Publikationsserver der Universitätsbibliothek Marburg

Titel:Synthese von neuartigen, Disulfid-verknüpften, bioabbaubaren Polyethylenglykol-Polyethylenimin-Copolymeren zur Anwendung in der Gentherapie
Autor:Zhao, Nan
Weitere Beteiligte: Kissel, Thomas (Prof. Dr.)
URN: urn:nbn:de:hebis:04-z2010-04695
DDC:540 Chemie
Titel(trans.):Synthesis of noval disulfide containing biodegradable Polyethylenglycol-Polyethylenimine-copolymers for the Application in gene therapy


gene therapy, Gentherapie

In der vorliegenden Dissertation wird die Synthese der neuartigen, disulfid-verbrückten, bioabbaubaren PEG-PEI-Copolymeren als nicht-virale Vektoren zur Gentherapie beschrieben. Die DNA-Polyplexe der Copolymere wurden charakterisiert und auf ihre Eignung als Genvektoren für die in-vivo-Anwendung untersucht

The aim of this dissertation is to synthesize the novel biodegradable, with disulfide bridges linked PEG-PEI copolymers, which are utilized as non-viral vectors in gene therapy. The DNA-polyplexes of the copolymers were characterized and investigated in respect to their suitability as gene vectors for the application in vivo.

Bibliographie / References

  1. U. Griesenbach, S. Ferrari, D.M. Geddes, E.W. Alton, Gene therapy progress and prospects: cystic fibrosis. Gene Ther. 9(20) (2002) 1344-1350.
  2. A. Kichler, M. Chillon, C. Leborgne, O. Danos, B. Frisch, Intranasal gene delivery with a polyethylenimine-PEG conjugate. J. Control. Release 81(3) (2002) 379-388.
  3. C.D. Hein, X.-M. Liu, D. Wang, Click Chemistry, A Powerful Tool for Pharmaceutical Sciences, Pharmaceutical Research, 25(10) (2008) 2216-2230.
  4. P. Marschall, N. Malik, Z. Larin, Transfer of YACs up to 2.3 Mb intact into human cells with polyethylenimine, Gene Ther. 6 (1999) 1634-1637.
  5. M. Moghimi, A.C. Hunter and J.C. Murray, Nanomedicine: current status and future prospects. The FASEB Journal 19 (2005) 311-330.
  6. V. Toncheva, M.A. Wolfert, P.R. Dash, D. Qupicky, K. Ulbrich, L.W. Seymour, E.H. Schacht, Novel vectors for gene delivery formed by self-assembly of DNA with poly(L-lysine) grafted with hydrophilic polymers. Biochim. Biophys. Acta 1380(3) (1998) 354-368.
  7. R. Huisgen. 1,3-Dipolar cycloadditions. Angew. Chem. 75 (1963) 604-637.
  8. G.L.Ellman, A Colorimetric Method for Determining Low Concentrations of Mercaptans. Archives of Biochemistry and Biophysics 74, 443-450 (1958).
  9. C. Plank, K. Mechtler, F.C. Szoka, E. Wagner, Activation of the Complement System by Synthetic DNA Complexes: A Potential Barrier for Intravenous Gene Deliver. Hum. Gene Ther. 7 (1996) 1437-1446.
  10. M.L. Forrest, J.T. Koerber, D.W. Pack, A degradable polyethylenimine derivative with low toxicity for highly efficient gene delivery. Bioconjug. Chem. 14(2003), 934-940.
  11. D. Fischer, T. Bieber, Y. Li, H.P. Elsasser, T. Kissel, A novel non-viral vector for DNA delivery based on low molecular weight, branched polyethylenimine: effect of molecular weight on transfection efficiency and cytotoxicity, Pharm. Res. 16 (1999) 1273-1279.
  12. G.L. Buchschacher Jr, F. Wong-Staal, Approaches to gene therapy for human immunodeficiency virus infection. Hum. Gene Ther. 12(9) (2001) 1013-1019.
  13. V.V. Rostovtsev, L.G. Green, V.V. Fokin, and K.B. Sharpless, A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective ''ligation'' of azides and Anhang -131- terminal alkynes. Angew. Chem., Int. Ed. Engl. 41 (2002) 2596-2599.
  14. Ferrari, D.M. Geddes, E.W. Alton, Barriers to and new approaches for gene therapy and gene delivery in cystic fibrosis. Adv. Drug. Deliv. Rev. 54(11) (2002) 1373-1393.
  15. C.H. Ahn, S.Y. Chae, Y.H. Bae, S.W. Kim, Biodegradable poly(ethylenimine) for plasmid DNA delivery. J. Control. Release 80 (2002) 273-282.
