Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Intracellular trafficking of nonviral vectors

Gene Therapy volume 12, pages 1734–1751 (2005)Cite this article

Abstract

Nonviral vectors continue to be attractive alternatives to viruses due to their low toxicity and immunogenicity, lack of pathogenicity, and ease of pharmacologic production. However, nonviral vectors also continue to suffer from relatively low levels of gene transfer compared to viruses, thus the drive to improve these vectors continues. Many studies on vector–cell interactions have reported that nonviral vectors bind and enter cells efficiently, but yield low gene expression, thus directing our attention to the intracellular trafficking of these vectors to understand where the obstacles occur. Here, we will review nonviral vector trafficking pathways, which will be considered here as the steps from cell binding to nuclear delivery. Studies on the intracellular trafficking of nonviral vectors has given us valuable insights into the barriers these vectors must overcome to mediate efficient gene transfer. Importantly, we will highlight the different approaches used by researchers to overcome certain trafficking barriers to gene transfer, many of which incorporate components from biological systems that have naturally evolved the capacity to overcome such obstacles. The tools used to study trafficking pathways will also be discussed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Zabner J et al. Cellular and molecular barriers to gene transfer by a cationic lipid. J Biol Chem 1995; 270: 18997–19007.

    Article  CAS  PubMed  Google Scholar 

  2. Duzgunes N et al. Cationic liposomes for gene delivery: novel cationic lipids and enhancement by proteins and peptides. Curr Med Chem 2003; 10: 1213–1220.

    CAS  PubMed  Google Scholar 

  3. Boussif O 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Howard KA, Alpar HO . The development of polyplex-based DNA vaccines. J Drug Targeting 2002; 10: 143–151.

    CAS  Google Scholar 

  5. Oupicky D, Ogris M, Seymour LW . Development of long-circulating polyelectrolyte complexes for systemic delivery of genes. J Drug Targeting 2002; 10: 93–98.

    CAS  Google Scholar 

  6. Tsai JT et al. Quantitative physical characterization of lipid-polycation-DNA lipopolyplexes. Biotechnol Appl Biochem 2002; 36: 13–20.

    CAS  PubMed  Google Scholar 

  7. Yang J-P, Huang L . Novel supramolecular assemblies for gene delivery. In: Kabanov AV, Felgner PL, Seymour LW (eds). Self-Assembling Complexes for Gene Delivery. John Wiley & Sons: Chichester, 1998.

    Google Scholar 

  8. Manning GS . The molecular theory of polyelectrolyte solutions with applications to the electrostatic properties of polynucleotides. Quart Rev Biophys 1978; 11: 179–246.

    CAS  Google Scholar 

  9. Tang MX, Szoka Jr FC . Characterization of polycation complexes with DNA. In: Kabanov AV, Felgner PL, Seymour LW (eds). Self-Assembling Complexes for Gene Delivery. John Wiley & Sons: Chichester, 1998.

    Google Scholar 

  10. Vigneron JP et al. Guanidinium-cholesterol cationic lipids: efficient vectors for the transfection of eukaryotic cells. Proc Natl Acad Sci USA 1996; 93: 9682–9686.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Felgner PL et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA 1987; 84: 7413–7417.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wattiaux R, Laurent N, Wattiaux-De Coninck S, Jadot M . Endosomes, lysosomes: their implication in gene transfer. Adv Drug Deliv Rev 2000; 41: 201–208.

    CAS  PubMed  Google Scholar 

  13. Graham FL, van der Eb AJ . A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 1973; 52: 456–467.

    CAS  PubMed  Google Scholar 

  14. Jordan M, Schallhorn A, Wurm FM . Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation. Nucleic Acids Res 1996; 24: 596–601.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Fraley R, Subramani S, Berg P, Papahadjopoulos D . Introduction of liposome-encapsulated SV40 DNA into cells. J Biol Chem 1980; 255: 10431–10435.

    CAS  PubMed  Google Scholar 

  16. Felgner PL . Progress in gene delivery research and development. In: Huang L, Hung MC, Wagner E (eds). Nonviral Vectors for Gene Therapy. Academic Press: San Diego, 1999, pp 25–38.

    Google Scholar 

  17. Wu GY, Wu CH . Receptor-mediated in vitro gene transformation by a soluble DNA carrier system (erratum appears in J Biol Chem 1988 Jan 5; 263(1): 588). J Biol Chem 1987; 262: 4429–4432.

    CAS  PubMed  Google Scholar 

  18. Wu GY, Wu CH . Receptor-mediated gene delivery and expression in vivo. J Biol Chem 1988; 263: 14621–14624.

    CAS  PubMed  Google Scholar 

  19. Wagner E et al. Transferrin-polycation conjugates as carriers for DNA uptake into cells. 1990; 87: 3410–3414.

  20. Curiel DT . High-efficiency gene transfer mediated by adenovirus–polylysine–DNA complexes. Ann NY Acad Sci 1994; 716: 36–56; discussion 56–38.

    CAS  PubMed  Google Scholar 

  21. Fominaya J, Uherek C, Wels W . A chimeric fusion protein containing transforming growth factor-alpha mediates gene transfer via binding to the EGF receptor. Gene Therapy 1998; 5: 521–530.

    CAS  PubMed  Google Scholar 

  22. Huckett B, Ariatti M, Hawtrey AO . Evidence for targeted gene transfer by receptor-mediated endocytosis. Stable expression following insulin-directed entry of NEO into HepG2 cells. Biochem Pharmacol 1990; 40: 253–263.

    CAS  PubMed  Google Scholar 

  23. Rosenkranz AA et al. Receptor-mediated endocytosis and nuclear transport of a transfecting DNA construct. Exp Cell Res 1992; 199: 323–329.

    CAS  PubMed  Google Scholar 

  24. Lee RJ, Huang L . Folate-targeted, anionic liposome-entrapped polylysine-condensed DNA for tumor cell-specific gene transfer. J Biol Chem 1996; 271: 8481–8487.

    CAS  PubMed  Google Scholar 

  25. Mislick KA, Baldeschwieler JD, Kayyem JF, Meade TJ . Transfection of folate–polylysine DNA complexes: evidence for lysosomal delivery. Bioconjugate Chem 1995; 6: 512–515.

    CAS  Google Scholar 

  26. Gottschalk S, Cristiano RJ, Smith LC, Woo SL . Folate receptor mediated DNA delivery into tumor cells: potosomal disruption results in enhanced gene expression. Gene Therapy 1994; 1: 185–191.

