Pharmaceutical Research

, Volume 23, Issue 8, pp 1631–1640

Ligand-Targeted Delivery of Therapeutic siRNA

Expert Review

Abstract

RNA interference (RNAi) is a post-transcriptional gene-silencing phenomenon that is triggered by double-stranded RNA (dsRNA). Since many diseases are associated with the inappropriate production of specific proteins, attempts are being made to exploit RNAi in a clinical settings. However, before RNAi can be exploited as therapeutically, several obstacles must be overcome. For example, small interfering RNA (siRNA) is unstable in the blood stream so any effects of injected siRNA are only transient. Accordingly, methods must be developed to prolong its activity. Furthermore, the efficient and safe delivery of siRNA into target tissues and cells is critical for successful therapy. Any useful delivery method should be designed to target siRNA to specific cells and to promote gene-silencing activity once the siRNA is inside the cells. Recent chemical modifications of siRNA have overcome problems associated with the instability of siRNA, and various ligands, including glycosylated molecules, peptides, proteins, antibodies and engineered antibody fragments, appear to be very useful or have considerable potential for the targeted delivery of siRNA. The use of such ligands improves the efficiency, specificity and, as a consequence, the safety of the corresponding delivery systems.

Key words

antibody antibody engineering ligand RNA interference targeted delivery 

References

  1. 1.
    C. D. Novina and P. A. Sharp. The RNAi revolution. Nature 430:161–164 (2004).PubMedCrossRefGoogle Scholar
  2. 2.
    D. M. Dykxhoorn and J. Lieberman. The silent revolution: RNA interference as basic biology, research tool, and therapeutic. Annu. Rev. Med. 56:401–423 (2005).PubMedCrossRefGoogle Scholar
  3. 3.
    A. P. McCaffrey, L. Meuse, T. T. Pham, D. S. Conklin, G. J. Hannon, and M. A. Kay. RNA interference in adult mice. Nature 418:38–39 (2002).PubMedCrossRefGoogle Scholar
  4. 4.
    D. L. Lewis and J. A. Wolff. Delivery of siRNA and siRNA expression constructs to adult mammals by hydrodynamic intravascular injection. Methods Enzymol. 392:336–350 (2005).PubMedCrossRefGoogle Scholar
  5. 5.
    D. L. Lewis, J. E. Hagstorm, A. G. Loomis, J. A. Wolff, and H. Herweijer. Efficient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat. Genet. 32:107–108 (2002).PubMedCrossRefGoogle Scholar
  6. 6.
    Z. Paroo and D. R. Corey. Challenges for RNAi in vivo. Trends Biotechnol. 22:390–394 (2004).PubMedCrossRefGoogle Scholar
  7. 7.
    D. A. Braasch, Z. Paroo, A. Constantinescu, G. Ren, O. K. Oz, R. P. Mason, and D. R. Corey. Biodistribution of phosphodiester and phosphorothioate siRNA. Bioorg. Med. Chem. Lett. 14:1139–1143 (2004).PubMedCrossRefGoogle Scholar
  8. 8.
    D. A. Braasch, S. Jensen, Y. Liu, K. Kaur, K. Arar, M. A. White, and D. R. Corey. RNA interference in mammalian cells by chemically modified RNA. Biochemistry 42:7967–7975 (2003).PubMedCrossRefGoogle Scholar
  9. 9.
    Y. L. Chiu and T. M. Rana. siRNA function in RNAi: a chemical modification analysis. RNA 9:1034–1048 (2003).PubMedCrossRefGoogle Scholar
  10. 10.
    M. Amarzguioui, T. Holen, E. Babaie, and H. Prydz. Tolerance for mutations and chemical modifications in a siRNA. Nucleic Acids Res. 31:589–595 (2003).PubMedCrossRefGoogle Scholar
  11. 11.
