a cardiac lineage and early heart development. Dev Cell 2006; 11: 535–546.PubMedGoogle Scholar
  99. 99.
    Davis ME, Pun SH, Bellocq NC, Reineke TM, Popielarski SR, Mishra S, et al. Self-assembling nucleic acid delivery vehicles via linear, water-soluble, cyclodextrin-containing polymers. Curr Med Chem 2004; 11: 179–197.PubMedGoogle Scholar
  100. 100.
    Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. Cancer Res 2005; 65: 8984–8992.PubMedGoogle Scholar
  101. 101.
    Heidel JD, Yu Z, Liu JY, Rele SM, Liang Y, Zeidan RK, et al. Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA. Proc Natl Acad Sci USA 2007; 104: 5715–5721.PubMedGoogle Scholar
  102. 102.
    Ochiya T, Nagahara S, Sano A, Itoh H, Terada M. Biomaterials for gene delivery: atelocollagen-mediated controlled release of molecular medicines. Curr Gene Ther 2001; 1: 31–52.PubMedGoogle Scholar
  103. 103.
    Minakuchi Y, Takeshita F, Kosaka N, Sasaki H, Yamamoto Y, Kouno M, et al. Atelocollagen-mediated synthetic small interfering RNA delivery for effective gene silencing in vitro and in vivo. Nucleic Acids Res 2004; 32: e109.PubMedGoogle Scholar
  104. 104.
    Takei Y, Kadomatsu K, Yuzawa Y, Matsuo S, Muramatsu T. A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res 2004; 64: 3365–3370.PubMedGoogle Scholar
  105. 105.
    Takeshita F, Minakuchi Y, Nagahara S, Honma K, Sasaki H, Hirai K, et al. Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. Proc Natl Acad Sci USA 2005; 102: 12177–12182.PubMedGoogle Scholar
  106. 106.
    Ikeda Y, Taira K. Ligand-targeted delivery of therapeutic siRNA. Pharm Res 2006; 23: 1631–1640.PubMedGoogle Scholar
  107. 107.
    Zhang Y, Zhang YF, Bryant J, Charles A, Boado RJ, Pardridge WM. Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin Cancer Res 2004; 10: 3667–3677.PubMedGoogle Scholar
  108. 108.
    Allen TM. Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer 2002; 2: 750–763.PubMedGoogle Scholar
  109. 109.
    Pirollo KF, Rait A, Zhou Q, Hwang SH, Dagata JA, Zon G, et al. Materializing the potential of small interfering RNA via a tumor-targeting nanodelivery system. Cancer Res 2007; 67: 2938–2943.PubMedGoogle Scholar
  110. 110.
    Pirollo KF, Zon G, Rait A, Zhou Q, Yu W, Hogrefe R, et al. Tumor-targeting nanoimmunoliposome complex for short interfering RNA delivery. Hum Gene Ther 2006; 17: 117–124.PubMedGoogle Scholar
  111. 111.
    Xu L, Huang CC, Huang W, Tang WH, Rait A, Yin YZ, et al. Systemic tumor-targeted gene delivery by anti-transferrin receptor scFv-immunoliposomes. Mol Cancer Ther 2002; 1: 337–346.PubMedGoogle Scholar
  112. 112.
    Agarwal A, Saraf S, Asthana A, Gupta U, Gajbhiye V, Jain NK. Ligand based dendritic systems for tumor targeting. Int J Pharm 2008; 350: 3–13.PubMedGoogle Scholar
  113. 113.
    Li H, Qian ZM. Transferrin/transferrin receptor-mediated drug delivery. Med Res Rev 2002; 22: 225–250.PubMedGoogle Scholar
  114. 114.
    Bartlett DW, Su H, Hildebrandt IJ, Weber WA, Davis ME. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc Natl Acad Sci USA 2007; 104: 15549–15554.PubMedGoogle Scholar
  115. 115.
    Cardoso AL, Simoes S, de Almeida LP, Pelisek J, Culmsee C, Wagner E, et al. siRNA delivery by a transferrin-associated lipid-based vector: a non-viral strategy to mediate gene silencing. J Gene Med 2007; 9: 170–183.PubMedGoogle Scholar
  116. 116.
    Bartlett DW, Davis ME. Impact of tumor-specific targeting and dosing schedule on tumor growth inhibition after intravenous administration of siRNA-containing nanoparticles. Biotechnol Bioeng 2008; 99: 975–985.PubMedGoogle Scholar
  117. 117.
    Zhang K, Wang Q, Xie Y, Mor G, Sega E, Low PS, et al. Receptor-mediated delivery of siRNAs by tethered nucleic acid base-paired interactions. RNA 2008; 14: 577–583.PubMedGoogle Scholar
  118. 118.