    CAS  PubMed  Google Scholar 

  27. Sosnowski BA et al. Targeting DNA to cells with basic fibroblast growth factor (FGF2). J Biol Chem 1996; 271: 33647–33653.

    CAS  PubMed  Google Scholar 

  28. Harbottle RP et al. An RGD-oligolysine peptide: a prototype construct for integrin-mediated gene delivery (see comment). Human Gene Ther 1998; 9: 1037–1047.

    CAS  Google Scholar 

  29. Hart SL et al. Gene delivery and expression mediated by an integrin-binding peptide (erratum appears in Gene Ther 1996 Nov; 3(11): 1032–1033). Gene Therapy 1995; 2: 552–554.

    CAS  PubMed  Google Scholar 

  30. Harvie P et al. Targeting of lipid-protamine-DNA (LPD) lipopolyplexes using RGD motifs. J Liposome Res 2003; 13: 231–247.

    CAS  PubMed  Google Scholar 

  31. Medina-Kauwe LK, Maguire M, Kasahara N, Kedes L . Non-viral gene delivery to human breast cancer cells by targeted Ad5 penton proteins. Gene Therapy 2001; 8: 1753–1761.

    CAS  PubMed  Google Scholar 

  32. Buschle M et al. Receptor-mediated gene transfer into human T lymphocytes via binding of DNA/CD3 antibody particles to the CD3T cell receptor complex. Hum Gene Ther 1995; 6: 753–761.

    CAS  PubMed  Google Scholar 

  33. Finke S et al. Increase of proliferation rate and enhancement of antitumor cytotoxicity of expanded human CD3+ CD56+ immunologic effector cells by receptor-mediated transfection with the interleukin-7 gene. Gene Therapy 1998; 5: 31–39.

    CAS  PubMed  Google Scholar 

  34. Ebert O et al. Lymphocyte apoptosis: induction by gene transfer techniques. Gene Therapy 1997; 4: 296–302.

    CAS  PubMed  Google Scholar 

  35. Kircheis R et al. Coupling of cell-binding ligands to polyethylenimine for targeted gene delivery. Gene Therapy 1997; 4: 409–418.

    CAS  PubMed  Google Scholar 

  36. Merwin JR et al. CD5-mediated specific delivery of DNA to T lymphocytes: compartmentalization augmented by adenovirus. J Immunol Methods 1995; 186: 257–266.

    CAS  PubMed  Google Scholar 

  37. Chen J, Stickles RJ, Daichendt KA . Galactosylated histone-mediated gene transfer and expression. Hum Gene Ther 1994; 5: 429–435.

    PubMed  Google Scholar 

  38. Cristiano RJ, Roth JA . Epidermal growth factor mediated DNA delivery into lung cancer cells via the epidermal growth factor receptor. Cancer Gene Therapy 1996; 3: 4–10.

    CAS  PubMed  Google Scholar 

  39. Foster BJ, Kern JA . HER2-targeted gene transfer. Hum Gene Ther 1997; 8: 719–727.

    CAS  PubMed  Google Scholar 

  40. Curiel DT, Agarwal S, Wagner E, Cotten M . Adenovirus enhancement of transferrin-polylysine-mediated gene delivery. 1991; 88: 8850–8854.

  41. Wagner E et al. Coupling of adenovirus to transferrin-polylysine/DNA complexes greatly enhances receptor-mediated gene delivery and expression of transfected genes. Proc Natl Acad Sci USA 1992; 89: 6099–6103.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Fominaya J, Wels W . Target cell-specific DNA transfer mediated by a chimeric multidomain protein. Novel non-viral gene delivery system. J Biol Chem 1996; 271: 10560–10568.

    CAS  PubMed  Google Scholar 

  43. Medina-Kauwe LK, Kasahara N, Kedes L . 3PO, a novel non-viral gene delivery system using engineered Ad5 penton proteins. Gene Therapy 2001; 8: 795–803.

    CAS  PubMed  Google Scholar 

  44. Hardingham TE, Fosang AJ . Proteoglycans: many forms and many functions. FASEB J 1992; 6: 861–870.

    CAS  PubMed  Google Scholar 

  45. Mislick KA, Baldeschwieler JD . Evidence for the role of proteoglycans in cation-mediated gene transfer. Proc Natl Acad Sci USA 1996; 93: 12349–12354.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Baeuerle PA, Huttner WB . Chlorate – a potent inhibitor of protein sulfation in intact cells. Biochem Biophys Res Commun 1986; 141: 870–877.

    CAS  PubMed  Google Scholar 

  47. Mounkes LC et al. Proteoglycans mediate cationic liposome–DNA complex-based gene delivery in vitro and in vivo. J Biol Chem 1998; 273: 26164–26170.

    CAS  PubMed  Google Scholar 

  48. Simoes S et al. Mechanisms of gene transfer mediated by lipoplexes associated with targeting ligands or pH-sensitive peptides. Gene Therapy 1999; 6: 1798–1807.

    CAS  PubMed  Google Scholar 

  49. Menozzi FD et al. Enhanced bacterial virulence through exploitation of host glycosaminoglycans. Mol Microbiol 2002; 43: 1379–1386.

    CAS  PubMed  Google Scholar 

  50. Bomsel M, Alfsen A . Entry of viruses through the epithelial barrier: pathogenic trickery. Nat Rev Mol Cell Biol 2003; 4: 57–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Rentsendorj A et al. The Ad5 fiber mediates non-viral gene transfer in the absence of the whole virus, utilizing a novel cell entry pathway. Gene Therapy 2004; advance online publication 14 October 2004; doi:10.1038/sj.gt.3302402.

    Google Scholar 

  52. Vives RR, Lortat-Jacob H, Chroboczek J, Fender P . Heparan sulfate proteoglycan mediates the selective attachment and internalization of serotype 3 human adenovirus dodecahedron. Virology 2004; 321: 332–340.

    CAS  PubMed  Google Scholar 

  53. Bergelson JM et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 1997; 275: 1320–1323.

    CAS  PubMed  Google Scholar 

  54. Wickham TJ, Mathias P, Cheresh DA, Nemerow GR . Integrins αvβ3 and αvβ5 promote adenovirus internalization but not virus attachment. Cell 1993; 73: 309–319.

    CAS  PubMed  Google Scholar 

  55. Dechecchi MC, Tamanini A, Bonizzato A, Cabrini G . Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions. Virology 2000; 268: 382–390.