    F. Czauderna, M. Fechtner, S. Dames, H. Aygun, A. Klippel, G. J. Pronk, K. Giese, and J. Kaufmann. Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. Nucleic Acids Res. 31:2705–2716 (2003).PubMedCrossRefGoogle Scholar
  12. 12.
    T. P. Prakash, C. R. Allerson, P. Dande, T. A. Vickers, N. Sioufi, R. Jarres, B. F. Baher, E. E. Swayze, R. H. Griffey, and B. Bhar. Positional effect of chemical modifications on short interference RNA activity in mammalian cells. J. Med. Chem. 48:4247–4253 (2005).PubMedCrossRefGoogle Scholar
  13. 13.
    J. Elmen, H. Thonberg, K. Ljungberg, M. Frieden, M. Westergaard, Y. Xu, B. Wahren, Z. Liang, H. Orum, T. Koch, and C. Wahlestedt. Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality. Nucleic Acids Res. 33:439–447 (2005).PubMedCrossRefGoogle Scholar
  14. 14.
    A. H. Hall, J. Wan, E. E. Shaughnessy, B. R. Shaw, and K. A. Alexander. RNA interference using boranophosphate siRNAs: structure-activity relationships. Nucleic Acids Res. 32:5991–6000 (2004).PubMedCrossRefGoogle Scholar
  15. 15.
    Y. Chiu, A. Ali, C. Chu, H. Cao, and T. Rana. Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells. Chem. Biol. 11:1165–1175 (2004).PubMedCrossRefGoogle Scholar
  16. 16.
    C. Rudolph, C. Plank, J. Lausier, U. Schillinger, R. H. Muller, and J. Rosenecker. Oligomers of the arginine-rich motif of the HIV-1 TAT protein are capable of transferring plasmid DNA into cells. J. Biol. Chem. 278:11411–11418 (2003).PubMedCrossRefGoogle Scholar
  17. 17.
    T. S. Levchenko, R. Rammohan, N, Volodina, and V. P. Torchilin VP. Tat peptide-mediated intracellular delivery of liposomes. Methods Enzymol. 372:339–349 (2003).PubMedCrossRefGoogle Scholar
  18. 18.
    S. Fawell, J. Seery, Y. Daikh, C. Moore, L. L. Chen, B. Pepinsky, and J. Barsoum. Tat-mediated delivery of heterologous proteins into cells. Proc. Natl. Acad. Sci. USA 91:664–668 (1994).PubMedCrossRefGoogle Scholar
  19. 19.
    S. R. Schwarze, A. Ho, A. Vocero-Akbani, and S. F. Dowdy. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285:1569–1572 (1999).PubMedCrossRefGoogle Scholar
  20. 20.
    J. Soutschek, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432:173–178 (2004).PubMedCrossRefGoogle Scholar
  21. 21.
    T. Akasaka, K. Matsuura, N. Emi, and K. Kobayashi. Conjugation of plasmid DNAs with lactose via diazocoupling enhances resistance to restriction enzymes and acquires binding affinity to galactose-specific lectin. Biochem. Biophys. Res. Commun. 260:323–328 (1999).PubMedCrossRefGoogle Scholar
  22. 22.
    C. Neves, G. Byk, V. Escriou, F. Bussone, D. Scherman, and P. Wils. Novel method for covalent fluorescent labeling of plasmid DNA that maintains structural integrity of the plasmid. Bioconjug. Chem. 11:51–55 (2000).PubMedCrossRefGoogle Scholar
  23. 23.
    T. Nagasaki, T. Myohoji, T. Tachibana, S. Futaki, and S. Tamagaki. Can nuclear localization signals enhance nuclear localization of plasmid DNA? Bioconjug. Chem. 14:282–286 (2003).PubMedCrossRefGoogle Scholar
  24. 24.