    Salazar MD, Ratnam M. The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev 2007; 26: 141–152.PubMedGoogle Scholar
  119. 119.
    Low PS, Henne WA, Doorneweerd DD. Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. Acc Chem Res 2008; 41: 120–129.PubMedGoogle Scholar
  120. 120.
    Temming K, Schiffelers RM, Molema G, Kok RJ. RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature. Drug Resist Updat 2005; 8: 381–402.PubMedGoogle Scholar
  121. 121.
    Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G, et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res 2004; 32: e149.PubMedGoogle Scholar
  122. 122.
    Hicke BJ, Stephens AW. Escort aptamers: a delivery service for diagnosis and therapy. J Clin Invest 2000; 106: 923–928.PubMedGoogle Scholar
  123. 123.
    McNamara JO, 2nd, Andrechek ER, Wang Y, Viles KD, Rempel RE, Gilboa E, et al. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol 2006; 24: 1005–1015.PubMedGoogle Scholar
  124. 124.
    Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 1997; 3: 81–85.PubMedGoogle Scholar
  125. 125.
    Dougherty CJ, Ichim TE, Liu L, Reznik G, Min WP, Ghochikyan A, et al. Selective apoptosis of breast cancer cells by siRNA targeting of BORIS. Biochem Biophys Res Commun 2008; 370: 109–112.PubMedGoogle Scholar
  126. 126.
    Jang JY, Choi Y, Jeon YK, Kim CW. Suppression of adenine nucleotide translocase-2 by vector-based siRNA in human breast cancer cells induces apoptosis and inhibits tumor growth in vitro and in vivo. Breast Cancer Res 2008; 10: R11.PubMedGoogle Scholar
  127. 127.
    Navakanit R, Graidist P, Leeanansaksiri W, Dechsukum C. Growth inhibition of breast cancer cell line MCF-7 by siRNA silencing of Wilms tumor 1 gene. J Med Assoc Thai 2007; 90: 2416–2421.PubMedGoogle Scholar
  128. 128.
    Wieczorek M, Paczkowska A, Guzenda P, Majorek M, Bednarek AK, Lamparska-Przybysz M. Silencing of Wnt-1 by siRNA induces apoptosis of MCF-7 human breast cancer cells. Cancer Biol Ther 2007; 7.Google Scholar
  129. 129.
    Meryet-Figuieres M, Resina S, Lavigne C, Barlovatz-Meimon G, Lebleu B, Thierry AR. Inhibition of PAI-1 expression in breast cancer carcinoma cells by siRNA at nanomolar range. Biochimie 2007; 89: 1228–1233.PubMedGoogle Scholar
  130. 130.
    Sutton D, Kim S, Shuai X, Leskov K, Marques JT, Williams BR, et al. Efficient suppression of secretory clusterin levels by polymer-siRNA nanocomplexes enhances ionizing radiation lethality in human MCF-7 breast cancer cells in vitro. Int J Nanomed 2006; 1: 155–162.Google Scholar
  131. 131.
    Zhang ZH, Chen Y, Zhao HJ, Xie CY, Ding J, Hou YT. Silencing of heparanase by siRNA inhibits tumor metastasis and angiogenesis of human breast cancer in vitro and in vivo. Cancer Biol Ther 2007; 6: 587–595.PubMedGoogle Scholar
  132. 132.
    Zhang X, Xu WH, Ge YL, Hou L, Li Q. Effect of siRNA transfection targeting VEGF gene on proliferation and apoptosis of human breast cancer cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2007; 23: 14–17.PubMedGoogle Scholar
  133. 133.
    Cao Q, Cai W, Li T, Yang Y, Chen K, Xing L, et al. Combination of integrin siRNA and irradiation for breast cancer therapy. Biochem Biophys Res Commun 2006; 351: 726–732.PubMedGoogle Scholar
  134. 134.
    Guan HT, Xue XH, Wang XJ, Li A, Qin ZY. Effects of siRNA targeted to survivin in suppressing proliferation and inducing apoptosis in breast cancer MCF-7 cells. Zhonghua Zhong Liu Za Zhi 2006; 28: 326–330.PubMedGoogle Scholar
  135. 135.
    Jiang L, Chen RS, Li JC. siRNA-cyclin D1 inhibit cell proliferation in breast cancer MCF-7 cell line. Fen Zi Xi Bao Sheng Wu Xue Bao 2006; 39: 118–122.PubMedGoogle Scholar
  136. 136.
    Subramanian R, Gondi CS, Lakka SS, Jutla A, Rao JS. siRNA-mediated simultaneous downregulation of uPA and its receptor inhibits angiogenesis and invasiveness triggering apoptosis in breast cancer cells. Int J Oncol 2006; 28: 831–839.PubMedGoogle Scholar
  137. 137.
