Chemically Programmed Polymers for Targeted DNA and siRNA Transfection

  • Eveline Edith Salcher
  • Ernst WagnerEmail author
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 296)


Plasmid DNA and siRNA have a large potential for use as therapeutic nucleic acids in medicine. The way to the target cell and its proper compartment is full of obstacles. Polymeric carriers help to overcome the encountered barriers. Cationic polymers can interact with the nucleic acid in a nondamaging way but still require optimization with regard to transfer efficiency and biocompatibility. Aiming at virus-like features, as viruses are the most efficient natural gene carriers, the design of bioresponsive polymers shows promising results regarding DNA and siRNA delivery. By specific chemical modifications dynamic structures are created, programmed to respond towards changing demands on the delivery pathway by cleavage of labile bonds or conformational changes, thus enhancing biocompatible gene delivery.


Bioresponsive Cationic polymers Chemical programming DNA siRNA 


  1. 1.
    Hannon GJ, Rossi JJ (2004) Unlocking the potential of the human genome with RNA interference. Nature 431:371–378PubMedGoogle Scholar
  2. 2.
    Sioud M (2004) Therapeutic siRNAs. Trends Pharmacol Sci 25:22–28PubMedGoogle Scholar
  3. 3.
    Behlke MA (2006) Progress towards in vivo use of siRNAs. Mol Ther 13:644–670PubMedGoogle Scholar
  4. 4.
    Aigner A (2006) Gene silencing through RNA interference (RNAi) in vivo: strategies based on the direct application of siRNAs. J Biotechnol 124:12–25PubMedGoogle Scholar
  5. 5.
    Meyer M, Wagner E (2006) Recent developments in the application of plasmid DNA-based vectors and small interfering RNA therapeutics for cancer. Hum Gene Ther 17:1062–1076PubMedGoogle Scholar
  6. 6.
    Blow N (2007) Small RNAs: delivering the future. Nature 450:1117–1120PubMedGoogle Scholar
  7. 7.
    de Fougerolles AR (2008) Delivery vehicles for small interfering RNA in vivo. Hum Gene Ther 19:125–132PubMedGoogle Scholar
  8. 8.
    Sen GL, Blau HM (2005) Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies. Nat Cell Biol 7:633–636PubMedGoogle Scholar
  9. 9.
    Boeckle S, Wagner E (2006) Optimizing targeted gene delivery: chemical modification of viral vectors and synthesis of artificial virus vector systems. AAPS J 8:E731–E742PubMedGoogle Scholar
  10. 10.
    Pack DW, Hoffman AS, Pun S et al (2005) Design and development of polymers for gene delivery. Nat Rev Drug Discov 4:581–593PubMedGoogle Scholar
  11. 11.
    Park TG, Jeong JH, Kim SW (2006) Current status of polymeric gene delivery systems. Adv Drug Deliv Rev 58:467–486PubMedGoogle Scholar
  12. 12.
    Wagner E, Kloeckner J (2006) Gene delivery using polymer therapeutics. Adv Polym Sci 192:135–173Google Scholar
  13. 13.
    Tiera MJ, Winnik FO, Fernandes JC (2006) Synthetic and natural polycations for gene therapy: state of the art and new perspectives. Curr Gene Ther 6:59–71PubMedGoogle Scholar
  14. 14.
    Wagner E (2004) Strategies to improve DNA polyplexes for in vivo gene transfer: will “artificial viruses” be the answer? Pharm Res 21:8–14PubMedGoogle Scholar
  15. 15.
    Wagner E (2007) Programmed drug delivery: nanosystems for tumor targeting. Expert Opin Biol Ther 7:587–593PubMedGoogle Scholar
  16. 16.
    Wolff JA, Rozema DB (2008) Breaking the bonds: non-viral vectors become chemically dynamic. Mol Ther 16:8–15PubMedGoogle Scholar
  17. 17.
    Noguchi Y, Wu J, Duncan R et al (1998) Early phase tumor accumulation of macromolecules: a great difference in clearance rate between tumor and normal tissues. Jpn J Cancer Res 89:307–314PubMedGoogle Scholar
  18. 18.
    Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41:189–207PubMedGoogle Scholar
  19. 19.
    Mislick KA, Baldeschwieler JD (1996) Evidence for the role of proteoglycans in cation-mediated gene transfer. Proc Natl Acad Sci USA 93:12349–12354PubMedGoogle Scholar
  20. 20.
    Brigger I, Dubernet C, Couvreur P (2002) Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev 54:631–651PubMedGoogle Scholar
  21. 21.