    Y. Ikeda, S. Kawahara, K. Yoshinari, S. Fujita, and K. Taira. Specific 3′-terminal modification of DNA with a novel nucleoside analogue that allows a covalent linkage of a nuclear localization signal and enhancement of DNA stability. Chembiochem 6:297–303 (2005).PubMedCrossRefGoogle Scholar
  25. 25.
    P. S. Eder, R. J. DeVine, J. M. Dagle, and J. A. Walder. Substrate specificity and kinetics of degradation of antisense oligonucleotides by a 3′ exonuclease in plasma. Antisense Res. Dev. 1:141–151 (1991).PubMedGoogle Scholar
  26. 26.
    M. A. Zanta, P. Belguise-Valladier, and J. P. Behr. Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus. Proc. Natl. Acad. Sci. USA 96:91–96 (1999).PubMedCrossRefGoogle Scholar
  27. 27.
    M. Taki, Y. Kato, M. Miyagishi, Y. Takagi, and K. Taira. Small-interfering-RNA expression in cells based on an efficiently constructed dumbbell-shaped DNA. Angew. Chem., Int. Ed. Engl. 43:3160–3163 (2004).CrossRefGoogle Scholar
  28. 28.
    M. Hashida, M. Nishikawa, F. Yamashita, and Y. Takakura. Cell-specific delivery of genes with glycosylated carriers. Adv. Drug. Deliv. Rev. 52:187–196 (2001).PubMedCrossRefGoogle Scholar
  29. 29.
    S. Kawakami, S. Fumoto, M. Nishikawa, F. Yamashita, and M. Hashida. In vivo gene delivery to the liver using novel galactosylated cationic liposomes. Pharm. Res. 17:306–313 (2000).PubMedCrossRefGoogle Scholar
  30. 30.
    J. C. Perales, T. Ferkol, H. Beegen, O. D. Ratnoff, and R. W. Hanson. Gene transfer in vivo: sustained expression and regulation of genes introduced into the liver by receptor-targeted uptake. Proc. Natl. Acad. Sci. USA 91:4086–4090 (1994).PubMedCrossRefGoogle Scholar
  31. 31.
    J. S. Remy, A. Kichler, V. Mordvinov, F. Schuber, and J. P. Behr. Targeted gene transfer into hepatoma cells with lipopolyamine-condensed DNA particles presenting galactose ligands: a stage toward artificial viruses. Proc. Natl. Acad. Sci. USA 92:1744–1748 (1995).PubMedCrossRefGoogle Scholar
  32. 32.
    M. Oishi, Y. Nagasaki, K. Itaka, N. Nishiyama, and K. Kataoka. Lactosylated poly(ethylene glycol)-siRNA conjugate through acid-labile beta-thiopropionate linkage to construct pH-sensitive polyion complex micelles achieving enhanced gene silencing in hepatoma cells. J. Am. Chem. Soc. 127:1624–1625 (2005).PubMedCrossRefGoogle Scholar
  33. 33.
    Y. Hattori, S. Kawakami, S. Suzuki, F. Yamashita, and M. Hashida. Enhancement of immune responses by DNA vaccination through targeted gene delivery using mannosylated cationic liposome formulations following intravenous administration in mice. Biochem. Biophys. Res. Commun. 317:992–999 (2004).PubMedCrossRefGoogle Scholar
  34. 34.
    S. Kawakami, Y. Hattori, Y. Lu, Y. Higuchi, F. Yamashita, and M. Hashida. Effect of cationic charge on receptor-mediated transfection using mannosylated cationic liposome/plasmid DNA complexes following the intravenous administration in mice. Pharmazie 59:405–408 (2004).PubMedGoogle Scholar
  35. 35.
    P. Erbacher, M. T. Bousser, J. Raimond, M. Monsigny, P. Midoux, and A. C. Roche. Gene transfer by DNA/glycosylated polylysine complexes into human blood monocyte-derived macrophages. Hum. Gene Ther. 7:721–729 (1996).PubMedCrossRefGoogle Scholar
  36. 36.