  16. J. Luten, C.F. van Nostrum, S.C.D. Smedt, W.E. Hennink, Biodegradable polymers as non-viral carriers for plasmid DNA delivery. J. Control. Rel. 126 (2008) 97-110.
  17. M. Neu, O. Germershaus, M. Behe, T. Kissel, Bioreversibly crosslinked polyplexes of PEI and high molecular weight PEG show extended circulation times in vivo. J. Control. Rel. 124 (2007) 69-80.
  18. Alakhov, A.V. Kabanov, Block and graft copolymers and NanoGel copolymer networks for DNA delivery into cell. J. Drug Target. 8(2) (2000) 91-105.
  19. Kataoka, Block catiomer polyplexes with regulated densities of charge and disulfide cross-linking directed to enhance gene expression. J. Am. Chem. Soc. 126(8) (2004) 2355-2361.
  20. J. Zabner, A.J. Fasbender, T. Moninger, K.A. Poellinger, M.J. Welsh. Cellular and molecular barriers to gene transfer by a cationic lipid. J. Biol. Chem. 270(32) (1995) 18997-19007.
  21. A.v. Harpe, H. Petersen, Y. Li, T. Kissel, Characterization of commercially available and synthesized polyethylenimines for gene delivery. J. Control. Release 69 (2000) 309-322.
  22. M.J. Roberts, M.D. Bentley, J.M. Harris, Chemistry for peptide and protein PEGylation. Adv. Drug. Deliv. Rev. 54 (2002) 459-476.
  23. H.C. Kolb, M.G. Finn, and K.B. Sharpless, Click Chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. Engl. 40 (2001) 2004-2021.
  24. G. Riess, G. Hurtrez, P. Bahdurin, Block Copolymers, Concise Enzyclopedia of Polymer Science and Engineering, J. I. Kroschwitz, Editor. 1990, John Wiley & Sons: New York, Chichester, Brisbane, Toronto, Singapore.
  25. M.C. Woodle, Controlling liposome blood clearance by surface-grafted polymers.
  26. Core-Shell Structured Polyion Complex Micelle by Reversible Cross-Linking of the Core through Disulfide Bond. J. Am. Chem. Soc. 121 (1999) 11247-11248.
  27. M. Neu, O. Germershaus, S. Mao, K.H. Voigt, M. Behe, and T. Kissel, Crosslinked nanocarriers based upon poly(ethylene imine) for systemic plasmid delivery: in vitro characterization and in vivo studies in mice. J Control Release. 118 (2007) 370-380.
  28. V.D. Bock, H. Hiemstra, and J.H.-V. Maarseveen. Cu I -Catalyzed alkyne-azide ''click'' cycloadditions from a mechanistic and synthetic perspective. Eur. J. Org.
  29. Cu I -catalyzed azide-alkyne cycloaddition reaction. Angew. Chem., Int. Ed. Engl. 44 (2005) 2210-2215.
  30. D.W. Pack, A.S. Hoffman, S. Pun and P.S. Stayton, Design and development of polymers for gene delivery. Nature Reviews Drug Discovery 4 (2005) 581-593.
  31. M. Gonçalves, K. Estieu-Gionnet, T. Berthelot, G. Laïn, M. Bayle, X. Canron, N. Betz, A. Bikfalvi, and G. Déléris, Design, Synthesis, and Evaluation of Original Carriers for Targeting Vascular Endothelial Growth Factor Receptor Interactions. Pharmaceutical Research 22(8) (2005) (1411-1421).
  32. Nietupski, R.J. Ziegler, M. B. Lane, K.X. Wang, N.C. Wan, R.K. Scheule, D.J. Harris, A. Smith and S.H. Cheng, Detailed analysis of structures and formulations of cationic lipids for efficient gene transfer to the lung. Human Gene Therapy 7(14) (1996) 1701-1717.
  33. W. Zauner, S. Brunner, M. Buschle, M. Ogris and E. Wagner, Differential behaviour of lipid based and polycation based gene transfer systems in transfecting primary human fibroblasts: a potential role of polylysine in nuclear transport. Biochim Biophys Acta 1428 (1999) 57–67.
  34. Felgner, Direct gene transfer into mouse muscle in vivo. Science 247(4949) (1990) 1465-1468.
  35. G. Saito, J.A. Swanson, K.-D. Lee, Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities. Adv. Drug. Deliv. Rev. 55(2) (2003) 199-215.
  36. J. Sung, S.H. Min, K.Y. Cho, S. Lee, Y.J. Min, Y.I. Yeom, J.K. Park, Effect of polyethylene glycol on gene delivery of polyethylenimine. Biol. Pharm. Bull. 26(4) (2003) 492-500.