    Allen TM, Cullis PR (2004) Drug delivery systems: entering the mainstream. Science 303:1818–1822PubMedGoogle Scholar
  22. 22.
    Wu GY, Wu CH (1987) Receptor-mediated in vitro gene transformation by a soluble DNA carrier system. J Biol Chem 262:4429–4432PubMedGoogle Scholar
  23. 23.
    Wagner E, Ogris M, Zauner W (1998) Polylysine-based transfection systems utilizing receptor-mediated delivery. Adv Drug Deliv Rev 30:97–113PubMedGoogle Scholar
  24. 24.
    Schaffer DV, Lauffenburger DA (2000) Targeted synthetic gene delivery vectors. Curr Opin Mol Ther 2:155–161PubMedGoogle Scholar
  25. 25.
    Wickham TJ (2003) Ligand-directed targeting of genes to the site of disease. Nat Med 9:135–139PubMedGoogle Scholar
  26. 26.
    Wagner E, Culmsee C, Boeckle S (2005) Targeting of polyplexes: toward synthetic virus vector systems. Adv Genet 53:333–354PubMedGoogle Scholar
  27. 27.
    Tietze N, Pelisek J, Philipp A et al (2008) Induction of apoptosis in murine neuroblastoma by systemic delivery of transferrin-shielded siRNA polyplexes for downregulation of Ran. Oligonucleotides 18:161–174PubMedGoogle Scholar
  28. 28.
    de Bruin K, Ruthardt N, von Gersdorff K et al (2007) Cellular dynamics of EGF receptor-targeted synthetic viruses. Mol Ther 15:1297–1305PubMedGoogle Scholar
  29. 29.
    Kim SH, Mok H, Jeong JH et al (2006) Comparative evaluation of target-specific GFP gene silencing efficiencies for antisense ODN, synthetic siRNA, and siRNA plasmid complexed with PEI–PEG–FOL conjugate. Bioconjug Chem 17:241–244PubMedGoogle Scholar
  30. 30.
    Liang B, He ML, Xiao ZP et al (2008) Synthesis and characterization of folate-PEG-grafted-hyperbranched-PEI for tumor-targeted gene delivery. Biochem Biophys Res Commun 367:874–880PubMedGoogle Scholar
  31. 31.
    Ikeda Y, Taira K (2006) Ligand-targeted delivery of therapeutic siRNA. Pharm Res 23:1631–1640PubMedGoogle Scholar
  32. 32.
    Oba M, Fukushima S, Kanayama N et al (2007) Cyclic RGD peptide-conjugated polyplex micelles as a targetable gene delivery system directed to cells possessing alphavbeta3 and alphavbeta5 integrins. Bioconjug Chem 18:1415–1423PubMedGoogle Scholar
  33. 33.
    Moffatt S, Wiehle S, Cristiano RJ (2006) A multifunctional PEI-based cationic polyplex for enhanced systemic p53-mediated gene therapy. Gene Ther 13:1512–1523PubMedGoogle Scholar
  34. 34.
    Rao GA, Tsai R, Roura D et al (2008) Evaluation of the transfection property of a peptide ligand for the fibroblast growth factor receptor as part of PEGylated polyethylenimine polyplex. J Drug Target 16:79–89PubMedGoogle Scholar
  35. 35.
    Dash PR, Read ML, Barrett LB et al (1999) Factors affecting blood clearance and in vivo distribution of polyelectrolyte complexes for gene delivery. Gene Ther 6:643–650PubMedGoogle Scholar
  36. 36.
    Ogris M, Steinlein P, Kursa M et al (1998) The size of DNA/transferrin-PEI complexes is an important factor for gene expression in cultured cells. Gene Ther 5:1425–1433PubMedGoogle Scholar
  37. 37.
    Lee M, Kim SW (2005) Polyethylene glycol-conjugated copolymers for plasmid DNA delivery. Pharm Res 22:1–10PubMedGoogle Scholar
  38. 38.
    Erbacher P, Bettinger T, Belguise-Valladier P et al (1999) Transfection and physical properties of various saccharide, poly(ethylene glycol), and antibody-derivatized polyethylenimines (PEI). J Gene Med 1:210–222PubMedGoogle Scholar
  39. 39.
    Oupicky D, Ogris M, Howard KA et al (2002) Importance of lateral and steric stabilization of polyelectrolyte gene delivery vectors for extended systemic circulation. Mol Ther 5:463–472PubMedGoogle Scholar
  40. 40.
    Kursa M, Walker GF, Roessler V et al (2003) Novel shielded transferrin–polyethylene glycol–polyethylenimine/DNA complexes for systemic tumor-targeted gene transfer. Bioconjug Chem 14:222–231PubMedGoogle Scholar
  41. 41.