    J. F. Ross, P. K. Chaudhuri, and M. Ratnam. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer 73:2432–2443 (1994).PubMedCrossRefGoogle Scholar
  37. 37.
    S. Wang, R. J. Lee, G. Cauchon, D. G. Gorenstein, and P. S. Low. Delivery of antisense oligodeoxyribonucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol. Proc. Natl. Acad. Sci. USA 92:3318–3322 (1995).PubMedCrossRefGoogle Scholar
  38. 38.
    J. J. Turek, C. P. Leamon, and P. S. Low. Endocytosis of folate-protein conjugates: ultrastructural localization in KB cells. J. Cell Sci. 106:423–430 (1993).PubMedGoogle Scholar
  39. 39.
    S. Hwa Kim, J. Hoon Jeong, K. Chul Cho, S. Wan Kim, and T. Gwan Park. Target-specific gene silencing by siRNA plasmid DNA complexed with folate-modified poly(ethylenimine). J. Control. Release 104:223–232 (2005).PubMedCrossRefGoogle Scholar
  40. 40.
    J. A. Eble. Collagen-binding integrins as pharmaceutical targets. Curr. Pharm. Des. 11:867–880 (2005).PubMedCrossRefGoogle Scholar
  41. 41.
    R. M. Schiffelers, A. Ansari, J. Xu, Q. Zhou, Q. Tang, G. Storm, G. Molema, P. Y. Lu, P. V. Scaria, and M. C. Woodle. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 32:e149 (2004).PubMedCrossRefGoogle Scholar
  42. 42.
    P. Aisen. Transferrin receptor 1. Int. J. Biochem. Cell Biol. 36:2137–2143 (2004).PubMedCrossRefGoogle Scholar
  43. 43.
    S. Hu-Lieskovan, J. D. Heidel, D. W. Bartlett, M. E. Davis, and T. J. Triche. 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. 65:8984–8992 (2005).PubMedCrossRefGoogle Scholar
  44. 44.
    M. Mammen, S. K. Choi, and G. M. Whitesides. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew. Chem. Int. Ed. 37:2754–2794 (1998).CrossRefGoogle Scholar
  45. 45.
    G. P. Adams and L. M. Weiner. Monoclonal antibody therapy of cancer. Nat. Biotechnol. 23:1147–1157 (2005).PubMedCrossRefGoogle Scholar
  46. 46.
    A. Wright and S. L. Morrison. Effect of glycosylation on antibody function: implications for genetic engineering. Trends Biotechnol. 15:26–32 (1997).PubMedCrossRefGoogle Scholar
  47. 47.
    R. Niwa, E. Shoji-Hosaka, M. Sakurada, T. Shinkawa, K. Uchida, K. Nakamura, K. Matsushima, R. Ueda, N. Hanai, and K. Shitara. Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res. 64:2127–2133 (2004).PubMedCrossRefGoogle Scholar
  48. 48.
    P. J. Hudson and C. Souriau. Engineered antibodies. Nat. Med. 9:129–134 (2003).PubMedCrossRefGoogle Scholar
  49. 49.
    P. Holliger and P. J. Hudson. Engineered antibody fragments and the rise of single domains. Nat. Biotechnol. 23:1126–1136 (2005).PubMedCrossRefGoogle Scholar
  50. 50.
    L. Grosse-Hovest, W. Wick, R. Minoia, M. Weller, H. G. Rammensee, G. Brem, and G. Jung. Supraagonistic, bispecific single-chain antibody purified from the serum of cloned, transgenic cows induces T-cell-mediated killing of glioblastoma cells in vitro and in vivo. Int. J. Cancer 117:1060–1064 (2005).PubMedCrossRefGoogle Scholar
  51. 51.