    CAS  PubMed  Google Scholar 

  56. Mukherjee S, Ghosh RN, Maxfield FR . Endocytosis. Physiol Rev 1997; 77: 759–803.

    CAS  PubMed  Google Scholar 

  57. Larkin JM, Donzell WC, Anderson RG . Potassium-dependent assembly of coated pits: new coated pits form as planar clathrin lattices. J Cell Biol 1986; 103: 2619–2627.

    CAS  PubMed  Google Scholar 

  58. Wang LH, Rothberg KG, Anderson RG . Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J Cell Biol 1993; 123: 1107–1117.

    CAS  PubMed  Google Scholar 

  59. Benmerah A et al. AP-2/Eps15 interaction is required for receptor-mediated endocytosis. J Cell Biol 1998; 140: 1055–1062.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Benmerah A, Bayrou M, Cerf-Bensussan N, Dautry-Varsat A . Inhibition of clathrin-coated pit assembly by an Eps15 mutant. J Cell Sci 1999; 112: 1303–1311.

    CAS  PubMed  Google Scholar 

  61. Hinrichsen L et al. Effect of clathrin heavy chain- and alpha-adaptin-specific small inhibitory RNAs on endocytic accessory proteins and receptor trafficking in HeLa cells. J Biol Chem 2003; 278: 45160–45170. Epub 2003 Sep 06.

    CAS  PubMed  Google Scholar 

  62. Hinshaw JE, Schmid SL . Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding [comment]. Nature 1995; 374: 190–192.

    CAS  PubMed  Google Scholar 

  63. Schmid SL, McNiven MA, De Camilli P . Dynamin and its partners: a progress report. Curr Opin Cell Biol 1998; 10: 504–512.

    CAS  PubMed  Google Scholar 

  64. Mousavi SA, Malerod L, Berg T, Kjeken R . Clathrin-dependent endocytosis. Biochem J 2004; 377: 1–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Rothman JE, Schmid SL . Enzymatic recycling of clathrin from coated vesicles. Cell 1986; 46: 5–9.

    CAS  PubMed  Google Scholar 

  66. Van Dyke RW . Acidification of lysosomes and endosomes. Subcell Biochem 1996; 27: 331–360.

    CAS  PubMed  Google Scholar 

  67. Presley JF et al. The End2 mutation in CHO cells slows the exit of transferrin receptors from the recycling compartment but bulk membrane recycling is unaffected. J Cell Biol 1993; 122: 1231–1241.

    CAS  PubMed  Google Scholar 

  68. Gluck SL . The vacuolar H(+)-ATPases: versatile proton pumps participating in constitutive and specialized functions of eukaryotic cells. Int Rev Cytol 1993; 137C: 105–137.

    CAS  PubMed  Google Scholar 

  69. Yoshimori T et al. Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem 1991; 266: 17707–17712.

    CAS  PubMed  Google Scholar 

  70. Bowman EJ, Siebers A, Altendorf K . Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proc Natl Acad Sci USA 1988; 85: 7972–7976.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Wagner E . Application of membrane-active peptides for nonviral gene delivery. Adv Drug Deliv Rev 1999; 38: 279–289.

    CAS  PubMed  Google Scholar 

  72. Phillips SC . Receptor-mediated DNA delivery approaches to human gene therapy. Biologicals 1995; 23: 13–16.

    CAS  PubMed  Google Scholar 

  73. Sheff DR, Daro EA, Hull M, Mellman I . The receptor recycling pathway contains two distinct populations of early endosomes with different sorting functions. J Cell Biol 1999; 145: 123–139.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Widera A, Norouziyan F, Shen WC . Mechanisms of TfR-mediated transcytosis and sorting in epithelial cells and applications toward drug delivery. Adv Drug Deliv Rev 2003; 55: 1439–1466.

    CAS  PubMed  Google Scholar 

  75. Mayor S, Presley JF, Maxfield FR . Sorting of membrane components from endosomes and subsequent recycling to the cell surface occurs by a bulk flow process. J Cell Biol 1993; 121: 1257–1269.

    CAS  PubMed  Google Scholar 

  76. Parton RG, Richards AA . Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms. Traffic 2003; 4: 724–738.

    CAS  PubMed  Google Scholar 

  77. Cohen AW, Hnasko R, Schubert W, Lisanti MP . Role of caveolae and caveolins in health and disease. Physiol Rev 2004; 84: 1341–1379.

    CAS  PubMed  Google Scholar 

  78. Rejman J, Oberle V, Zuhorn IS, Hoekstra D . Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J 2004; 377: 159–169.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Mundy DI et al. Dual control of caveolar membrane traffic by microtubules and the actin cytoskeleton. J Cell Sci 2002; 115: 4327–4339.

    CAS  PubMed  Google Scholar 

  80. Pelkmans L, Kartenbeck J, Helenius A . Caveolar endocytosis of simian virus 40 reveals a new two-step vesicular-transport pathway to the ER. Nat Cell Biol 2001; 3: 473–483.

    CAS  PubMed  Google Scholar 

  81. McIntosh DP, Tan XY, Oh P, Schnitzer JE . Targeting endothelium and its dynamic caveolae for tissue-specific transcytosis in vivo: a pathway to overcome cell barriers to drug and gene delivery. Proc Natl Acad Sci USA 2002; 99: 1996–2001.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Carver LA, Schnitzer JE . Caveolae: mining little caves for new cancer targets. Nat Rev Cancer 2003; 3: 571–581.

    CAS  PubMed  Google Scholar 

  83. Schnitzer JE . Caveolae: from basic trafficking mechanisms to targeting transcytosis for tissue-specific drug and gene delivery in vivo. Adv Drug Deliv Rev 2001; 49: 265–280.

    CAS  PubMed  Google Scholar 

  84. Grimmer S, van Deurs B, Sandvig K . Membrane ruffling and macropinocytosis in A431 cells require cholesterol. J Cell Sci 2002; 115: 2953–2962.

    CAS  PubMed  Google Scholar 

  85. Dangoria NS et al. Extracellular simian virus 40 induces an ERK/MAP kinase-independent signalling pathway that activates primary response genes and promotes virus entry. J Gen Virol 1996; 77: 2173–2182.

    CAS  PubMed  Google Scholar 

  86. Dowrick P, Kenworthy P, McCann B, Warn R . Circular ruffle formation and closure lead to macropinocytosis in hepatocyte growth factor/scatter factor-treated cells. Eur J Cell Biol 1993; 61: 44–53.

    CAS  PubMed  Google Scholar 

  87. Araki N, Johnson MT, Swanson JA . A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages. J Cell Biol 1996; 135: 1249–1260.