  37. M.A. Gosselin, W. Guo, R.J. Lee, Efficient gene transfer using reversibly cross-linked low molecular weight polyethylenimine. Bioconjug. Chem. 12(6) (2001) 989-994.
  38. Enhance DNA Condensation of Low Molecular Weight Polyethylenimines.
  39. H.K. Nguyen, P. Lemieux, S.V. Vinogradov, C.L. Gebhart, N. Guerin, G. Paradis, T.K. Bronich, V.Y Alakhov, A.V. Kabanov, Evaluation of polyether-polyethylenimine graft copolymers as gene transfer agents. Gene Ther. 7(2) (2000) 126-138.
  40. F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K.B. Sharpless, and, V.V. Fokin, copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity intermediates. J. Am. Chem. Soc. 127 (2005) 210-216.
  41. M. Gore, Gene therapy can cause leukaemia: no shock, mild horror but a probe.
  42. M.A. Kay, S.L.C. Woo, Gene therapy for metabolic disorders. TIG 10(7) (1994) 253-257.
  43. Y. Kakizawa, A. Harada, K. Kataoka, Glutathione-sensitive stabilization of block copolymer micelles composed of antisense DNA and thiolated poly(ethylene Anhang -129- glycol)-block-poly(L-lysine): a potential carrier for systemic delivery of antisense DNA. Biomacromolecules 2(2) (2001) 491-497.
  44. S. Dokka, D. Toledo, X. Shi, J. Ye, Y. Rojanasakul, High-efficiency gene transfection of macrophages by lipoplex. Int J Pharm 206 (2000) 97-104.
  45. K. Kunath, T. Merdan, O. Hegener, H. Haberlein, T. Kissel, Integrin targeting using RGD-PEI conjugates for in vitro gene transfer. J. Gene Med. 5(7) (2003) 588-599.
  46. D. Fischer, Y. Li, B. Ahlemeyer, J. Krieglstein, T. Kissel, In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. Biomaterials 24 (7) (2003) 1121-1131.
  47. H. Petersen, T. Merdan, K. Kunath, D. Fischer, T. Kissel, poly(ethylenimine- co-L-Lactamide-co-succinamide): a biodegradable polyethyleneimine derivative with an advantageous pH-dependent hydrolytic degradation for gene delivery. Bioconjug.
  48. Northrop, G.M. Ringold, M. Danielsen, Lipofection: A highly efficient, lipidmediated DNA-transfection procedure. Proc. Nati. Acad. Sci. USA 84 (1987) 7413-7417.
  49. Tannahill, S.L.D. MacKay, L.L. Moldawer, Liposome-mediated, nonviral gene transfer induces a systemic inflammatory response which can exacerbate pre-existing inflammation. Gene Therapy 7 (2000) 1425–1430.
  50. O.W. Webster. Living polymerization methods, Science (Wash. D.C.). 251 (1991) 887-893.
  51. D.L. McKenzie, E. Smiley, K.Y. Kwok, K.G. Rice, Low molecular weight disulfide cross-linking peptides as nonviral gene delivery carriers. Bioconjug. Chem. 11(6) (2000) 901-909.
  52. K. Kunath, A.v. Harpe, D. Fischer, H. Petersen, U. Bickel, K. Voigt, T. Kissel, Low-molecular-weight polyethylenimine as a non-viral vector for DNA delivery: comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecular-weight polyethylenimine. J. Control. Release 89(1) (2003) 113-125.
  53. A. Warnecke and F. Kratz, Maleimide-oligo(ethylene glycol) Derivatives of Camptothecin as Albumin-Binding Prodrugs: Synthesis and Antitumor Efficacy.
  54. M.C. Davies, W. Seeger, T. Kissel, Modified polyethylenimines as non-viral gene delivery systems for aerosol gene therapy: investigations of the complex structure and stability during air-jet and ultrasonic nebulization. J. Control. Release 100(3) 2004 437-450.
  55. Kissel, Nano-carriers for DNA delivery to the lung based upon a TAT-derived peptide covalently coupled to PEG-PEI. Journal of Controlled Release 109(1-3) (2005) 299-316.
  56. Li, L. Huang, Nonviral gene therapy: promises and challenges, gene Ther. 7 (2000) 31-34.
  57. M. Kursa, G.F. Walker, V. Roessler, M. Ogris, W. Roedl, R. Kircheis, E. Wagner, Novel shielded transferrin-polyethylene glycol-polyethylenimine/DNA complexes for systemic tumor-targeted gene transfer. Bioconjugate Chem. 14(2003) 222-231.