    M. K. Robinson, M. Doss, C. Shaller, D. Narayanan, J. D. Marks, L. P. Adler, D. E. Gonzalez Trotter, and G. P. Adams. Quantitative immuno-positron emission tomography imaging of HER2-positive tumor xenografts with an iodine-124 labeled anti-HER2 diabody. Cancer Res. 65:1471–1478 (2005).PubMedCrossRefGoogle Scholar
  52. 52.
    I. Tomlinson and P. Holliger. Methods for generating multivalent and bispecific antibody fragments. Methods Enzymol. 326:461–479 (2000).PubMedGoogle Scholar
  53. 53.
    J. L. Casey, M. P. Napier, D. P. King, R. B. Pedley, L. C. Chaplin, N. Weir, L. Skelton, A. J. Green, L. D. Hope-Stone, G. T. Yarranton, and R. H. Begent. Tumour targeting of humanised cross-linked divalent-Fab' antibody fragments: a clinical phase I/II study. Br. J. Cancer 86:1401–1410 (2002).PubMedCrossRefGoogle Scholar
  54. 54.
    D. J. King, et al. Improved tumor targeting with chemically cross-linked recombinant antibody fragments. Cancer Res. 54:6176–6185 (1994).PubMedGoogle Scholar
  55. 55.
    P. Holliger, T. Prospero, and G. Winter. “Diabodies”: small bivalent and bispecific antibody fragments. Proc. Natl. Acad. Sci. USA 90:6444–6448 (1993).PubMedCrossRefGoogle Scholar
  56. 56.
    A. M. Merchant, Z. Zhu, J. Q. Yuan, A. Goddard, C. W. Adams, L. G. Presta, and P. Carter. An efficient route to human bispecific IgG. Nat. Biotechnol. 16:677–681 (1998).PubMedCrossRefGoogle Scholar
  57. 57.
    J. Kriangkum, B. Xu, L. P. Nagata, R. E. Fulton, and M. R. Suresh. Bispecific and bifunctional single chain recombinant antibodies. Biomol. Eng. 18:31–40 (2001).PubMedCrossRefGoogle Scholar
  58. 58.
    P. Hoffmann, R. Hofmeister, K. Brischwein, C. Brandl, S. Crommer, R. Bargou, C. Itin, N. Prang, and P. A. Baeuerle. Serial killing of tumor cells by cytotoxic T-cells redirected with a CD19-/CD3-bispecific single-chain antibody construct. Int. J. Cancer 115:98–104 (2005).PubMedCrossRefGoogle Scholar
  59. 59.
    J. Schlenzka, T. M. Moehler, S. M. Kipriyanov, M. Kornacker, A. Benner, A. Bahre, M. J. Stassar, H. J. Schafer, M. Little, H. Goldschmidt, and B. Cochlovius. Combined effect of recombinant CD19 × CD16 diabody and thalidomide in a preclinical model of human B cell lymphoma. Anti-cancer Drugs 15:915–919 (2004).PubMedCrossRefGoogle Scholar
  60. 60.
    A. P. Chapman. PEGylated antibodies and antibody fragments for improved therapy. Adv. Drug Deliv. Rev. 54:531–545 (2002).PubMedCrossRefGoogle Scholar
  61. 61.
    S. Frokjaer and D. E. Otzen. Protein drug stability: a formulation challenge. Nat. Rev. Drug Discov. 4:298–306 (2005).PubMedCrossRefGoogle Scholar
  62. 62.
    A. P. Chapman, P. Antoniw, M. Spitali, S. West, S. Stephens, and D. J. King. Therapeutic antibody fragments with prolonged in vivo half-lives. Nat. Biotechnol. 17:780–783 (1999).PubMedCrossRefGoogle Scholar
  63. 63.
    A. N. Weir, A. Nesbitt, A. P. Chapman, A. G. Popplewell, P. Antoniw, and A. D. Lawson. Formatting antibody fragments to mediate specific therapeutic functions. Biochem. Soc. Trans. 30:512–516 (2002)PubMedCrossRefGoogle Scholar
  64. 64.