    Brissault B, Kichler A, Leborgne C et al (2006) Synthesis, characterization, and gene transfer application of poly(ethylene glycol-b-ethylenimine) with high molar mass polyamine block. Biomacromolecules 7:2863–2870PubMedGoogle Scholar
  42. 42.
    Meyer M, Wagner E (2006) pH-responsive shielding of non-viral gene vectors. Expert Opin Drug Deliv 3:563–571PubMedGoogle Scholar
  43. 43.
    Ogris M, Brunner S, Schuller S et al (1999) PEGylated DNA/transferrin-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery. Gene Ther 6:595–605PubMedGoogle Scholar
  44. 44.
    Ogris M, Walker G, Blessing T et al (2003) Tumor-targeted gene therapy: strategies for the preparation of ligand–polyethylene glycol–polyethylenimine/DNA complexes. J Control Release 91:173–181PubMedGoogle Scholar
  45. 45.
    Wolschek MF, Thallinger C, Kursa M et al (2002) Specific systemic nonviral gene delivery to human hepatocellular carcinoma xenografts in SCID mice. Hepatology 36:1106–1114PubMedGoogle Scholar
  46. 46.
    Kim WJ, Yockman JW, Lee M et al (2005) Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis. J Control Release 106:224–234PubMedGoogle Scholar
  47. 47.
    Moffatt S, Papasakelariou C, Wiehle S et al (2006) Successful in vivo tumor targeting of prostate-specific membrane antigen with a highly efficient J591/PEI/DNA molecular conjugate. Gene Ther 13:761–772PubMedGoogle Scholar
  48. 48.
    Moffatt S, Wiehle S, Cristiano RJ (2005) Tumor-specific gene delivery mediated by a novel peptide–polyethylenimine–DNA polyplex targeting aminopeptidase N/CD13. Hum Gene Ther 16:57–67PubMedGoogle Scholar
  49. 49.
    Knorr V, Allmendinger L, Walker GF et al (2007) An acetal-based PEGylation reagent for pH-sensitive shielding of DNA polyplexes. Bioconjug Chem 18:1218–1225PubMedGoogle Scholar
  50. 50.
    Murthy N, Campbell J, Fausto N et al (2003) Design and synthesis of pH-responsive polymeric carriers that target uptake and enhance the intracellular delivery of oligonucleotides. J Control Release 89:365–374PubMedGoogle Scholar
  51. 51.
    Knorr V, Ogris M, Wagner E (2008) An acid sensitive ketal-based polyethylene glycol–oligoethylenimine copolymer mediates improved transfection efficiency at reduced toxicity. Pharm Res 25:2937–2945PubMedGoogle Scholar
  52. 52.
    Lin S, Du F, Wang Y et al (2008) An acid-labile block copolymer of PDMAEMA and PEG as potential carrier for intelligent gene delivery systems. Biomacromolecules 9:109–115PubMedGoogle Scholar
  53. 53.
    Walker GF, Fella C, Pelisek J et al (2005) Toward synthetic viruses: endosomal pH-triggered deshielding of targeted polyplexes greatly enhances gene transfer in vitro and in vivo. Mol Ther 11:418–425PubMedGoogle Scholar
  54. 54.
    Xiong MP, Bae Y, Fukushima S et al (2007) pH-responsive multi-PEGylated dual cationic nanoparticles enable charge modulations for safe gene delivery. ChemMedChem 2:1321–1327PubMedGoogle Scholar
  55. 55.
    Fella C, Walker GF, Ogris M et al (2008) Amine-reactive pyridylhydrazone-based PEG reagents for pH-reversible PEI polyplex shielding. Eur J Pharm Sci 34:309–320PubMedGoogle Scholar
  56. 56.
    Oishi M, Nagasaki Y, Itaka K et al (2005) 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 127:1624–1625PubMedGoogle Scholar
  57. 57.
    Takae S, Miyata K, Oba M et al (2008) PEG-detachable polyplex micelles based on disulfide-linked block catiomers as bioresponsive nonviral gene vectors. J Am Chem Soc 130:6001–6009PubMedGoogle Scholar
  58. 58.
    Mellman I (1996) Endocytosis and molecular sorting. Annu Rev Cell Dev Biol 12:575–625PubMedGoogle Scholar
  59. 59.
    Boussif O, Lezoualc’h F, Zanta MA et al (1995) A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci USA 92:7297–7301PubMedGoogle Scholar
  60. 60.