    CAS  PubMed  Google Scholar 

  88. West MA et al. Rac is required for constitutive macropinocytosis by dendritic cells but does not control its downregulation. Curr Biol 2000; 10: 839–848.

    CAS  PubMed  Google Scholar 

  89. Just I et al. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 1995; 375: 500–503.

    CAS  PubMed  Google Scholar 

  90. Conner SD, Schmid SL . Regulated portals of entry into the cell. Nature 2003; 422: 37–44.

    CAS  PubMed  Google Scholar 

  91. Meier O et al. Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. J Cell Biol 2002; 158: 1119–1131.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Zuhorn IS, Kalicharan R, Hoekstra D . Lipoplex-mediated transfection of mammalian cells occurs through the cholesterol-dependent clathrin-mediated pathway of endocytosis. J Biol Chem 2002; 277: 18021–18028. Epub 2002 Mar 01.

    CAS  PubMed  Google Scholar 

  93. Castanho MA, Prieto M, Jameson DM . The pentaene macrolide antibiotic filipin prefers more rigid DPPC bilayers: a fluorescence pressure dependence study. Biochim Biophys Acta 1999; 1419: 1–14.

    CAS  PubMed  Google Scholar 

  94. Rodal SK et al. Extraction of cholesterol with methyl-beta-cyclodextrin perturbs formation of clathrin-coated endocytic vesicles. Mol Biol Cell 1999; 10: 961–974.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Shin JS, Abraham SN . Cell biology. Caveolae – not just craters in the cellular landscape. Science 2001; 293: 1447–1448.

    CAS  PubMed  Google Scholar 

  96. Huth S et al. Insights into the mechanism of magnetofection using PEI-based magnetofectins for gene transfer. J Gene Med 2004; 6: 923–936.

    CAS  PubMed  Google Scholar 

  97. Tammi R et al. Hyaluronan enters keratinocytes by a novel endocytic route for catabolism. J Biol Chem 2001; 276: 35111–35122. Epub 2001 Jul 12.

    CAS  PubMed  Google Scholar 

  98. Schnitzer JE, Oh P, Pinney E, Allard J . Filipin-sensitive caveolae-mediated transport in endothelium: reduced transcytosis, scavenger endocytosis, and capillary permeability of select macromolecules. J Cell Biol 1994; 127: 1217–1232.

    CAS  PubMed  Google Scholar 

  99. Goncalves C et al. Macropinocytosis of polyplexes and recycling of plasmid via the clathrin-dependent pathway impair the transfection efficiency of human hepatocarcinoma cells. Mol Ther 2004; 10: 373–385.

    CAS  PubMed  Google Scholar 

  100. Colin M et al. Cell delivery, intracellular trafficking and expression of an integrin-mediated gene transfer vector in tracheal epithelial cells. Gene Therapy 2000; 7: 139–152.

    CAS  PubMed  Google Scholar 

  101. Heuser JE, Anderson RG . Hypertonic media inhibit receptor-mediated endocytosis by blocking clathrin-coated pit formation. J Cell Biol 1989; 108: 389–400.

    CAS  PubMed  Google Scholar 

  102. Li G et al. Evidence for phosphatidylinositol 3-kinase as a regulator of endocytosis via activation of Rab5. Proc Natl Acad Sci USA 1995; 92: 10207–10211.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Salisbury JL, Keller GA . Structural investigations on the role of microfilaments in ligand translocation. Methods Enzymol 1983; 98: 368–375.

    CAS  PubMed  Google Scholar 

  104. Brown EJ . Phagocytosis. Bioessays 1995; 17: 109–117.

    CAS  PubMed  Google Scholar 

  105. Kichler A et al. Efficient DNA transfection mediated by the C-terminal domain of human immunodeficiency virus type 1 viral protein R. J Virol 2000; 74: 5424–5431.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Coeytaux E et al. The cationic amphipathic alpha-helix of HIV-1 viral protein R (Vpr) binds to nucleic acids, permeabilizes membranes, and efficiently transfects cells. J Biol Chem 2003; 278: 18110–18116. Epub 2003 Mar 14.

    CAS  PubMed  Google Scholar 

  107. Fujimoto T, Kogo H, Nomura R, Une T . Isoforms of caveolin-1 and caveolar structure. J Cell Sci 2000; 113: 3509–3517.

    CAS  PubMed  Google Scholar 

  108. Schwarze SR, Hruska KA, Dowdy SF . Protein transduction: unrestricted delivery into all cells? Trends Cell Biol 2000; 10: 290–295.

    CAS  PubMed  Google Scholar 

  109. Futaki S et al. Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J Biol Chem 2001; 276: 5836–5840.

    CAS  PubMed  Google Scholar 

  110. Lundberg M, Wikstrom S, Johansson M . Cell surface adherence and endocytosis of protein transduction domains. Mol Ther: J Am Soc Gene Ther 2003; 8: 143–150.

    CAS  Google Scholar 

  111. Console S et al. 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 2003; 278: 35109–35114.

    CAS  PubMed  Google Scholar 

  112. Silhol M et al. Different mechanisms for cellular internalization of the HIV-1 Tat-derived cell penetrating peptide and recombinant proteins fused to Tat. Eur J Biochem 2002; 269: 494–501.

    CAS  PubMed  Google Scholar 

  113. Tyagi M, Rusnati M, Presta M, Giacca M . Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans. J Biol Chem 2001; 276: 3254–3261. Epub 2000 Oct 06.

    CAS  PubMed  Google Scholar 

  114. Fuchs SM, Raines RT . Pathway for polyarginine entry into mammalian cells. Biochemistry 2004; 43: 2438–2444.

    CAS  PubMed  Google Scholar 

  115. Wadia JS, Stan RV, Dowdy SF . Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nat Med 2004; 10: 310–315. Epub 2004 Feb 08.

    CAS  PubMed  Google Scholar 

  116. Norbury CC et al. Class I MHC presentation of exogenous soluble antigen via macropinocytosis in bone marrow macrophages. Immunity 1995; 3: 783–791.

    CAS  PubMed  Google Scholar 

  117. Rentsendorj A et al. The Ad5 fiber mediates nonviral gene transfer in the absence of the whole virus, utilizing a novel cell entry pathway. Gene Therapy 2005; 12: 225–237.

    CAS  PubMed  Google Scholar 

  118. Eguchi A et al. Protein transduction domain of HIV-1 Tat protein promotes efficient delivery of DNA into mammalian cells. J Biol Chem 2001; 276: 26204–26210. Epub 2001 May 09.

    CAS  PubMed  Google Scholar 

  119. Fittipaldi A et al. Cell membrane lipid rafts mediate caveolar endocytosis of HIV-1 Tat fusion proteins. J Biol Chem 2003; 278: 34141–34149. Epub 2003 May 27.

    CAS  PubMed  Google Scholar 

  120. Hyndman L et al. HIV-1 Tat protein transduction domain peptide facilitates gene transfer in combination with cationic liposomes. J Control Release 2004; 99: 435–444.

    CAS  PubMed  Google Scholar 

  121. Zhou X, Huang L . DNA transfection mediated by cationic liposomes containing lipopolylysine: characterization and mechanism of action. Biochim Biophys Acta 1994; 1189: 195–203.

    CAS  PubMed  Google Scholar 

  122. Friend DS, Papahadjopoulos D, Debs RJ . Endocytosis and intracellular processing accompanying transfection mediated by cationic liposomes. Biochim Biophys Acta 1996; 1278: 41–50.

    PubMed  Google Scholar 

  123. Vendeville A et al. HIV-1 Tat enters T cells using coated pits before translocating from acidified endosomes and eliciting biological responses. Mol Biol Cell 2004; 15: 2347–2360. Epub 2004 Mar 2312.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Zatloukal K et al. Transferrinfection: a highly efficient way to express gene constructs in eukaryotic cells. Ann NY Acad Sci 1992; 660: 136–153.

    CAS  PubMed  Google Scholar 

  125. Olsnes S, van Deurs B, Sandvig K . Protein toxins acting on intracellular targets: cellular uptake and translocation to the cytosol. Med Microbiol Immunol 1993; 182: 51–61.

    CAS  PubMed  Google Scholar 

  126. Zhan H et al. Interaction of the isolated transmembrane domain of diphtheria toxin with membranes. Biochemistry 1995; 34: 4856–4863.

    CAS  PubMed  Google Scholar 

  127. Fisher KJ, Wilson JM . The transmembrane domain of diphtheria toxin improves molecular conjugate gene transfer. Biochem J 1997; 321: 49–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Uherek C, Fominaya J, Wels W . A modular DNA carrier protein based on the structure of diphtheria toxin mediates target cell-specific gene delivery. J Biol Chem 1998; 273: 8835–8841.

    CAS  PubMed  Google Scholar 

  129. Allende D, Simon SA, McIntosh TJ . Melittin-induced bilayer leakage depends on lipid material properties: evidence for toroidal pores. Biophys J 2004; 13: 13.

    Google Scholar 

  130. Yang L et al. Barrel-stave model or toroidal model? A case study on melittin pores. Biophys J 2001; 81: 1475–1485.

    PubMed  PubMed Central  Google Scholar 

  131. Ogris M, Carlisle RC, Bettinger T, Seymour LW . Melittin enables efficient vesicular escape and enhanced nuclear access of nonviral gene delivery vectors. J Biol Chem 2001; 276: 47550–47555. Epub 2001 Oct 12.

    CAS  PubMed  Google Scholar 

  132. Li W, Nicol F, Szoka Jr FC . GALA: a designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery. Adv Drug Deliv Rev 2004; 56: 967–985.

    CAS  PubMed  Google Scholar 

  133. Parente RA, Nir S, Szoka Jr FC . Mechanism of leakage of phospholipid vesicle contents induced by the peptide GALA. Biochemistry 1990; 29: 8720–8728.

    CAS  PubMed  Google Scholar 

  134. Nir S, Nicol F, Szoka Jr FC . Surface aggregation and membrane penetration by peptides: relation to pore formation and fusion. Mol Membr Biol 1999; 16: 95–101.

    CAS  PubMed  Google Scholar 

  135. Kakudo T et al. Transferrin-modified liposomes equipped with a pH-sensitive fusogenic peptide: an artificial viral-like delivery system. Biochemistry 2004; 43: 5618–5628.

    CAS  PubMed  Google Scholar 

  136. Haensler J, Szoka Jr FC . Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug Chem 1993; 4: 372–379.

    CAS  PubMed  Google Scholar 

  137. Gottschalk S et al. A novel DNA–peptide complex for efficient gene transfer and expression in mammalian cells. Gene Therapy 1996; 3: 48–57.

    Google Scholar 

  138. Wyman TB et al. Design, synthesis, and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers. Biochemistry 1997; 36: 3008–3017.

    CAS  PubMed  Google Scholar 

  139. Legendre JY, Szoka Jr FC . Cyclic amphipathic peptide–DNA complexes mediate high-efficiency transfection of adherent mammalian cells. Proc Natl Acad Sci USA 1993; 90: 893–897.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Fattal E, Nir S, Parente RA, Szoka Jr FC . Pore-forming peptides induce rapid phospholipid flip-flop in membranes. Biochemistry 1994; 33: 6721–6731.

    CAS  PubMed  Google Scholar 

  141. Kumar VV et al. Single histidine residue in head-group region is sufficient to impart remarkable gene transfection properties to cationic lipids: evidence for histidine-mediated membrane fusion at acidic pH. Gene Therapy 2003; 10: 1206–1215.

    CAS  PubMed  Google Scholar 

  142. Farhood H, Serbina N, Huang L . The role of dioleoyl phosphatidylethanolamine in cationic liposome mediated gene transfer. Biochim Biophys Acta 1995; 1235: 289–295.

    PubMed  Google Scholar 

  143. Mok KW, Cullis PR . Structural and fusogenic properties of cationic liposomes in the presence of plasmid DNA. Biophys J 1997; 73: 2534–2545.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Koltover I, Salditt T, Radler JO, Safinya CR . An inverted hexagonal phase of cationic liposome–DNA complexes related to DNA release and delivery. Science 1998; 281: 78–81.

    CAS  PubMed  Google Scholar 

  145. Allen TM, Hong K, Papahadjopoulos D . Membrane contact, fusion, and hexagonal (HII) transitions in phosphatidylethanolamine liposomes. Biochemistry 1990; 29: 2976–2985.

    CAS  PubMed  Google Scholar 

  146. Xu Y, Szoka Jr FC . Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection. Biochemistry 1996; 35: 5616–5623.

    CAS  PubMed  Google Scholar 

  147. Devaux PF . Protein involvement in transmembrane lipid asymmetry. Annu Rev Biophys Biomol Struct 1992; 21: 417–439.

    CAS  PubMed  Google Scholar 

  148. Barron LG, Szoka Jr FC . The perplexing delivery mechanism of lipoplexes. In: Huang L, Hung MC, Wagner E (eds). Nonviral Vectors for Gene Therapy. Academic Press: San Diego, 1999, pp 229–266.