    S. Kubetzko, C. A. Sarkar, and A. Pluckthun. Protein PEGylation decreases observed target association rates via a dual blocking mechanism. Mol. Pharmacol. 68:1439–1454 (2005).PubMedCrossRefGoogle Scholar
  65. 65.
    K. Yang, A. Basu, M. Wang, R. Chintala, M. C. Hsieh, S. Liu, J. Hua, Z. Zhang, J. Zhou, M. Li, H. Phyu, G. Petti, M. Mendez, H. Janjua, P. Peng, C. Longley, V. Borowski, M. Mehlig, and D. Filpula. Tailoring structure-function and pharmacokinetic properties of single-chain Fv proteins by site-specific PEGylation. Protein Eng. 16:761–770 (2003).PubMedCrossRefGoogle Scholar
  66. 66.
    H. K. Binz, P. Amstutz, and A. Pluckthun. Engineering novel binding proteins from nonimmunoglobulin domains. Nat. Biotechnol. 23:1257–1268 (2005).PubMedCrossRefGoogle Scholar
  67. 67.
    R. C. Ladner, A. K. Sato, J. Gorzelany, and M. de Souza. Phage display-derived peptides as therapeutic alternatives to antibodies. Drug Discov. Today 9:525–529 (2004).PubMedCrossRefGoogle Scholar
  68. 68.
    M. Hust and S. Dubel. Phage display vectors for the in vitro generation of human antibody fragments. Methods Mol. Biol. 295:71–96 (2005).PubMedGoogle Scholar
  69. 69.
    J. Hanes, C. Schaffitzel, A. Knappik, and A. Pluckthun. Picomolar affinity antibodies from a fully synthetic naive library selected and evolved by ribosome display. Nat. Biotechnol. 18:1287–1292 (2000).PubMedCrossRefGoogle Scholar
  70. 70.
    S. Fujita, S. Y. Sawata, R. Yamamoto-Fujita R, Y. Endo, H. Kise, M. Iwakura, and K. Taira. Novel approach for linking genotype to phenotype in vitro by exploiting an extremely strong interaction between RNA and protein. J. Med. Chem. 45:1598–1606 (2002).PubMedCrossRefGoogle Scholar
  71. 71.
    J. M. Zhou, S. Fujita, M. Warashina, T. Baba, and K. Taira. A novel strategy by the action of ricin that connects phenotype and genotype without loss of the diversity of libraries. J. Am. Chem. Soc. 124:538–543 (2002).PubMedCrossRefGoogle Scholar
  72. 72.
    S. Y. Sawata, E. Suyama, and K. Taira. A system based on specific protein-RNA interactions for analysis of target protein-protein interactions in vitro: successful selection of membrane-bound Bak-Bcl-xL proteins in vitro. Protein Eng. Des. Sel. 17:501–518 (2004).PubMedCrossRefGoogle Scholar
  73. 73.
    S. Y. Sawata and K. Taira. Modified peptide selection in vitro by introduction of a protein-RNA interaction. Protein Eng. 16:1115–1124 (2003).PubMedCrossRefGoogle Scholar
  74. 74.
    D. S. Wilson, A. D. Keefe, and J. W. Szostak. The use of mRNA display to select high-affinity protein-binding peptides. Proc. Natl. Acad. Sci. USA 98:3750–3755 (2001).PubMedCrossRefGoogle Scholar
  75. 75.
    M. A. Poul, B. Becerril, U. B. Nielsen, P. Morisson, and J. D. Marks. Selection of tumor-specific internalizing human antibodies from phage libraries. J. Mol. Biol. 301:1149–1161 (2000).PubMedCrossRefGoogle Scholar
  76. 76.
    B. Liu, F. Conrad, M. R. Cooperberg, D. B. Kirpotin, and J. D. Marks. Mapping tumor epitope space by direct selection of single-chain Fv antibody libraries on prostate cancer cells. Cancer Res. 64:704–710 (2004).PubMedCrossRefGoogle Scholar
  77. 77.
    J. W. Park, et al. Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery. Clin. Cancer Res. 8:1172–1181 (2002).PubMedGoogle Scholar
  78. 78.
    X. Li, P. Stuckert, I. Bosch, J. D. Marks, and W. A. Marasco. Single-chain antibody-mediated gene delivery into ErbB2-positive human breast cancer cells. Cancer Gene Ther. 8:555–565 (2001).PubMedCrossRefGoogle Scholar
  79. 79.
    M. A. Eaton, et al. A new self-assembling system for targeted gene delivery. Angew. Chem., Int. Ed. Engl. 39:4063–4067 (2000).CrossRefGoogle Scholar
  80. 80.
    Y. Zhang, Y. F. Zhang, J. Bryant, A. Charles, R. J. Boado, and W. M. Pardridge. Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin. Cancer Res. 10:3667–3677 (2004).PubMedCrossRefGoogle Scholar
  81. 81.
    M. C. de Lima, M. T. da Cruz, A. L. Cardoso, S. Simoes, and L. P. de Almeida. Liposomal and viral vectors for gene therapy of the central nervous system. Curr. Drug Targets CNS Neurol Disord. 4:453–465 (2005).PubMedCrossRefGoogle Scholar
  82. 82.
    E. Song, P. Zhu, S. K. Lee, D. Chowdhury, S. Kussman, D. M. Dykxhoorn, Y. Feng, D. Palliser, D. B. Weiner, P. Shankar, W. A. Marasco, and J. Lieberman. Antibody-mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat. Biotechnol. 23:709–717 (2005).PubMedCrossRefGoogle Scholar
  83. 83.
    A. M. Wu and P. D. Senter. Arming antibodies: prospects and challenges for immunoconjugates. Nat. Biotechnol. 23:1137–1146 (2005).PubMedCrossRefGoogle Scholar
  84. 84.
    T. Yokota, D. E. Milenic, M. Whitlow, and J. Schlom. Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res. 52:3402–3408 (1992).PubMedGoogle Scholar
  85. 85.
    K. Fujimori, D. C. Covell, J. E. Fletcher, and J. N. Weinstein. Modeling analysis of the global and microscopic distribution of immunoglobulin G, F(ab)2, and Fab in tumors. Cancer Res. 49:5656–5663 (1989).PubMedGoogle Scholar
  86. 86.
    G. P. Adams, R. Schier, A. M. McCall, H. H. Simmons, E. M. Horak, R. K. Alpaugh, J. D. Marks, and L. M. Weiner. High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res. 61:4750–4755 (2001).PubMedGoogle Scholar
  87. 87.
    R. K. Jain and L. T. Baxter. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 48:7022–7032 (1988).PubMedGoogle Scholar
  88. 88.
    R. K. Jain. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 50:814s–819s (1990).PubMedGoogle Scholar
  89. 89.
    E. N. Kaufman and R. K. Jain. Effect of bivalent interaction upon apparent antibody affinity: experimental confirmation of theory using fluorescence photobleaching and implications for antibody binding assays. Cancer Res. 52:4157–4167 (1992).PubMedGoogle Scholar
  90. 90.
    U. B. Nielsen, G. P. Adams, L. M. Weiner LM, and Marks J. D. Targeting of bivalent anti-ErbB2 diabody antibody fragments to tumor cells is independent of the intrinsic antibody affinity. Cancer Res. 60:6434–6440 (2000).PubMedGoogle Scholar
  91. 91.
    A. Balmain, J. Gray, and B. Ponder. The genetics and genomics of cancer. Nat. Genet. 33:238–244 (2003).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Gene Function Research CenterNational Institute of Advanced Industrial Science and Technology (AIST)Tsukuba Science CityJapan
  2. 2.Department of Chemistry and Biotechnology, School of EngineeringThe University of TokyoTokyoJapan

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