    Zhang Y, Wang Y, Gao W, Zhang R, Han X, Jia M, et al. Transfer of siRNA against XIAP induces apoptosis and reduces tumor cells growth potential in human breast cancer in vitro and in vivo. Breast Cancer Res Treat 2006; 96: 267–277.PubMedGoogle Scholar
  138. 138.
    Huh JW, Choi MM, Yang SJ, Yoon SY, Choi SY, Cho SW. Inhibition of human UDP-glucose dehydrogenase expression using siRNA expression vector in breast cancer cells. Biotechnol Lett 2005; 27: 1229–1232.PubMedGoogle Scholar
  139. 139.
    Faltus T, Yuan J, Zimmer B, Kramer A, Loibl S, Kaufmann M, et al. Silencing of the HER2/neu gene by siRNA inhibits proliferation and induces apoptosis in HER2/neu-overexpressing breast cancer cells. Neoplasia 2004; 6: 786–795.PubMedGoogle Scholar
  140. 140.
    Wu WD, Fang CH, Yang ZX, Bao JJ. Effects of RNA interference on epidermal growth factor receptor expression in breast cancer cells: a study in tumor-bearing nude mice. Nan Fang Yi Ke Da Xue Xue Bao 2008; 28: 60–64.PubMedGoogle Scholar
  141. 141.
    Liu TG, Yin JQ, Shang BY, Min Z, He HW, Jiang JM, et al. Silencing of hdm2 oncogene by siRNA inhibits p53-dependent human breast cancer. Cancer Gene Ther 2004; 11: 748–756.PubMedGoogle Scholar
  142. 142.
    Mohammed K, Shervington A. Can CYP1A1 siRNA be an effective treatment for lung cancer? Cell Mol Biol Lett 2008; 13: 240–249.PubMedGoogle Scholar
  143. 143.
    Zhang Z, Jiang G, Yang F, Wang J. Knockdown of mutant K-ras expression by adenovirus-mediated siRNA inhibits the in vitro and in vivo growth of lung cancer cells. Cancer Biol Ther 2006; 5: 1481–1486.PubMedGoogle Scholar
  144. 144.
    Guo W, Ahmed KM, Hui Y, Guo G, Li JJ. siRNA-mediated MDM2 inhibition sensitizes human lung cancer A549 cells to radiation. Int J Oncol 2007; 30: 1447–1452.PubMedGoogle Scholar
  145. 145.
    Dong AQ, Kong MJ, Ma ZY, Qian JF, Xu XH. Down-regulation of IGF-IR using small, interfering, hairpin RNA (siRNA) inhibits growth of human lung cancer cell line A549 in vitro and in nude mice. Cell Biol Int 2007; 31: 500–507.PubMedGoogle Scholar
  146. 146.
    Kakar SS, Malik MT. Suppression of lung cancer with siRNA targeting PTTG. Int J Oncol 2006; 29: 387–395.PubMedGoogle Scholar
  147. 147.
    Yamanaka S, Gu Z, Sato M, Fujisaki R, Inomata K, Sakurada A, et al. siRNA targeting against EGFR, a promising candidate for a novel therapeutic application to lung adenocarcinoma. Pathobiology 2008; 75: 2–8.PubMedGoogle Scholar
  148. 148.
    Lee MW, Kim DS, Min NY, Kim HT. Akt1 inhibition by RNA interference sensitizes human non-small cell lung cancer cells to cisplatin. Int J Cancer 2008; 122: 2380–2384.PubMedGoogle Scholar
  149. 149.
    Kim HR, Kim S, Kim EJ, Park JH, Yang SH, Jeong ET, et al. Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin. Lung Cancer 2008; 60: 47–56.PubMedGoogle Scholar
  150. 150.
    Gan PP, Pasquier E, Kavallaris M. Class III beta-tubulin mediates sensitivity to chemotherapeutic drugs in non small cell lung cancer. Cancer Res 2007; 67: 9356–9363.PubMedGoogle Scholar
  151. 151.
    Mano Y, Takahashi K, Ishikawa N, Takano A, Yasui W, Inai K, et al. Fibroblast growth factor receptor 1 oncogene partner as a novel prognostic biomarker and therapeutic target for lung cancer. Cancer Sci 2007; 98: 1902–1913.PubMedGoogle Scholar
  152. 152.
    Cho NH, Choi YP, Moon DS, Kim H, Kang S, Ding O, et al. Induction of cell apoptosis in non-small cell lung cancer cells by cyclin A1 small interfering RNA. Cancer Sci 2006; 97: 1082–1092.PubMedGoogle Scholar
  153. 153.
    Ohnishi K, Scuric Z, Schiestl RH, Okamoto N, Takahashi A, Ohnishi T. siRNA targeting NBS1 or XIAP increases radiation sensitivity of human cancer cells independent of TP53 status. Radiat Res 2006; 166: 454–462.PubMedGoogle Scholar
  154. 154.
    Ko K, Furukawa K, Takahashi T, Urano T, Sanai Y, Nagino M, et al. Fundamental study of small interfering RNAs for ganglioside GD3 synthase gene as a therapeutic target of lung cancers. Oncogene 2006; 25: 6924–6935.PubMedGoogle Scholar
  155. 155.
    Xu XF, Zhang ZY, Ge JP, Cheng W, Zhou SW, Zhang X et al. RNA interference-mediated silencing of the PAR gene inhibits the growth of PC3 cells via the induction of G2/M cell cycle arrest and apoptosis. J Gene Med 2007; 9: 1065–1070.PubMedGoogle Scholar
  156. 156.
    Sanlioglu AD, Karacay B, Koksal IT, Griffith TS, Sanlioglu S. DcR2 (TRAIL-R4) siRNA and adenovirus delivery of TRAIL (Ad5hTRAIL) break down in vitro tumorigenic potential of prostate carcinoma cells. Cancer Gene Ther 2007; 14: 976–984.PubMedGoogle Scholar
  157. 157.
    Takei Y, Kadomatsu K, Goto T, Muramatsu T. Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts. Cancer 2006; 107: 864–873.PubMedGoogle Scholar
  158. 158.
    Bandyopadhyay S, Pai SK, Watabe M, Gross SC, Hirota S, Hosobe S, et al. FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis. Oncogene 2005; 24: 5389–5395.PubMedGoogle Scholar
  159. 159.
    Zhang L, Gao L, Zhao L, Guo B, Ji K, Tian Y, et al. Intratumoral delivery and suppression of prostate tumor growth by attenuated Salmonella enterica serovar typhimurium carrying plasmid-based small interfering RNAs. Cancer Res 2007; 67: 5859–5864.PubMedGoogle Scholar
  160. 160.
    Das S, Roth CP, Wasson LM, Vishwanatha JK. Signal transducer and activator of transcription-6 (STAT6) is a constitutively expressed survival factor in human prostate cancer. Prostate 2007; 67: 1550–1564.PubMedGoogle Scholar
  161. 161.
    Reagan-Shaw S, Ahmad N. Silencing of polo-like kinase (Plk) 1 via siRNA causes induction of apoptosis and impairment of mitosis machinery in human prostate cancer cells: implications for the treatment of prostate cancer. FASEB J 2005; 19: 611–613.PubMedGoogle Scholar
  162. 162.
    Grzmil M, Voigt S, Thelen P, Hemmerlein B, Helmke K, Burfeind P. Up-regulated expression of the MAT-8 gene in prostate cancer and its siRNA-mediated inhibition of expression induces a decrease in proliferation of human prostate carcinoma cells. Int J Oncol 2004; 24: 97–105.PubMedGoogle Scholar
  163. 163.
    Mizutani K, Nagata K, Ito H, Ehara H, Nozawa Y, Deguchi T. Possible roles of vinexinbeta in growth and paclitaxel sensitivity in human prostate cancer PC-3 cells. Cancer Biol Ther 2007; 6: 1800–1804.PubMedGoogle Scholar
  164. 164.
    Yamasaki M, Nomura T, Sato F, Mimata H. Metallothionein is up-regulated under hypoxia and promotes the survival of human prostate cancer cells. Oncol Rep 2007; 18: 1145–1153.PubMedGoogle Scholar
  165. 165.
    Saad AF, Meacham WD, Bai A, Anelli V, Elojeimy S, Mahdy AE, et al. The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy. Cancer Biol Ther 2007; 6: 1455–1460.PubMedGoogle Scholar
  166. 166.
    Pulukuri SM, Rao JS. Small interfering RNA directed reversal of urokinase plasminogen activator demethylation inhibits prostate tumor growth and metastasis. Cancer Res 2007; 67: 6637–6646.PubMedGoogle Scholar
  167. 167.
    Priulla M, Calastretti A, Bruno P, Azzariti A, Paradiso A, Canti G, et al. Preferential chemosensitization of PTEN-mutated prostate cells by silencing the Akt kinase. Prostate 2007; 67: 782–789.PubMedGoogle Scholar
  168. 168.
    Rocchi P, Jugpal P, So A, Sinneman S, Ettinger S, Fazli L, et al. Small interference RNA targeting heat-shock protein 27 inhibits the growth of prostatic cell lines and induces apoptosis via caspase-3 activation in vitro. BJU Int 2006; 98: 1082–1089.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUniversity of Missouri-Kansas CityKansas CityUSA

Personalised recommendations