    Google Scholar 

  149. Zelphati O, Szoka Jr FC . Mechanism of oligonucleotide release from cationic liposomes. Proc Natl Acad Sci USA 1996; 93: 11493–11498.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Daleke DL . Regulation of transbilayer plasma membrane phospholipid asymmetry. J Lipid Res 2003; 44: 233–242. Epub 2002 Dec 16.

    CAS  PubMed  Google Scholar 

  151. Schneider E, Haest CW, Plasa G, Deuticke B . Bacterial cytotoxins, amphotericin B and local anesthetics enhance transbilayer mobility of phospholipids in erythrocyte membranes. Consequences for phospholipid asymmetry. Biochim Biophys Acta 1986; 855: 325–336.

    CAS  PubMed  Google Scholar 

  152. Kichler A, Leborgne C, Coeytaux E, Danos O . Polyethylenimine-mediated gene delivery: a mechanistic study. J Gene Med 2001; 3: 135–144.

    CAS  PubMed  Google Scholar 

  153. Sonawane ND, Szoka Jr FC, Verkman AS . Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine–DNA polyplexes. J Biol Chem 2003; 278: 44826–44831. Epub 2003 Aug 27.

    CAS  PubMed  Google Scholar 

  154. Midoux P et al. Histidine containing peptides and polypeptides as nucleic acid vectors. Somat Cell Mol Genet 2002; 27: 27–47.

    CAS  PubMed  Google Scholar 

  155. Midoux P, Monsigny M . Efficient gene transfer by histidylated polylysine/pDNA complexes. Bioconjug Chem 1999; 10: 406–411.

    CAS  PubMed  Google Scholar 

  156. Kichler A et al. Histidine-rich amphipathic peptide antibiotics promote efficient delivery of DNA into mammalian cells. Proc Natl Acad Sci USA 2003; 100: 1564–1568. Epub 2003 Jan 31.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Vogt TC, Bechinger B . The interactions of histidine-containing amphipathic helical peptide antibiotics with lipid bilayers. The effects of charges and pH. J Biol Chem 1999; 274: 29115–29121.

    CAS  PubMed  Google Scholar 

  158. Bechinger B . Towards membrane protein design: pH-sensitive topology of histidine-containing polypeptides. J Mol Biol 1996; 263: 768–775.

    CAS  PubMed  Google Scholar 

  159. Wilson IA, Skehel JJ, Wiley DC . Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature 1981; 289: 366–373.

    CAS  PubMed  Google Scholar 

  160. Bullough PA, Hughson FM, Skehel JJ, Wiley DC . Structure of influenza haemagglutinin at the pH of membrane fusion.[see comment]. Nature 1994; 371: 37–43.

    CAS  PubMed  Google Scholar 

  161. Steinhauer DA, Wharton SA, Skehel JJ, Wiley DC . Studies of the membrane fusion activities of fusion peptide mutants of influenza virus hemagglutinin. J Virol 1995; 69: 6643–6651.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Nishikawa M et al. Hepatocyte-targeted in vivo gene expression by intravenous injection of plasmid DNA complexed with synthetic multi-functional gene delivery system. Gene Therapy 2000; 7: 548–555.

    CAS  PubMed  Google Scholar 

  163. Seth P, Willingham MC, Pastan I . Binding of adenovirus and its external proteins to Triton X-114. Dependence on pH. J Biol Chem 1985; 260: 14431–14434.

    CAS  PubMed  Google Scholar 

  164. Wang K, Guan T, Cheresh DA, Nemerow GR . Regulation of adenovirus membrane penetration by the cytoplasmic tail of integrin beta5. J Virol 2000; 74: 2731–2739.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Wickham TJ, Filardo EJ, Cheresh DA, Nemerow GR . Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization. J Cell Biol 1994; 127: 257–264.

    CAS  PubMed  Google Scholar 

  166. Fender P et al. Adenovirus dodecahedron, a new vector for human gene transfer [see comments]. Nat Biotechnol 1997; 15: 52–56.

    CAS  PubMed  Google Scholar 

  167. Bal HP et al. Adenovirus type 7 penton purification of soluble pentamers from Escherichia coli and development of an integrin-dependent gene delivery system. Eur J Biochem 2000; 267: 6074–6081.

    CAS  PubMed  Google Scholar 

  168. Prchla E et al. Virus-mediated release of endosomal content in vitro: different behavior of adenovirus and rhinovirus serotype 2. J Cell Biol 1995; 131: 111–123.

    CAS  PubMed  Google Scholar 

  169. Rogers SL, Gelfand VI . Membrane trafficking, organelle transport, and the cytoskeleton. Curr Opin Cell Biol 2000; 12: 57–62.

    CAS  PubMed  Google Scholar 

  170. Vallee RB, Sheetz MP . Targeting of motor proteins. Science 1996; 271: 1539–1544.

    CAS  PubMed  Google Scholar 

  171. Ward BM . Visualization and characterization of the intracellular movement of vaccinia virus intracellular mature virions. J Virol 2005; 79: 4755–4763.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Kelkar SA, Pfister KK, Crystal RG, Leopold PL . Cytoplasmic dynein mediates adenovirus binding to microtubules. J Virol 2004; 78: 10122–10132.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Douglas MW et al. Herpes simplex virus type 1 capsid protein VP26 interacts with dynein light chains RP3 and Tctex1 and plays a role in retrograde cellular transport. J Biol Chem 2004; 279: 28522–28530. Epub 2004 Apr 26.

    CAS  PubMed  Google Scholar 

  174. Suikkanen S et al. Exploitation of microtubule cytoskeleton and dynein during parvoviral traffic toward the nucleus. J Virol 2003; 77: 10270–10279.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Lakadamyali M, Rust MJ, Babcock HP, Zhuang X . Visualizing infection of individual influenza viruses. Proc Natl Acad Sci USA 2003; 100: 9280–9285. Epub 2003 Jul 25.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Petit C et al. Targeting of incoming retroviral Gag to the centrosome involves a direct interaction with the dynein light chain 8. J Cell Sci 2003; 116: 3433–3442.

    CAS  PubMed  Google Scholar 

  177. Hasegawa S, Hirashima N, Nakanishi M . Microtubule involvement in the intracellular dynamics for gene transfection mediated by cationic liposomes. Gene Therapy 2001; 8: 1669–1673.

    CAS  PubMed  Google Scholar 

  178. Durrbach A, Louvard D, Coudrier E . Actin filaments facilitate two steps of endocytosis. J Cell Sci 1996; 109: 457–465.

    CAS  PubMed  Google Scholar 

  179. Lindberg J, Fernandez MA, Ropp JD, Hamm-Alvarez SF . Nocodazole treatment of CV-1 cells enhances nuclear/perinuclear accumulation of lipid–DNA complexes and increases gene expression. Pharm Res 2001; 18: 246–249.

    CAS  PubMed  Google Scholar 

  180. Wang L, MacDonald RC . Effects of microtubule-depolymerizing agents on the transfection of cultured vascular smooth muscle cells: enhanced expression with free drug and especially with drug-gene lipoplexes. Mol Ther 2004; 9: 729–737.

    CAS  PubMed  Google Scholar 

  181. Elkjaer ML et al. Effects of microtubule disruption on endocytosis, membrane recycling and polarized distribution of Aquaporin-1 and gp330 in proximal tubule cells. Eur J Cell Biol 1995; 67: 57–72.

    CAS  PubMed  Google Scholar 

  182. Matteoni R, Kreis TE . Translocation and clustering of endosomes and lysosomes depends on microtubules. J Cell Biol 1987; 105: 1253–1265.

    CAS  PubMed  Google Scholar 

  183. Thatte HS, Bridges KR, Golan DE . Microtubule inhibitors differentially affect translational movement, cell surface expression, and endocytosis of transferrin receptors in K562 cells. J Cell Physiol 1994; 160: 345–357.

    CAS  PubMed  Google Scholar 

  184. Liu SM, Magnusson KE, Sundqvist T . Microtubules are involved in transport of macromolecules by vesicles in cultured bovine aortic endothelial cells. J Cell Physiol 1993; 156: 311–316.

    CAS  PubMed  Google Scholar 

  185. Rosette C, Karin M . Cytoskeletal control of gene expression: depolymerization of microtubules activates NF-kappa B. J Cell Biol 1995; 128: 1111–1119.

    CAS  PubMed  Google Scholar 

  186. Krauzewicz N et al. Virus-like gene transfer into cells mediated by polyoma virus pseudocapsids. Gene Therapy 2000; 7: 2122–2131.

    CAS  PubMed  Google Scholar 

  187. Medina-Kauwe LK . Endocytosis of adenovirus and adenovirus capsid proteins. Adv Drug Del Rev 2003; 55: 1485–1496.

    CAS  Google Scholar 

  188. Hamm-Alvarez SF, Xie J, Wang Y, Medina-Kauwe LK . Modulation of secretory functions in epithelia by adenovirus capsid proteins. J Control Release 2003; 93: 129–140.

    CAS  PubMed  Google Scholar 

  189. Meier O, Greber UF . Adenovirus endocytosis. J Gene Med 2004; 6: S152–S163.

    PubMed  Google Scholar 

  190. Wang Y et al. Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland. Gene Therapy 2004; 11: 970–981.

    CAS  PubMed  Google Scholar 

  191. Cervantes-Acosta G, Lodge R, Lemay G, Cohen EA . Influence of human immunodeficiency virus type 1 envelope glycoprotein YXXL endocytosis/polarization signal on viral accessory protein functions. J Hum Virol 2001; 4: 249–259.

    CAS  PubMed  Google Scholar 

  192. Lechardeur D et al. Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer. Gene Therapy 1999; 6: 482–497.

    CAS  PubMed  Google Scholar 

  193. Pollard H et al. Ca2+-sensitive cytosolic nucleases prevent efficient delivery to the nucleus of injected plasmids. J Gene Med 2001; 3: 153–164.

    CAS  PubMed  Google Scholar 

  194. Torriglia A, Chaudun E, Courtois Y, Counis MF . On the use of Zn2+ to discriminate endonucleases activated during apoptosis. Biochimie 1997; 79: 435–438.

    CAS  PubMed  Google Scholar 

  195. Lukacs GL et al. Size-dependent DNA mobility in cytoplasm and nucleus. J Biol Chem 2000; 275: 1625–1629.

    CAS  PubMed  Google Scholar 

  196. Leonetti JP et al. Intracellular distribution of microinjected antisense oligonucleotides. Proc Natl Acad Sci USA 1991; 88: 2702–2706.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Zelphati O, Szoka Jr FC . Intracellular distribution and mechanism of delivery of oligonucleotides mediated by cationic lipids. Pharm Res 1996; 13: 1367–1372.

    CAS  PubMed  Google Scholar 

  198. Pante N, Aebi U . Molecular dissection of the nuclear pore complex. Crit Rev Biochem Mol Biol 1996; 31: 153–199.

    CAS  PubMed  Google Scholar 

  199. Stoffler D, Fahrenkrog B, Aebi U . The nuclear pore complex: from molecular architecture to functional dynamics. Curr Opin Cell Biol 1999; 11: 391–401.

    CAS  PubMed  Google Scholar 

  200. Imamoto N . Diversity in nucleocytoplasmic transport pathways. Cell Struct Funct 2000; 25: 207–216.

    CAS  PubMed  Google Scholar 

  201. Conti E, Izaurralde E . Nucleocytoplasmic transport enters the atomic age. Curr Opin Cell Biol 2001; 13: 310–319.

    CAS  PubMed  Google Scholar 

  202. Clever J, Yamada M, Kasamatsu H . Import of simian virus 40 virions through nuclear pore complexes. Proc Natl Acad Sci USA 1991; 88: 7333–7337.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Sodeik B, Ebersold MW, Helenius A . Microtubule-mediated transport of incoming herpes simplex virus 1 capsids to the nucleus. J Cell Biol 1997; 136: 1007–1021.

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Pante N, Aebi U . Sequential binding of import ligands to distinct nucleopore regions during their nuclear import. Science 1996; 273: 1729–1732.

    CAS  PubMed  Google Scholar 

  205. Dabauvalle MC, Schulz B, Scheer U, Peters R . Inhibition of nuclear accumulation of karyophilic proteins in living cells by microinjection of the lectin wheat germ agglutinin. Exp Cell Res 1988; 174: 291–296.

    CAS  PubMed  Google Scholar 

  206. Greber UF et al. The role of the nuclear pore complex in adenovirus DNA entry. EMBO J 1997; 16: 5998–6007.

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Finlay DR, Newmeyer DD, Price TM, Forbes DJ . Inhibition of in vitro nuclear transport by a lectin that binds to nuclear pores. J Cell Biol 1987; 104: 189–200.

    CAS  PubMed  Google Scholar 

  208. Martin K, Helenius A . Transport of incoming influenza virus nucleocapsids into the nucleus. J Virol 1991; 65: 232–244.

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Pollard VW et al. A novel receptor-mediated nuclear protein import pathway. Cell 1996; 86: 985–994.

    CAS  PubMed  Google Scholar 

  210. Dean DA . Import of plasmid DNA into the nucleus is sequence specific. Exp Cell Res 1997; 230: 293–302.

    CAS  PubMed  Google Scholar 

  211. Holmes AR et al. Intracellular compartmentalization of DNA fragments in cultured airway epithelial cells mediated by cationic lipids. Pharm Res 1999; 16: 1020–1025.

    CAS  PubMed  Google Scholar 

  212. Gao X, Huang L . Potentiation of cationic liposome-mediated gene delivery by polycations. Biochemistry 1996; 35: 1027–1036.

    CAS  PubMed  Google Scholar 

  213. Sorgi FL, Bhattacharya S, Huang L . Protamine sulfate enhances lipid-mediated gene transfer. Gene Therapy 1997; 4: 961–968.

    CAS  PubMed  Google Scholar 

  214. Kaneda Y, Iwai K, Uchida T . Increased expression of DNA cointroduced with nuclear protein in adult rat liver. Science 1989; 243: 375–378.

    CAS  PubMed  Google Scholar 

  215. Fritz JD, Herweijer H, Zhang G, Wolff JA . Gene transfer into mammalian cells using histone-condensed plasmid DNA. Hum Gene Ther 1996; 7: 1395–1404.

    CAS  PubMed  Google Scholar 

  216. Breeuwer M, Goldfarb DS . Facilitated nuclear transport of histone H1 and other small nucleophilic proteins. Cell 1990; 60: 999–1008.

    CAS  PubMed  Google Scholar 

  217. Kurz M, Doenecke D, Albig W . Nuclear transport of H1 histones meets the criteria of a nuclear localization signal-mediated process. J Cell Biochem 1997; 64: 573–578.

    CAS  PubMed  Google Scholar 

  218. Kalderon D, Roberts BL, Richardson WD, Smith AE . A short amino acid sequence able to specify nuclear location. Cell 1984; 39: 499–509.

    CAS  PubMed  Google Scholar 

  219. Collas P, Husebye H, Alestrom P . The nuclear localization sequence of the SV40T antigen promotes transgene uptake and expression in zebrafish embryo nuclei. Transgenic Res 1996; 5: 451–458.

    CAS  PubMed  Google Scholar 

  220. Collas P, Alestrom P . Nuclear localization signal of SV40T antigen directs import of plasmid DNA into sea urchin male pronuclei in vitro. Mol Reprod Dev 1996; 45: 431–438.

    CAS  PubMed  Google Scholar 

  221. Carlisle RC et al. Adenovirus hexon protein enhances nuclear delivery and increases transgene expression of polyethylenimine/plasmid DNA vectors. Mol Ther 2001; 4: 473–483.

    CAS  PubMed  Google Scholar 

  222. Wienhues U et al. A novel method for transfection and expression of reconstituted DNA–protein complexes in eukaryotic cells. DNA 1987; 6: 81–89.

    CAS  PubMed  Google Scholar 

  223. Fischer N et al. Epstein–Barr virus nuclear antigen 1 forms a complex with the nuclear transporter karyopherin alpha2. J Biol Chem 1997; 272: 3999–4005.

    CAS  PubMed  Google Scholar 

  224. Kapoor P, Frappier L . EBNA1 partitions Epstein–Barr virus plasmids in yeast cells by attaching to human EBNA1-binding protein 2 on mitotic chromosomes. J Virol 2003; 77: 6946–6956.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Lee CG, Vieira WD, Pastan I, Gottesman MM . An episomally maintained MDR1 gene for gene therapy. Hum Gene Ther 2001; 12: 945–953.

    CAS  PubMed  Google Scholar 

  226. Cassell GD, Weitzman MD . Characterization of a nuclear localization signal in the C-terminus of the adeno-associated virus Rep68/78 proteins. Virology 2004; 327: 206–214.

    CAS  PubMed  Google Scholar 

  227. Brunner S et al. Cell cycle dependence of gene transfer by lipoplex, polyplex and recombinant adenovirus. Gene Therapy 2000; 7: 401–407.

    CAS  PubMed  Google Scholar 

  228. Brunner S et al. Overcoming the nuclear barrier: cell cycle independent nonviral gene transfer with linear polyethylenimine or electroporation. Mol Ther 2002; 5: 80–86.

    CAS  PubMed  Google Scholar 

  229. Dowty ME et al. Plasmid DNA entry into postmitotic nuclei of primary rat myotubes. Proc Natl Acad Sci USA 1995; 92: 4572–4576.

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Ludtke JJ, Sebestyen MG, Wolff JA . The effect of cell division on the cellular dynamics of microinjected DNA and dextran. Mol Ther 2002; 5: 579–588.

    CAS  PubMed  Google Scholar 

  231. Remy JS et al. Targeted gene transfer into hepatoma cells with lipopolyamine-condensed DNA particles presenting galactose ligands: a stage toward artificial viruses. 1995; 92: 1744–1748.

  232. Pollard H et al. Polyethylenimine but not cationic lipids promotes transgene delivery to the nucleus in mammalian cells. J Biol Chem 1998; 273: 7507–7511.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful for support from the NIH/NCI (R01 CA102126-01) and the Susan G Komen Breast Cancer Foundation to LKMK, and from the NIH/NEI (RO3 EY-13949) to SHA. We are also extremely grateful to Drs Altan Rentsendorj and Hasmik Agadjanian for their critical discussion and review.

Author information

Authors and Affiliations

  1. Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    L K Medina-Kauwe

  2. Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    L K Medina-Kauwe

  3. Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA

    J Xie & S Hamm-Alvarez

Authors
  1. L K Medina-Kauwe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Hamm-Alvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Medina-Kauwe, L., Xie, J. & Hamm-Alvarez, S. Intracellular trafficking of nonviral vectors. Gene Ther 12, 1734–1751 (2005). https://doi.org/10.1038/sj.gt.3302592

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302592

Keywords

This article is cited by

Search

Advanced search

Quick links