    Akinc A, Thomas M, Klibanov AM et al (2005) Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis. J Gene Med 7:657–663PubMedGoogle Scholar
  61. 61.
    Boeckle S, Wagner E, Ogris M (2005) C- versus N-terminally linked melittin–polyethylenimine conjugates: the site of linkage strongly influences activity of DNA polyplexes. J Gene Med 7:1335–1347PubMedGoogle Scholar
  62. 62.
    Ogris M, Carlisle RC, Bettinger T et al (2001) Melittin enables efficient vesicular escape and enhanced nuclear access of nonviral gene delivery vectors. J Biol Chem 276:47550–47555PubMedGoogle Scholar
  63. 63.
    Shir A, Ogris M, Wagner E et al (2006) EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice. PLoS Med 3:e6PubMedGoogle Scholar
  64. 64.
    Kloeckner J, Boeckle S, Persson D et al (2006) DNA polyplexes based on degradable oligoethylenimine-derivatives: combination with EGF receptor targeting and endosomal release functions. J Control Release 116:115–122PubMedGoogle Scholar
  65. 65.
    Bettinger T, Carlisle RC, Read ML et al (2001) Peptide-mediated RNA delivery: a novel approach for enhanced transfection of primary and post-mitotic cells. Nucleic Acids Res 29:3882–3891PubMedGoogle Scholar
  66. 66.
    Dempsey CE (1990) The actions of melittin on membranes. Biochim Biophys Acta 1031:143–161PubMedGoogle Scholar
  67. 67.
    Rozema DB, Ekena K, Lewis DL et al (2003) Endosomolysis by masking of a membrane-active agent (EMMA) for cytoplasmic release of macromolecules. Bioconjug Chem 14:51–57PubMedGoogle Scholar
  68. 68.
    Meyer M, Philipp A, Oskuee R et al (2008) Breathing life into polycations: functionalization with pH-responsive endosomolytic peptides and polyethylene glycol enables siRNA delivery. J Am Chem Soc 130:3272–3273PubMedGoogle Scholar
  69. 69.
    Meyer M, Dohmen C, Philipp A et al. (2009) Synthesis and biological evaluation of a bioresponsive and endosomolytic siRNA-polymer conjugate. Mol Pharm 6:752–762Google Scholar
  70. 70.
    Boeckle S, Fahrmeir J, Roedl W et al (2006) Melittin analogs with high lytic activity at endosomal pH enhance transfection with purified targeted PEI polyplexes. J Control Release 112:240–248PubMedGoogle Scholar
  71. 71.
    Rozema DB, Lewis DL, Wakefield DH et al (2007) Dynamic polyconjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc Natl Acad Sci USA 104:12982–12987PubMedGoogle Scholar
  72. 72.
    Saito G, Swanson JA, Lee KD (2003) Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities. Adv Drug Deliv Rev 55:199–215PubMedGoogle Scholar
  73. 73.
    Zou SM, Erbacher P, Remy JS et al (2000) Systemic linear polyethylenimine (L-PEI)-mediated gene delivery in the mouse. J Gene Med 2:128–134PubMedGoogle Scholar
  74. 74.
    Moghimi SM, Symonds P, Murray JC et al (2005) A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene transfer/therapy. Mol Ther 11:990–995PubMedGoogle Scholar
  75. 75.
    Chollet P, Favrot MC, Hurbin A et al (2002) Side-effects of a systemic injection of linear polyethylenimine–DNA complexes. J Gene Med 4:84–91PubMedGoogle Scholar
  76. 76.
    Li Z, Huang L (2004) Sustained delivery and expression of plasmid DNA based on biodegradable polyester, poly(d,l-lactide-co-4-hydroxy-l-proline). J Control Release 98:437–446PubMedGoogle Scholar
  77. 77.
    Lim Y, Choi YH, Park J (1999) A self-destroying polycationic polymer: biodegradable poly(4-hydroxy-l-proline ester). J Am Chem Soc 121:5633–5639Google Scholar
  78. 78.
    Lim YB, Han SO, Kong HU et al (2000) Biodegradable polyester, poly[alpha-(4-aminobutyl)-l-glycolic acid], as a non-toxic gene carrier. Pharm Res 17:811–816PubMedGoogle Scholar
  79. 79.
    Wong SY, Pelet JM, Putnam D (2007) Polymer systems for gene delivery – past, present, future. Prog Polym Sci 32:799–837Google Scholar
  80. 80.
    Green JJ, Zugates GT, Langer R et al (2009) Poly(beta-amino esters): procedures for synthesis and gene delivery. Methods Mol Biol 480:53–63PubMedGoogle Scholar
  81. 81.