  58. M. Ogris, S. Brunner, S. Schuller, R. Kircheis, E. Wagner, PEGylated DNA/transferrin-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery. Gene Ther. 6(4) (1999) 595-605.
  59. Kissel, J. Kopecek, Pegylated polyethylenimine-fabántibody fragment conjugates for targeted gene delivery to human ovarian carcinoma cells. Bioconjug. Chem. 14(5) (2003) 989-996.
  60. Smith, G.E. Francis, PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum. Gene Ther. 10(8) Anhang -127- (1999) 1349-1358.
  61. J. Haensler, F.C. Szoka, Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjugate Chem. 4 (1993) 372-379.
  62. Wagner, polycation-based DNA complexes for tumor-targeted gene delivery in vivo. J.
  63. G.P. Tang, J.M. Zeng, S.J. Gao, Y.X. Ma, L. Shi, Y. Li, H.P. Too, S. Wang, Polyethylene glycol modified polyethylenimine for improved CNS gene transfer: effects of PEGylation extent. Biomaterials 24(13) (2003) 2351-2362.
  64. Y. Lee, H. Koo, G.-w. Jin, H. Mo, M.Y. Cho, J.-Y. Park, J.S. Choi, j.S. Park, Poly(ethylene oxide sulfide): New Poly(ethylene glycol) Derivatives Degradable in Reductive Conditions. Biomacromolecules 6 (2005) 24-26.
  65. W.T. Godbey, K.K. Wu, a.G. Mikos, Poly(ethylenimine) and its role in gene delivery. J. Control. Release 60(1999) 149-160.
  66. Elke Kleemann, Polyethylenimine-and lipid-based nanoparticles as gene and drug delivery systems for aerosol therapy to the lung. Dissertation 2005.
  67. Fischer, M.C. Davies, T. Kissel, Polyethylenimine-graft-poly(ethylene glycol) copolymers: influence of copolymer block structure on DNA complexation and biological activities as gene delivery system. Bioconjug. Chem. 13(4) (2002) 845-854.
  68. B. Simonot and G. Rousseau, Preparation of 3-(n-alkenoxy)propanoic acids.
  69. T.D. Clark, E.C. Dugan, Preparation of Oligo(ethylene glycol)-Terminated Icosanedisulfides. Synthesis 7 (2006) 1083-1086.
  70. D.W.v. Krewelen, Properties of polymers. 1990: Elsevier. Ch. 9.
  71. D. Finsinger, J.S. Remy, P. Erbacher, C. Koch, C. Plank, Protective copolymers for nonviral gene vectors: synthesis, vector characterization and application in gene delivery. Gene Ther. 7(14) (2000) 1183-1192.
  72. L.C. Mounkes, W. Zhong, C.-P. G, T.D. Heath, R.J. Debs, Proteoglycans mediate cationic liposome-DNA complex-based gene delivery in vitro and in vivo. J. biolog. Chem. 273(40) (1998) 26164-72610.
  73. K.D. Lee, S. Nir, D. Papahadjopoulos, Quantitative analysis of liposome-cell interactions in vitro: rate constants of binding and endocytosis with suspension and adherent J774 cells and human monocytes. Biochemistry 32(3) (1993) 889-99.
  74. T. Mosmann, Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1-2) (1983) 55-63.
  75. D.S. Collins, e.R. Unanue, C.V. Harding, Reduction of disulfide bonds within lysosomes is a key step in antigen processing. J. Immunol. 147(12) (1991) 4054-4059.
  76. B. Gansbacher, Report of a second serious adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID). Position of the European Society of Gene Therapy (ESGT). J. Gene Med. 5(3) (2003) 261-262.
  77. S.V. Vinogradov, T.K. Bronich, A.V. Kabanov, Self-assembly of Anhang -128- polyamine-poly(ethylene glycol) copolymers with phosphorothioate oligonucleotides. Bioconjug. Chem. 9(6) (1998) 805-812.
  78. W.T. Godbey, K.K. Wu, A.G. Mikos, Size matters: molecular weight affects the efficiency of poly(ethylene imine) as a gene delivery vehicle. J. Biomed. Mater. Res. 45 (1999) 268-275.
  79. M. Neu, J. Sitterberg, U. Bakowsky, T. Kissel, Stabilized Nanocarriers for Plasmids Based Upon Cross-linked Poly(ethylene imine). Biomacromolecules 7(12) (2006) 3428-3438.