    Green JJ, Shi J, Chiu E et al (2006) Biodegradable polymeric vectors for gene delivery to human endothelial cells. Bioconjug Chem 17:1162–1169PubMedGoogle Scholar
  82. 82.
    Kloeckner J, Bruzzano S, Ogris M et al (2006) Gene carriers based on hexanediol diacrylate linked oligoethylenimine: effect of chemical structure of polymer on biological properties. Bioconjug Chem 17:1339–1345PubMedGoogle Scholar
  83. 83.
    Thomas M, Lu JJ, Zhang C et al (2007) Identification of novel superior polycationic vectors for gene delivery by high-throughput synthesis and screening of a combinatorial library. Pharm Res 24:1564–1571PubMedGoogle Scholar
  84. 84.
    Lynn DM, Langer R (2000) Degradable poly(-amino esters): synthesis, characterization, and self-assembly with plasmid DNA. J Am Chem Soc 122:10761–10768Google Scholar
  85. 85.
    Zhong Z, Song Y, Engbersen JF et al (2005) A versatile family of degradable non-viral gene carriers based on hyperbranched poly(ester amine)s. J Control Release 109:317–329PubMedGoogle Scholar
  86. 86.
    Arote R, Kim TH, Kim YK et al (2007) A biodegradable poly(ester amine) based on polycaprolactone and polyethylenimine as a gene carrier. Biomaterials 28:735–744PubMedGoogle Scholar
  87. 87.
    Lim YB, Kim SM, Suh H et al (2002) Biodegradable, endosome disruptive, and cationic network-type polymer as a highly efficient and nontoxic gene delivery carrier. Bioconjug Chem 13:952–957PubMedGoogle Scholar
  88. 88.
    Forrest ML, Koerber JT, Pack DW (2003) A degradable polyethylenimine derivative with low toxicity for highly efficient gene delivery. Bioconjug Chem 14:934–940PubMedGoogle Scholar
  89. 89.
    Ahn CH, Chae SY, Bae YH et al (2002) Biodegradable poly(ethylenimine) for plasmid DNA delivery 1. J Control Release 80:273–282PubMedGoogle Scholar
  90. 90.
    Shuai X, Merdan T, Unger F et al (2005) Supramolecular gene delivery vectors showing enhanced transgene expression and good biocompatibility. Bioconjug Chem 16:322–329PubMedGoogle Scholar
  91. 91.
    Shuai X, Merdan T, Unger F et al (2003) Novel biodegradable ternary copolymers hy-PEI-g-PCL-b-PEG: synthesis, characterization, and potential as efficient nonviral gene delivery vectors. Macromolecules 36:5751–5759Google Scholar
  92. 92.
    Russ V, Elfberg H, Thoma C et al (2008) Novel degradable oligoethylenimine acrylate ester-based pseudodendrimers for in vitro and in vivo gene transfer. Gene Ther 15:18–29PubMedGoogle Scholar
  93. 93.
    Anderson DG, Lynn DM, Langer R (2003) Semi-automated synthesis and screening of a large library of degradable cationic polymers for gene delivery. Angew Chem Int Ed Engl 42:3153–3158PubMedGoogle Scholar
  94. 94.
    Kloeckner J, Wagner E, Ogris M (2006) Degradable gene carriers based on oligomerized polyamines. Eur J Pharm Sci 29:414–425PubMedGoogle Scholar
  95. 95.
    Lynn DM, Anderson DG, Putnam D et al (2001) Accelerated discovery of synthetic transfection vectors: parallel synthesis and screening of a degradable polymer library. J Am Chem Soc 123:8155–8156PubMedGoogle Scholar
  96. 96.
    Kim TI, Seo HJ, Choi JS et al (2005) Synthesis of biodegradable cross-linked poly(beta-amino ester) for gene delivery and its modification, inducing enhanced transfection efficiency and stepwise degradation. Bioconjug Chem 16:1140–1148PubMedGoogle Scholar
  97. 97.
    Kim HJ, Kwon MS, Choi JS et al (2007) Synthesis and characterization of poly (amino ester) for slow biodegradable gene delivery vector. Bioorg Med Chem 15:1708–1715PubMedGoogle Scholar
  98. 98.
    Knorr V, Russ V, Allmendinger L et al (2008) Acetal linked oligoethylenimines for use as pH-sensitive gene carriers. Bioconjug Chem 19:1625–1634PubMedGoogle Scholar
  99. 99.
    Kim YH, Park JH, Lee M et al (2005) Polyethylenimine with acid-labile linkages as a biodegradable gene carrier. J Control Release 103:209–219PubMedGoogle Scholar
  100. 100.
    Shim MS, Kwon YJ (2009) Acid-responsive linear polyethylenimine for efficient, specific, and biocompatible siRNA delivery. Bioconjug Chem 20:488–499PubMedGoogle Scholar
  101. 101.
    Read ML, Bremner KH, Oupicky D et al (2003) Vectors based on reducible polycations facilitate intracellular release of nucleic acids. J Gene Med 5:232–245PubMedGoogle Scholar
  102. 102.
    Read ML, Singh S, Ahmed Z et al (2005) A versatile reducible polycation-based system for efficient delivery of a broad range of nucleic acids. Nucleic Acids Res 33:e86PubMedGoogle Scholar
  103. 103.
    Christensen LV, Chang CW, Kim WJ et al (2006) Reducible poly(amido ethylenimine)s designed for triggered intracellular gene delivery. Bioconjug Chem 17:1233–1240PubMedGoogle Scholar
  104. 104.
    Lin C, Zhong Z, Lok MC et al (2006) Linear poly(amido amine)s with secondary and tertiary amino groups and variable amounts of disulfide linkages: synthesis and in vitro gene transfer properties. J Control Release 116:130–137PubMedGoogle Scholar
  105. 105.
    Lin C, Zhong Z, Lok MC et al (2007) Novel bioreducible poly(amido amine)s for highly efficient gene delivery. Bioconjug Chem 18:138–145PubMedGoogle Scholar
  106. 106.
    Lin C, Zhong Z, Lok MC et al (2007) Random and block copolymers of bioreducible poly(amido amine)s with high- and low-basicity amino groups: study of DNA condensation and buffer capacity on gene transfection. J Control Release 123:67–75PubMedGoogle Scholar
  107. 107.
    Lin C, Blaauboer CJ, Timoneda MM et al (2008) Bioreducible poly(amido amine)s with oligoamine side chains: synthesis, characterization, and structural effects on gene delivery. J Control Release 126:166–174PubMedGoogle Scholar
  108. 108.
    Zugates GT, Anderson DG, Little SR et al (2006) Synthesis of poly(beta-amino ester)s with thiol-reactive side chains for DNA delivery. J Am Chem Soc 128:12726–12734PubMedGoogle Scholar
  109. 109.
    Gosselin MA, Guo W, Lee RJ (2001) Efficient gene transfer using reversibly cross-linked low molecular weight polyethylenimine. Bioconjug Chem 12:989–994PubMedGoogle Scholar
  110. 110.
    Neu M, Germershaus O, Mao S et al (2007) Crosslinked nanocarriers based upon poly(ethylene imine) for systemic plasmid delivery: in vitro characterization and in vivo studies in mice. J Control Release 118:370–380PubMedGoogle Scholar
  111. 111.
    Peng Q, Hu C, Cheng J et al (2009) Influence of disulfide density and molecular weight on disulfide cross-linked polyethylenimine as gene vectors. Bioconjug Chem 20:340–346PubMedGoogle Scholar
  112. 112.
    Peng Q, Zhong Z, Zhuo R (2008) Disulfide cross-linked polyethylenimines (PEI) prepared via thiolation of low molecular weight PEI as highly efficient gene vectors. Bioconjug Chem 19:499–506PubMedGoogle Scholar
  113. 113.
    Kim WJ, Kim SW (2009) Efficient siRNA delivery with non-viral polymeric vehicles. Pharm Res 26:657–666PubMedGoogle Scholar
  114. 114.
    Breunig M, Hozsa C, Lungwitz U et al (2008) Mechanistic investigation of poly(ethylene imine)-based siRNA delivery: disulfide bonds boost intracellular release of the cargo. J Control Release 130:57–63PubMedGoogle Scholar
  115. 115.
    Jeong JH, Christensen LV, Yockman JW et al (2007) Reducible poly(amido ethylenimine) directed to enhance RNA interference. Biomaterials 28:1912–1917Google Scholar
  116. 116.
    Bolcato-Bellemin AL, Bonnet ME, Creusat G et al (2007) Sticky overhangs enhance siRNA-mediated gene silencing. Proc Natl Acad Sci USA 104:16050–16055PubMedGoogle Scholar
  117. 117.
    Meyer M, Dohmen C, Philipp A et al (2009) Synthesis and biological evaluation of a bioresponsive and endosomolytic siRNA-polymer conjugate. Mol Pharm 6:752–762PubMedGoogle Scholar
  118. 118.
    Tomalia DA, Baker H, Dewald J et al (1985) A new class of polymers: starburst-dendritic macromolecules. Polym J 17:117–132Google Scholar
  119. 119.
    Tomalia DA, Baker H, Dewald J et al (1986) Dendritic macromolecules: synthesis of starburst dendrimers. Macromolecules 19:2466–2468Google Scholar
  120. 120.
    Worner C, Mulhaupt R (1993) Polynitrile- and polyamine-functional poly(trimethylene imine) dendrimers. Angew Chem Int Ed Engl 32:1306–1311Google Scholar
  121. 121.
    Zinselmeyer BH, Mackay SP, Schatzlein AG et al (2002) The lower-generation polypropylenimine dendrimers are effective gene-transfer agents. Pharm Res 19:960–967PubMedGoogle Scholar
  122. 122.
    Schatzlein AG, Zinselmeyer BH, Elouzi A et al (2005) Preferential liver gene expression with polypropylenimine dendrimers. J Control Release 101:247–258PubMedGoogle Scholar
  123. 123.
    Harada A, Kawamura M, Matsuo T et al (2006) Synthesis and characterization of a head-tail type polycation block copolymer as a nonviral gene vector. Bioconjug Chem 17:3–5PubMedGoogle Scholar
  124. 124.
    Choi JS, Nam K, Park JY et al (2004) Enhanced transfection efficiency of PAMAM dendrimer by surface modification with l-arginine. J Control Release 99:445–456PubMedGoogle Scholar
  125. 125.
    Arima H, Kihara F, Hirayama F et al (2001) Enhancement of gene expression by polyamidoamine dendrimer conjugates with alpha-, beta-, and gamma-cyclodextrins. Bioconjug Chem 12:476–484PubMedGoogle Scholar
  126. 126.
    Wood KC, Azarin SM, Arap W et al (2008) Tumor-targeted gene delivery using molecularly engineered hybrid polymers functionalized with a tumor-homing peptide. Bioconjug Chem 19:403–405PubMedGoogle Scholar
  127. 127.
    Kim TI, Baek JU, Zhe BC et al (2007) Arginine-conjugated polypropylenimine dendrimer as a non-toxic and efficient gene delivery carrier. Biomaterials 28:2061–2067PubMedGoogle Scholar
  128. 128.
    Lee JW, Ko YH, Park SH et al (2001) Novel pseudorotaxane-terminated dendrimers: supramolecular modification of dendrimer periphery. Angew Chem Int Ed Engl 40:746–749PubMedGoogle Scholar
  129. 129.
    Lim YB, Kim T, Lee JW et al (2002) Self-assembled ternary complex of cationic dendrimer, cucurbituril, and DNA: noncovalent strategy in developing a gene delivery carrier. Bioconjug Chem 13:1181–1185PubMedGoogle Scholar
  130. 130.
    Kim TI, Baek JU, Zhe Bai C et al (2007) Arginine-conjugated polypropylenimine dendrimer as a non-toxic and efficient gene delivery carrier. Biomaterials 28:2061–2067PubMedGoogle Scholar
  131. 131.
    Taratula O, Garbuzenko OB, Kirkpatrick P et al (2009) Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery. J Control Release 140:284–293PubMedGoogle Scholar
  132. 132.
    Hartmann L, Krause E, Antonietti M et al (2006) Solid-phase supported polymer synthesis of sequence-defined, multifunctional poly(amidoamines). Biomacromolecules 7:1239–1244PubMedGoogle Scholar
  133. 133.
    Hartmann L, Hafele S, Peschka-Suss R et al (2008) Tailor-made poly(amidoamine)s for controlled complexation and condensation of DNA. Chemistry 14:2025–2033PubMedGoogle Scholar
  134. 134.
    Leng Q, Mixson AJ (2005) Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo. Cancer Gene Ther 12:682–690PubMedGoogle Scholar
  135. 135.
    Leng Q, Scaria P, Zhu J et al (2005) Highly branched HK peptides are effective carriers of siRNA. J Gene Med 7:977–986PubMedGoogle Scholar
  136. 136.
    Wang XL, Ramusovic S, Nguyen T et al (2007) Novel polymerizable surfactants with pH-sensitive amphiphilicity and cell membrane disruption for efficient siRNA delivery. Bioconjug Chem 18:2169–2177PubMedGoogle Scholar
  137. 137.
    Yu TL, Lu W-C, Liu W-H et al (2004) Solvents effect on the physical properties of semi-dilute poly(N-isopropyl acryl amide) solutions. Polymer 45:5579–5589Google Scholar
  138. 138.
    Liu RCW, Cantin S, Perrot F et al (2006) Effects of polymer architecture and composition on the interfacial properties of temperature-responsive hydrophobically-modified poly(N-isopropylacrylamides). Polym Adv Technol 17:798–803Google Scholar
  139. 139.
    CdLH A, Pennadam S, Alexander C (2005) Stimuli responsive polymers for biomedical applications. Chem Soc Rev 34:276–285Google Scholar
  140. 140.
    Griffiths PC, Alexander C, Nilmini R et al (2008) Physicochemical characterization of thermoresponsive poly(N-isopropylacrylamide)-poly(ethylene imine) graft copolymers. Biomacromolecules 9:1170–1178PubMedGoogle Scholar
  141. 141.
    Lavigne MD, Pennadam SS, Ellis J et al (2007) Enhanced gene expression through temperature profile-induced variations in molecular architecture of thermoresponsive polymer vectors. J Gene Med 9:44–54PubMedGoogle Scholar
  142. 142.
    Twaites BR, CdlH A, Cunliffe D et al (2004) Thermo and pH responsive polymers as gene delivery vectors: effect of polymer architecture on DNA complexation in vitro. J Control Release 97:551–566PubMedGoogle Scholar
  143. 143.
    Twaites BR, CdLH A, Lavigne M et al (2005) Thermoresponsive polymers as gene delivery vectors: cell viability, DNA transport and transfection studies. J Control Release 108:472–483PubMedGoogle Scholar
  144. 144.
    Zintchenko A, Ogris M, Wagner E (2006) Temperature dependent gene expression induced by PNIPAM-based copolymers: potential of hyperthermia in gene transfer. Bioconjug Chem 17:766–772PubMedGoogle Scholar
  145. 145.
    Türk M, Dinçer S, Pişkin E (2007) Smart and cationic poly(NIPA)/PEI block copolymers as non-viral vectors: in vitro and in vivo transfection studies. J Tissue Eng Regen Med 1:377–388PubMedGoogle Scholar
  146. 146.
    Sun T, Wang G, Feng L et al (2004) Reversible Switching between superhydrophilicity and superhydrophobicity. Angew Chem Int Ed 43:357–360Google Scholar
  147. 147.
    Roux E, Francis M, Winnik FM et al (2002) Polymer based pH-sensitive carriers as a means to improve the cytoplasmic delivery of drugs. Int J Pharm 242:25–36PubMedGoogle Scholar
  148. 148.
    Berg K, Selbo PK, Prasmickaite L et al (1999) Photochemical internalization: a novel technology for delivery of macromolecules into cytosol. Cancer Res 59:1180–1183PubMedGoogle Scholar
  149. 149.
    Hogset A, Prasmickaite L, Engesaeter BO et al (2003) Light directed gene transfer by photochemical internalisation. Curr Gene Ther 3:89–112PubMedGoogle Scholar
  150. 150.
    de Bruin KG, Fella C, Ogris M et al (2008) Dynamics of photoinduced endosomal release of polyplexes. J Control Release 130:175–182PubMedGoogle Scholar
  151. 151.
    Kloeckner J, Prasmickaite L, Hogset A et al (2004) Photochemically enhanced gene delivery of EGF receptor-targeted DNA polyplexes. J Drug Target 12:205–213PubMedGoogle Scholar
  152. 152.
    Bonsted A, Wagner E, Prasmickaite L et al (2008) Photochemical enhancement of DNA delivery by EGF receptor targeted polyplexes. Methods Mol Biol 434:171–181PubMedGoogle Scholar
  153. 153.
    Nishiyama N, Arnida JWD et al (2006) Photochemical enhancement of transgene expression by polymeric micelles incorporating plasmid DNA and dendrimer-based photosensitizer. J Drug Target 14:413–424PubMedGoogle Scholar
  154. 154.
    Nishiyama N, Iriyama A, Jang WD et al (2005) Light-induced gene transfer from packaged DNA enveloped in a dendrimeric photosensitizer. Nat Mater 4:934–941PubMedGoogle Scholar
  155. 155.
    Oliveira S, Fretz MM, Høgset A et al (2007) Photochemical internalization enhances silencing of epidermal growth factor receptor through improved endosomal escape of siRNA. Biochim Biophys Acta 1768:1211–1217PubMedGoogle Scholar
  156. 156.
    Wagner E (2008) Converging paths of viral and non-viral vector engineering. Mol Ther 16:1–2PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of Pharmacy, Pharmaceutical Biotechnology, Center for System-Based Drug ResearchLudwig-Maximilians UniversityMunichGermany
  2. 2.Center for Nanoscience (CeNS)Ludwig-Maximilians UniversityMunichGermany

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