  80. Kissel, Star-Shaped Poly(ethylene glycol)-block-polyethylenimine Copolymers Anhang -130-
  81. Yang, Y. Pan, K. Weng, C. Gu, S. Torkelson, Sterically stabilized polyplex: ligand-mediated activity. Journal of Controlled Release 74 (2001) 309–311.
  82. P. Casper, Synthese von amphiphilen Blockcopolymeren auf Basis von Cystein- bzw. Thiol-modifiziertem Polyethylenglykol. Dissertation 2004.
  83. H. Petersen, P.M. Fechner, D. Fischer, T. Kissel, Synthesis, Characterization, and Biocompatibility of Polyethylenimine-graft-poly(ethylene glycol) Block Copolymers. Macromolecules 35 (18) (2002) 6867-6874.
  84. W.H. Zhan, H.N. Barnhill, K. Sivakumar, H. Tian, and Q. Wang, Synthesis of hemicyanine dyes for 'click' bioconjugation. Tetrahedron Lett. 46 (2005) 1691-1695.
  85. M.J. Tiera, F.M. Winnik, J.C. Fernandes, Synthetic and Natural Polycations for Gene Therapy: State of the Art and New Perspectives. Current Gene Therapy 6 (2006) 59-71.
  86. E. Franta, and P.F. Rempp, The block copolymer bag of tricks. Chemtech. 26 (1996) 24-28.
  87. Ruth Duncan, The dawning era of polymer therapeutics. Nature Reviews Drug Discovery 2 (2003) 347-360.
  88. H.C. Kolv, and K.B. Sharpless, The growing impact of click chemistry on drug discovery. Drug Discov. Today. 8 (2003) 1128-1137.
  89. M.X. Tang, F.C. Szoka, The influence of polymer structure on the interactions of cationic polymers with DNA and morphology of the resulting complexes. Gene Therapy 4 (1997) 823–832.
  90. D´Emanuele, The influence of surface modification on the cytotoxicity of PAMAM dendrimers. Int. J. Pharm. 252(1-2) (2003) 263-266.
  91. W.-C. Tseng, F.R. Haselton, T.D. Giorgio, Transfection by cationic liposomes Anhang -124- using simultaneous single cell measurements of plasmid delivery and transgene expression. J. Biol. Chem. 272 (1997) 25641–25647.
  92. P. Campeau, P. Chapdelaine, S. Seigneurin-Venin, B. Massie, J.P. Tremblay, Transfection of large plasmids in primary human myoblasts, Gene Ther. 8 (2001) 1387-1394.
  93. R. Kircheis, T. Blessing, S. Brunner, L. Wightman, E. Wagner, Tumor targeting with surface-shielded ligand—polycation DNA complexes. J Control Release 72(1-3) (2001) 165-170.
  94. Brase, C. Gil, K. Knepper, and V. Zimmermann. Organic azides: an exploding diversity of a unique class of compounds. Angew. Chem., Int. Ed., Engl. 44 (2005) 5518-5240.
  95. T.D. Perrine and W.R. Landis, Analysis of polyethylenimine by spectrophotometry of its copper chelate. J. Polym. Sci., Polym. Chem. Ed. 5 (1967) 1993-2003.
  96. P.S. Shirude, V.A. Kumar, and K.N. Ganesh, BisPNA Targeting to DNA: Effect of Neutral Loop on DNA Duplex Strand Invasion by aepPNA-N7G/aepPNA-C Substituted Peptide Nucleic Acids. Eur. J. Org. Chem. (2005) 5207-5215.
  97. A.G. Ziady, P.B. Davis, M.w. Konstan, Non-viral gene transfer therapy for cystic fibrosis. Expert Opin. Biol. Ther. 3(3) (2003) 449-458.
  98. X. Gao, K.-S. Kim, D. Liu, Nonviral Gene Delivery: What We Know and What Is Next. The AAPS Journal 9 (1) (2007) E92-E104.
  99. K.A. Mislick, J.D. Baldeschwieler, Evidence for the role of proteoglycans in cation-mediated gene transfer. Proc Natl Acad Sci USA, 93(22) (1996) 12349-12354.
  100. Smith, and S.H. Chang, A novel cationic lipid greatly enhances plasmid DNA delivery and expression in mouse lung. Proceedings of the National Academy of Sciences of the United States of America 93(21) (1996) 11454-11459.
  101. Boussif, Lezoualc'h et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: Polyethylenimine. Proc. Natl Acad. Sci. USA 92 Anhang -125- (1995) 7297-7301.
  102. Freeman and P.M. Corry, Stress protection by a fluorescent Hsp27 chimera that is independent of nuclear translocation or multimeric dissociation. Cell Stress & Chaperones 7(3) (2002) 281–296.

* Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten