Skip to main content

Advertisement

SpringerLink
Log in

History of Polymeric Gene Delivery Systems

  • Review
  • Published:
Topics in Current Chemistry Aims and scope Submit manuscript

Abstract

As an option for genetic disease treatment and an alternative for traditional cancer chemotherapy, gene therapy achieves significant attention. Nucleic acid delivery, however, remains a main challenge in human gene therapy. Polymer-based delivery systems offer a safer and promising route for therapeutic gene delivery. Over the past five decades, various cationic polymers have been optimized for increasingly effective nucleic acid transfer. This resulted in a chemical evolution of cationic polymers from the first-generation polycations towards bioinspired multifunctional sequence-defined polymers and nanocomposites. With the increasing of knowledge in molecular biological processes and rapid progress of macromolecular chemistry, further improvement of polymeric nucleic acid delivery systems will provide effective tool for gene-based therapy in the near future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

References

  1. Mulligan RC (1993) The basic science of gene therapy. Science 260:926–932

    Article  CAS  Google Scholar 

  2. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG (2014) Non-viral vectors for gene-based therapy. Nat Rev Genet 15:541–555

    Article  CAS  Google Scholar 

  3. Yin H, Song CQ, Dorkin JR, Zhu LJ, Li Y, Wu Q, Park A, Yang J, Suresh S, Bizhanova A, Gupta A, Bolukbasi MF, Walsh S, Bogorad RL, Gao G, Weng Z, Dong Y, Koteliansky V, Wolfe SA, Langer R, Xue W, Anderson DG (2016) Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat Biotechnol 34:328–333

    Article  CAS  Google Scholar 

  4. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J (2013) Gene therapy clinical trials worldwide to 2012—an update. J Gene Med 15:65–77

    Article  CAS  Google Scholar 

  5. Lachelt U, Wagner E (2015) Nucleic acid therapeutics using polyplexes: a journey of 50 years (and beyond). Chem Rev 115:11043–11078

    Article  CAS  Google Scholar 

  6. Mintzer MA, Simanek EE (2009) Nonviral vectors for gene delivery. Chem Rev 109:259–302

    Article  CAS  Google Scholar 

  7. Pack DW, Hoffman AS, Pun S, Stayton PS (2005) Design and development of polymers for gene delivery. Nat Rev Drug Discov 4:581–593

    Article  CAS  Google Scholar 

  8. Verma IM, Somia N (1997) Gene therapy—promises, problems and prospects. Nature 389:239–242

    Article  CAS  Google Scholar 

  9. Bessis N, GarciaCozar FJ, Boissier MC (2004) Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene Ther 11:S10–S17

    Article  CAS  Google Scholar 

  10. Thomas CE, Ehrhardt A, Kay MA (2003) Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 4:346–358

    Article  CAS  Google Scholar 

  11. Bouard D, Alazard-Dany D, Cosset FL (2009) Viral vectors: from virology to transgene expression. Br J Pharmacol 157:153–165

    Article  CAS  Google Scholar 

  12. Wagner E (2014) Polymers for nucleic acid transfer—an overview. Adv Genet 88:231–261

    Google Scholar 

  13. Wagner E (2012) Polymers for siRNA delivery: inspired by viruses to be targeted, dynamic, and precise. Accounts Chem Res 45:1005–1013

    Article  CAS  Google Scholar 

  14. Stingl G, Brocker EB, Mertelsmann R, Wolff K, Schreiber S, Kampgen E, Schneeberger A, Dummer W, Brennscheid U, Veelken H, Birnstiel ML, Zatloukal K, Schmidt W, Maass G, Wagner E, Baschle M, Giese M, Kempe ER, Weber HA, Voigt T (1996) Phase I study to the immunotherapy of metastatic malignant melanoma by a cancer vaccine consisting of autologous cancer cells transfected with the human IL-2 gene. Hum Gene Ther 7:551–563

    Article  CAS  Google Scholar 

  15. Schreiber S, Kampgen E, Wagner E, Pirkhammer D, Trcka J, Korschan H, Lindemann A, Dorffner R, Kittler H, Kasteliz F, Kupcu Z, Sinski A, Zatloukal K, Buschle M, Schmidt W, Birnstiel M, Kempe RE, Voigt T, Weber HA, Pehamberger H, Mertelsmann R, Brocker EB, Wolff K, Stingl G (1999) Immunotherapy of metastatic malignant melanoma by a vaccine consisting of autologous interleukin 2-transfected cancer cells: outcome of a phase I study. Hum Gene Ther 10:983–993

    Article  CAS  Google Scholar 

  16. Ohana P, Gofrit O, Ayesh S, Al-Sharef W, Mizrahi A, Birman T, Schneider T, Matouk I, de Groot N, Tavdy E, Sidi AA, Hochberg A (2004) Regulatory sequences of the H19 gene in DNA based therapy of bladder cancer. Gene Ther Mol Biol 8:181–192

    Google Scholar 

  17. Konstan MW, Davis PB, Wagener JS, Hilliard KA, Stern RC, Milgram LJ, Kowalczyk TH, Hyatt SL, Fink TL, Gedeon CR, Oette SM, Payne JM, Muhammad O, Ziady AG, Moen RC, Cooper MJ (2004) Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution. Hum Gene Ther 15:1255–1269

    Article  CAS  Google Scholar 

  18. Sidi AA, Ohana P, Benjamin S, Shalev M, Ransom JH, Lamm D, Hochberg A, Leibovitch I (2008) Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin. J Urology 180:2379–2383

    Article  Google Scholar 

  19. Fewell JG, Matar MM, Rice JS, Brunhoeber E, Slobodkin G, Pence C, Worker M, Lewis DH, Anwer K (2009) Treatment of disseminated ovarian cancer using nonviral interleukin-12 gene therapy delivered intraperitoneally. J Gene Med 11:718–728

    Article  CAS  Google Scholar 

  20. Davis ME (2009) The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. Mol Pharm 6:659–668

    Article  CAS  Google Scholar 

  21. Anwer K, Barnes MN, Fewell J, Lewis DH, Alvarez RD (2010) Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer. Gene Ther 17:360–369

    Article  CAS  Google Scholar 

  22. Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, Yen Y, Heidel JD, Ribas A (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464:1067–1070

    Article  CAS  Google Scholar 

  23. Lisziewicz J, Bakare N, Calarota SA, Banhegyi D, Szlavik J, Ujhelyi E, Toke ER, Molnar L, Lisziewicz Z, Autran B, Lori F (2012) Single DermaVir immunization: dose-dependent expansion of precursor/memory T cells against all HIV antigens in HIV-1 infected individuals. PLoS One 7:e35416

    Article  CAS  Google Scholar 

  24. Gofrit ON, Benjamin S, Halachmi S, Leibovitch I, Dotan Z, Lamm DL, Ehrlich N, Yutkin V, Ben-Am M, Hochberg A (2014) DNA based therapy with diphtheria toxin-A BC-819: a Phase 2b marker lesion trial in patients with intermediate risk nonmuscle invasive bladder cancer. J Urology 191:1697–1702

    Article  CAS  Google Scholar 

  25. Rodriguez B, Asmuth DM, Matining RM, Spritzler J, Jacobson JM, Mailliard RB, Li XD, Martinez AI, Tenorio AR, Lori F, Lisziewicz J, Yesmin S, Rinaldo CR, Pollard RB (2013) Safety, tolerability, and immunogenicity of repeated doses of dermavir, a candidate therapeutic HIV vaccine, in HIV-infected patients receiving combination antiretroviral therapy: results of the ACTG 5176 trial. J Acquir Immune Defic Syndr 64:351–359

    Article  CAS  Google Scholar 

  26. Smull CE, Ludwig EH (1962) Enhancement of the plaque forming capacity of poliovirus ribonucleic acid with basic proteins. J Bacteriol 84:1035–1040

    CAS  Google Scholar 

  27. Vaheri A, Pagano JS (1965) Infectious poliovirus RNA: a sensitive method of assay 2. Virology 27:434–436

    Article  CAS  Google Scholar 

  28. McCutchan JH, Pagano JS (1968) Enchancement of the infectivity of simian virus 40 deoxyribonucleic acid with diethylaminoethyl-dextran. J Natl Cancer I 41:351–357

    CAS  Google Scholar 

  29. Farber FE, Melnick JL, Butel JS (1975) Optimal conditions for uptake of exogenous DNA by Chinese hamster lung cells deficient in hypoxanthine-guanine phosphoribosyltransferase. Biochim Biophys Acta 390:298–311

    Article  CAS  Google Scholar 

  30. Kabanov AV, Astafyeva IV, Chikindas ML, Rosenblat GF, Kiselev VI, Severin ES, Kabanov VA (1991) DNA interpolyelectrolyte complexes as a tool for efficient cell transformation. Biopolymers 31:1437–1443

    Article  CAS  Google Scholar 

  31. Kabanov AV, Astafieva IV, Maksimova IV, Lukanidin EM, Georgiev GP, Kabanov VA (1993) Efficient transformation of mammalian cells using DNA interpolyelectrolyte complexes with carbon chain polycations. Bioconjugate Chem 4:448–454

    Article  CAS  Google Scholar 

  32. Laemmli UK (1975) Characterization of DNA condensates induced by poly(ethylene oxide) and polylysine. Proc Natl Acad Sci 72:4288–4292

    Article  CAS  Google Scholar 

  33. Chattoraj DK, Gosule LC, Schellman A (1978) DNA condensation with polyamines. II. Electron microscopic studies 95. J Mol Biol 121:327–337

    Article  CAS  Google Scholar 

  34. Hinde E, Thammasiraphop K, Duong HTT, Yeow J, Karagoz B, Boyer C, Gooding JJ, Gaus K (2016) Pair correlation microscopy reveals the role of nanoparticle shape in intracellular transport and site of drug release. Nat Nanotechnol. doi:10.1038/nnano.2016.160

    Google Scholar 

  35. Wu GY, Wu CH (1987) Receptor-mediated in vitro gene transformation by a soluble DNA carrier system. J Biol Chem 262:4429–4432

    CAS  Google Scholar 

  36. Wu GY, Wu CH (1988) Receptor-mediated gene delivery and expression in vivo 738. J Biol Chem 262:14621–14624

    Google Scholar 

  37. Wu CH, Wilson JM, Wu GY (1989) Targeting genes: delivery and persistent expression of a foreign gene driven by mammalian regulatory elements in vivo 939. J Biol Chem 264:16985–16987

    CAS  Google Scholar 

  38. Chowdhury NR, Wu CH, Wu GY, Yerneni PC, Bommineni VR, Chowdhury JR (1993) Fate of DNA targeted to the liver by asialoglycoprotein receptor-mediated endocytosis in vivo. Prolonged persistence in cytoplasmic vesicles after partial hepatectomy 111. J Biol Chem 268:11265–11271

    CAS  Google Scholar 

  39. Wu GY, Wilson JM, Shalaby F, Grossman M, Shafritz DA, Wu CH (1991) Receptor-mediated gene delivery in vivo. Partial correction of genetic analbuminemia in Nagase rats. J Biol Chem 266:14338–14342

    CAS  Google Scholar 

  40. Wilson JM, Grossman M, Wu CH, Chowdhury NR, Wu GY, Chowdhury JR (1992) Hepatocyte-directed gene transfer in vivo leads to transient improvement of hypercholesterolemia in low density lipoprotein receptor-deficient rabbits 720. J Biol Chem 267:963–967

    CAS  Google Scholar 

  41. Ogris M, Wagner E (2011) To be targeted: is the magic bullet concept a viable option for synthetic nucleic acid therapeutics? Hum Gene Ther 22:799–807

    Article  CAS  Google Scholar 

  42. Wagner E, Zenke M, Cotten M, Beug H, Birnstiel ML (1990) Transferrin-polycation conjugates as carriers for DNA uptake into cells. Proc Natl Acad Sci 87:3410–3414

    Article  CAS  Google Scholar 

  43. Cotten M, Langle-Rouault F, Kirlappos H, Wagner E, Mechtler K, Zenke M, Beug H, Birnstiel ML (1990) Transferrin-polycation-mediated introduction of DNA into human leukemic cells: stimulation by agents that affect the survival of transfected DNA or modulate transferrin receptor levels. Proc Natl Acad Sci 87:4033–4037

    Article  CAS  Google Scholar 

  44. Zenke M, Steinlein P, Wagner E, Cotten M, Beug H, Birnstiel ML (1990) Receptor-mediated endocytosis of transferrin-polycation conjugates: an efficient way to introduce DNA into hematopoietic cells. Proc Natl Acad Sci 87:3655–3659

    Article  CAS  Google Scholar 

  45. Ferkol T, Kaetzel CS, Davis PB (1993) Gene transfer into respiratory epithelial cells by targeting the polymeric immunoglobulin receptor 831. J Clin Invest 92:2394–2400

    Article  CAS  Google Scholar 

  46. Wagner E, Ogris M, Zauner W (1998) Polylysine-based transfection systems utilizing receptor-mediated delivery. Adv Drug Deliver Rev 30:97–113

    Article  CAS  Google Scholar 

  47. Luthman H, Magnusson G (1983) High efficiency polyoma DNA transfection of chloroquine treated cells. Nucleic Acids Res 11:1295–1308

    Article  CAS  Google Scholar 

  48. Erbacher P, Roche AC, Monsigny M, Midoux P (1996) Putative role of chloroquine in gene transfer into a human hepatoma cell line by DNA/lactosylated polylysine complexes. Exp Cell Res 225:186–194

    Article  CAS  Google Scholar 

  49. Cheng JJ, Zeidan R, Mishra S, Liu A, Pun SH, Kulkarni RP, Jensen GS, Bellocq NC, Davis ME (2006) Structure—function correlation of chloroquine and analogues as transgene expression enhancers in nonviral gene delivery. J Med Chem 49:6522–6531

    Article  CAS  Google Scholar 

  50. Mellman I, Fuchs R, Helenius A (1986) Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 55:663–700

    Article  CAS  Google Scholar 

  51. Cain CC, Sipe DM, Murphy RF (1989) Regulation of endocytic pH by the Na+, K+-ATPase in living cells. Proc Natl Acad Sci 86:544–548

    Article  CAS  Google Scholar 

  52. Maxfield FR, McGraw TE (2004) Endocytic recycling. Nat Rev Mol Cell Bio 5:121–132

    Article  CAS  Google Scholar 

  53. Curiel DT, Agarwal S, Wagner E, Cotten M (1991) Adenovirus enhancement of transferrin-polylysine-mediated gene delivery. Proc Natl Acad Sci 88:8850–8854

    Article  CAS  Google Scholar 

  54. Cotten M, Wagner E, Zatloukal K, Birnstiel ML (1993) Chicken adenovirus (CELO virus) particles augment receptor-mediated DNA delivery to mammalian cells and yield exceptional levels of stable transformants. J Virol 67:3777–3785

    CAS  Google Scholar 

  55. Zauner W, Blaas D, Kuechler E, Wagner E (1995) Rhinovirus-mediated endosomal release of transfection complexes. J Virol 69:1085–1092

    CAS  Google Scholar 

  56. Curiel DT, Wagner E, Cotten M, Birnstiel ML, Agarwal S, Li CM, Loechel S, Hu PC (1992) High-efficiency gene transfer mediated by adenovirus coupled to DNA-polylysine complexes. Hum Gene Ther 3:147–154

    Article  CAS  Google Scholar 

  57. Wagner E, Zatloukal K, Cotten M, Kirlappos H, Mechtler K, Curiel DT, Birnstiel ML (1992) Coupling of adenovirus to transferrin-polylysine/DNA complexes greatly enhances receptor-mediated gene delivery and expression of transfected genes. Proc Natl Acad Sci 89:6099–6103

    Article  CAS  Google Scholar 

  58. Cotten M, Wagner E, Zatloukal K, Phillips S, Curiel DT, Birnstiel ML (1992) High-efficiency receptor-mediated delivery of small and large (48 kilobase gene constructs using the endosome-disruption activity of defective or chemically inactivated adenovirus particles. Proc Natl Acad Sci 89:6094–6098

    Article  CAS  Google Scholar 

  59. Zatloukal K, Wagner E, Cotten M, Phillips S, Plank C, Steinlein P, Curiel DT, Birnstiel ML (1992) Transferrinfection: a highly efficient way to express gene constructs in eukaryotic cells. Ann NY Acad Sci 660:136–153

    Article  CAS  Google Scholar 

  60. Gao L, Wagner E, Cotten M, Agarwal S, Harris C, Romer M, Miller L, Hu PC, Curiel D (1993) Direct in vivo gene transfer to airway epithelium employing adenovirus-polylysine-DNA complexes. Hum Gene Ther 4:17–24

    Article  Google Scholar 

  61. Cristiano RJ, Smith LC, Kay MA, Brinkley BR, Woo SL (1993) Hepatic gene therapy: efficient gene delivery and expression in primary hepatocytes utilizing a conjugated adenovirus-DNA complex 139. Proc Natl Acad Sci 90:11548–11552

    Article  CAS  Google Scholar 

  62. Cotten M, Saltik M, Kursa M, Wagner E, Maass G, Birnstiel ML (1994) Psoralen treatment of adenovirus particles eliminates virus replication and transcription while maintaining the endosomolytic activity of the virus capsid. Virology 205:254–261

    Article  CAS  Google Scholar 

  63. Curiel TJ, Cook DR, Bogedain C, Jilg W, Harrison GS, Cotten M, Curiel DT, Wagner E (1994) Efficient foreign gene expression in Epstein-Barr virus-transformed human B-cells. Virology 198:577–585

    Article  CAS  Google Scholar 

  64. Frank S, Krasznai K, Durovic S, Lobentanz EM, Dieplinger H, Wagner E, Zatloukal K, Cotten M, Utermann G, Kostner GM (1994) High-level expression of various apolipoprotein(a) isoforms by “transferrinfection”: the role of kringle IV sequences in the extracellular association with low-density lipoprotein. Biochemistry 33:12329–12339

    Article  CAS  Google Scholar 

  65. Zatloukal K, Cotten M, Berger M, Schmidt W, Wagner E, Birnstiel ML (1994) In vivo production of human factor VII in mice after intrasplenic implantation of primary fibroblasts transfected by receptor-mediated, adenovirus-augmented gene delivery. Proc Natl Acad Sci 91:5148–5152

    Article  CAS  Google Scholar 

  66. Zatloukal K, Schneeberger A, Berger M, Koszik F, Schmidt W, Wagner E, Cotten M, Buschle M, Maass G, Stingl G (1994) Genetic modification of cells by receptor-mediated adenovirus-augmented gene delivery: a new approach for immunotherapy of cancer. Verh Deut G 78:171–176

    CAS  Google Scholar 

  67. Buschle M, Cotten M, Kirlappos H, Mechtler K, Schaffner G, Zauner W, Birnstiel ML, Wagner E (1995) Receptor-mediated gene transfer into human T lymphocytes via binding of DNA/CD3 antibody particles to the CD3 T cell receptor complex. Hum Gene Ther 6:753–761

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  69. Gagnoux-Palacios L, Vailly J, Durand-Clement M, Wagner E, Ortonne JP, Meneguzzi G (1996) Functional Re-expression of laminin-5 in laminin-gamma2-deficient human keratinocytes modifies cell morphology, motility, and adhesion. J Biol Chem 271:18437–18444

    Article  CAS  Google Scholar 

  70. Nguyen DM, Wiehle SA, Koch PE, Branch C, Yen N, Roth JA, Cristiano RJ (1997) Delivery of the p53 tumor suppressor gene into lung cancer cells by an adenovirus/DNA complex 884. Cancer Gene Ther 4:191–198

    CAS  Google Scholar 

  71. Wagner E, Curiel D, Cotten M (1994) Delivery of drugs, proteins and genes into cells using transferrin as a ligand for receptor-mediated endocytosis. Adv Drug Deliver Rev 14:113–136

    Article  CAS  Google Scholar 

  72. Saito G, Amidon GL, Lee KD (2003) Enhanced cytosolic delivery of plasmid DNA by a sulfhydryl-activatable listeriolysin O/protamine conjugate utilizing cellular reducing potential. Gene Ther 10:72–83

    Article  CAS  Google Scholar 

  73. Gottschalk S, Tweten RK, Smith LC, Woo SL (1995) Efficient gene delivery and expression in mammalian cells using DNA coupled with perfringolysin O 244. Gene Ther 2:498–503

    CAS  Google Scholar 

  74. Fominaya J, Wels W (1996) Target cell-specific DNA transfer mediated by a chimeric multidomain protein. Novel non-viral gene delivery system 835. J Biol Chem 271:10560–10568

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  77. Wagner E, Plank C, Zatloukal K, Cotten M, Birnstiel ML (1992) Influenza virus hemagglutinin HA-2 N-terminal fusogenic peptides augment gene transfer by transferrin-polylysine-DNA complexes: toward a synthetic virus-like gene-transfer vehicle. Proc Natl Acad Sci 89:7934–7938

    Article  CAS  Google Scholar 

  78. Plank C, Zatloukal K, Cotten M, Mechtler K, Wagner E (1992) Gene transfer into hepatocytes using asialoglycoprotein receptor mediated endocytosis of DNA complexed with an artificial tetra-antennary galactose ligand. Bioconjugate Chem 3:533–539

    Article  CAS  Google Scholar 

  79. Plank C, Oberhauser B, Mechtler K, Koch C, Wagner E (1994) The influence of endosome-disruptive peptides on gene transfer using synthetic virus-like gene transfer systems. J Biol Chem 269:12918–12924

    CAS  Google Scholar 

  80. Plank C, Zauner W, Wagner E (1998) Application of membrane-active peptides for drug and gene delivery across cellular membranes. Adv Drug Deliver Rev 34:21–35

    Article  CAS  Google Scholar 

  81. Wagner E (1998) Effects of membrane-active agents in gene delivery. J Control Release 53:155–158

    Article  CAS  Google Scholar 

  82. Wagner E (1999) Application of membrane-active peptides for nonviral gene delivery. Adv Drug Deliver Rev 38:279–289

    Article  CAS  Google Scholar 

  83. Dohmen C, Edinger D, Frohlich T, Schreiner L, Lachelt U, Troiber C, Radler J, Hadwiger P, Vornlocher HP, Wagner E (2012) Nanosized multifunctional polyplexes for receptor-mediated siRNA delivery. ACS Nano 6:5198–5208

    Article  CAS  Google Scholar 

  84. Zhang W, Muller K, Kessel E, Reinhard S, He D, Klein PM, Hohn M, Rodl W, Kempter S, Wagner E (2016) Targeted siRNA delivery using a lipo-oligoaminoamide nanocore with an influenza peptide and transferrin shell. Adv Healthc Mater 5:1493–1504

    Article  CAS  Google Scholar 

  85. Haensler J, Szoka FC Jr (1993) Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjugate Chem 4:372–379

    Article  CAS  Google Scholar 

  86. Wyman TB, Nicol F, Zelphati O, Scaria PV, Plank C, Szoka FC Jr (1997) Design, synthesis, and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers. Biochemistry 36:3008–3017

    Article  CAS  Google Scholar 

  87. Gottschalk S, Sparrow JT, Hauer J, Mims MP, Leland FE, Woo SL, Smith LC (1996) A novel DNA-peptide complex for efficient gene transfer and expression in mammalian cells 844. Gene Ther 3:48–57

    Google Scholar 

  88. Mechtler K, Wagner E (1997) Gene transfer mediated by influenza virus peptides: the role of peptide sequence. New J Chem 21:105–111

    CAS  Google Scholar 

  89. Midoux P, Kichler A, Boutin V, Maurizot JC, Monsigny M (1998) Membrane permeabilization and efficient gene transfer by a peptide containing several histidines 878. Bioconjugate Chem 9:260–267

    Article  CAS  Google Scholar 

  90. Kichler A, Leborgne C, Marz J, Danos O, Bechinger B (2003) Histidine-rich amphipathic peptide antibiotics promote efficient delivery of DNA into mammalian cells. Proc Natl Acad Sci 100:1564–1568

    Article  CAS  Google Scholar 

  91. Berg K, Weyergang A, Prasmickaite L, Bonsted A, Hogset A, Strand MT, Wagner E, Selbo PK (2010) Photochemical internalization (PCI): a technology for drug delivery. Methods Mol Biol 635:133–145

    Article  CAS  Google Scholar 

  92. de Bruin KG, Fella C, Ogris M, Wagner E, Ruthardt N, Brauchle C (2008) Dynamics of photoinduced endosomal release of polyplexes. J Control Release 130:175–182

    Article  CAS  Google Scholar 

  93. Kloeckner J, Prasmickaite L, Hogset A, Berg K, Wagner E (2004) Photochemically enhanced gene delivery of EGF receptor-targeted DNA polyplexes. J Drug Target 12:205–213

    Article  CAS  Google Scholar 

  94. Tang MX, Redemann CT, Szoka FC Jr (1996) In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjugate Chem 7:703–714

    Article  CAS  Google Scholar 

  95. Tang MX, Szoka FC (1997) The influence of polymer structure on the interactions of cationic polymers with DNA and morphology of the resulting complexes 2. Gene Ther 4:823–832

    Article  CAS  Google Scholar 

  96. Sonawane ND, Szoka FC Jr, Verkman AS (2003) Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem 278:44826–44831

    Article  CAS  Google Scholar 

  97. Behr JP, Demeneix B, Loeffler JP, Perez-Mutul J (1989) Efficient gene transfer into mammalian primary endocrine cells with lipopolyamine-coated DNA 6. Proc Natl Acad Sci 86:6982–6986

    Article  CAS  Google Scholar 

  98. Remy JS, Sirlin C, Vierling P, Behr JP (1994) Gene transfer with a series of lipophilic DNA-binding molecules 547. Bioconjugate Chem 5:647–654

    Article  CAS  Google Scholar 

  99. Boussif O, Lezoualc’h F, Zanta MA, Mergny MD, Scherman D, Demeneix B, Behr JP (1995) A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci 92:7297–7301

    Article  CAS  Google Scholar 

  100. Behr JP (1997) The proton sponge: a trick to enter cells the viruses did not exploit. Chimia 51:34–36

    CAS  Google Scholar 

  101. Coll JL, Chollet P, Brambilla E, Desplanques D, Behr JP, Favrot M (1999) In vivo delivery to tumors of DNA complexed with linear polyethylenimine. Hum Gene Ther 10:1659–1666

    Article  CAS  Google Scholar 

  102. Zou SM, Erbacher P, Remy JS, Behr JP (2000) Systemic linear polyethylenimine (L-PEI)-mediated gene delivery in the mouse. J Gene Med 2:128–134

    Article  CAS  Google Scholar 

  103. Neuberg P, Kichler A (2014) Recent developments in nucleic acid delivery with polyethylenimines. Adv Genet 88:263–288

    Google Scholar 

  104. Godbey WT, Ku KK, Hirasaki GJ, Mikos AG (1999) Improved packing of poly(ethylenimine)/DNA complexes increases transfection efficiency. Gene Ther 6:1380–1388

    Article  CAS  Google Scholar 

  105. Itaka K, Harada A, Yamasaki Y, Nakamura K, Kawaguchi H, Kataoka K (2004) In situ single cell observation by fluorescence resonance energy transfer reveals fast intra-cytoplasmic delivery and easy release of plasmid DNA complexed with linear polyethylenimine. J Gene Med 6:76–84

    Article  CAS  Google Scholar 

  106. Wightman L, Kircheis R, Rossler V, Carotta S, Ruzicka R, Kursa M, Wagner E (2001) Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo. J Gene Med 3:362–372

    Article  CAS  Google Scholar 

  107. Brunner S, Sauer T, Carotta S, Cotten M, Saltik M, Wagner E (2000) Cell cycle dependence of gene transfer by lipoplex, polyplex and recombinant adenovirus. Gene Ther 7:401–407

    Article  CAS  Google Scholar 

  108. Brunner S, Furtbauer E, Sauer T, Kursa M, Wagner E (2002) Overcoming the nuclear barrier: cell cycle independent nonviral gene transfer with linear polyethylenimine or electroporation. Mol Ther 5:80–86

    Article  CAS  Google Scholar 

  109. Grandinetti G, Reineke TM (2012) Exploring the mechanism of plasmid DNA nuclear internalization with polymer-based vehicles. Mol Pharm 9:2256–2267

    Article  CAS  Google Scholar 

  110. Godbey WT, Wu KK, Mikos AG (1999) Tracking the intracellular path of poly(ethylenimine)/DNA complexes for gene delivery. Proc Natl Acad Sci 96:5177–5181

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  112. Akinc A, Langer R (2002) Measuring the pH environment of DNA delivered using nonviral vectors: implications for lysosomal trafficking. Biotechnol Bioeng 78:503–508

    Article  CAS  Google Scholar 

  113. Akinc A, Thomas M, Klibanov AM, Langer R (2005) Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis. J Gene Med 7:657–663

    Article  CAS  Google Scholar 

  114. Miyata K, Nishiyama N, Kataoka K (2012) Rational design of smart supramolecular assemblies for gene delivery: chemical challenges in the creation of artificial viruses. Chem Soc Rev 41:2562–2574

    Article  CAS  Google Scholar 

  115. Benjaminsen RV, Mattebjerg MA, Henriksen JR, Moghimi SM, Andresen TL (2013) The possible “proton sponge “ effect of polyethylenimine (PEI) does not include change in lysosomal pH. Mol Ther 21:149–157

    Article  CAS  Google Scholar 

  116. Boeckle S, von Gersdorff K, van der Piepen S, Culmsee C, Wagner E, Ogris M (2004) Purification of polyethylenimine polyplexes highlights the role of free polycations in gene transfer. J Gene Med 6:1102–1111

    Article  CAS  Google Scholar 

  117. Funhoff AM, van Nostrum CF, Koning GA, Schuurmans-Nieuwenbroek NME, Crommelin DJA, Hennink WE (2004) Endosomal escape of polymeric gene delivery complexes is not always enhanced by polymers buffering at low pH. Biomacromolecules 5:32–39

    Article  CAS  Google Scholar 

  118. Walker GF, Fella C, Pelisek J, Fahrmeir J, Boeckle S, Ogris M, Wagner E (2005) Toward synthetic viruses: endosomal pH-triggered deshielding of targeted polyplexes greatly enhances gene transfer in vitro and in vivo. Mol Ther 11:418–425

    Article  CAS  Google Scholar 

  119. Meyer M, Wagner E (2006) pH-responsive shielding of non-viral gene vectors. Expert Opin Drug Del 3:563–571

    Article  CAS  Google Scholar 

  120. Fella C, Walker GF, Ogris M, Wagner E (2008) Amine-reactive pyridylhydrazone-based PEG reagents for pH-reversible PEI polyplex shielding. Eur J Pharm Sci 34:309–320

    Article  CAS  Google Scholar 

  121. Lee SH, Choi SH, Kim SH, Park TG (2008) Thermally sensitive cationic polymer nanocapsules for specific cytosolic delivery and efficient gene silencing of siRNA: swelling induced physical disruption of endosome by cold shock. J Control Release 125:25–32

    Article  CAS  Google Scholar 

  122. Midoux P, Monsigny M (1999) Efficient gene transfer by histidylated polylysine/pDNA complexes. Bioconjugate Chem 10:406–411

    Article  CAS  Google Scholar 

  123. Pack DW, Putnam D, Langer R (2000) Design of imidazole-containing endosomolytic biopolymers for gene delivery. Biotechnol Bioeng 67:217–223

    Article  CAS  Google Scholar 

  124. Pichon C, Goncalves C, Midoux P (2001) Histidine-rich peptides and polymers for nucleic acids delivery. Adv Drug Deliver Rev 53:75–94

    Article  CAS  Google Scholar 

  125. Bertrand E, Goncalves C, Billiet L, Gomez JP, Pichon C, Cheradame H, Midoux P, Guegan P (2011) Histidinylated linear PEI: a new efficient non-toxic polymer for gene transfer. Chem Commun 47:12547–12549

    Article  CAS  Google Scholar 

  126. Chen QR, Zhang L, Stass SA, Mixson AJ (2001) Branched co-polymers of histidine and lysine are efficient carriers of plasmids. Nucleic Acids Res 29:1334–1340

    Article  CAS  Google Scholar 

  127. Leng Q, Mixson AJ (2016) The neuropilin-1 receptor mediates enhanced tumor delivery of H2K polyplexes. J Gene Med 18:134–144

    Article  CAS  Google Scholar 

  128. Lachelt U, Kos P, Mickler FM, Herrmann A, Salcher EE, Rodl W, Badgujar N, Brauchle C, Wagner E (2014) Fine-tuning of proton sponges by precise diaminoethanes and histidines in pDNA polyplexes. Nanomedicine 10:35–44

    Article  CAS  Google Scholar 

  129. Moghimi SM, Symonds P, Murray JC, Hunter AC, Debska G, Szewczyk A (2005) A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene transfer/therapy. Mol Ther 11:990–995

    Article  CAS  Google Scholar 

  130. Grandinetti G, Ingle NP, Reineke TM (2011) Interaction of poly(ethylenimine)-DNA polyplexes with mitochondria: implications for a mechanism of cytotoxicity. Mol Pharm 8:1709–1719

    Article  CAS  Google Scholar 

  131. Hall A, Larsen AK, Parhamifar L, Meyle KD, Wu LP, Moghimi SM (2013) High resolution respirometry analysis of polyethylenimine-mediated mitochondrial energy crisis and cellular stress: mitochondrial proton leak and inhibition of the electron transport system. Biochim Biophys Acta 1827:1213–1225

    Article  CAS  Google Scholar 

  132. Plank C, Mechtler K, Szoka FC Jr, Wagner E (1996) Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery. Hum Gene Ther 7:1437–1446

    Article  CAS  Google Scholar 

  133. Merkel OM, Urbanics R, Bedocs P, Rozsnyay Z, Rosivall L, Toth M, Kissel T, Szebeni J (2011) In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers. Biomaterials 32:4936–4942

    Article  CAS  Google Scholar 

  134. Wakefield DH, Klein JJ, Wolff JA, Rozema DB (2005) Membrane activity and transfection ability of amphipathic polycations as a function of alkyl group size. Bioconjugate Chem 16:1204–1208

    Article  CAS  Google Scholar 

  135. Rozema DB, Lewis DL, Wakefield DH, Wong SC, Klein JJ, Roesch PL, Bertin SL, Reppen TW, Chu Q, Blokhin AV, Hagstrom JE, Wolff JA (2007) Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc Natl Acad Sci 104:12982–12987

    Article  CAS  Google Scholar 

  136. Murthy N, Robichaud JR, Tirrell DA, Stayton PS, Hoffman AS (1999) The design and synthesis of polymers for eukaryotic membrane disruption. J Control Release 61:137–143

    Article  CAS  Google Scholar 

  137. Bulmus V, Woodward M, Lin L, Murthy N, Stayton P, Hoffman A (2003) A new pH-responsive and glutathione-reactive, endosomal membrane-disruptive polymeric carrier for intracellular delivery of biomolecular drugs. J Control Release 93:105–120

    Article  CAS  Google Scholar 

  138. Dang JM, Leong KW (2006) Natural polymers for gene delivery and tissue engineering. Adv Drug Deliver Rev 58:487–499

    Article  CAS  Google Scholar 

  139. Zaitsev SV, Haberland A, Otto A, Vorob’ev VI, Haller H, Bottger M (1997) H1 and HMG17 extracted from calf thymus nuclei are efficient DNA carriers in gene transfer. Gene Ther 4:586–592

    Article  CAS  Google Scholar 

  140. Bottger M, Vogel F, Platzer M, Kiessling U, Grade K, Strauss M (1988) Condensation of vector DNA by the chromosomal protein HMG1 results in efficient transfection. Biochim Biophys Acta 950:221–228

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  142. Takeshita F, Minakuchi Y, Nagahara S, Honma K, Sasaki H, Hirai K, Teratani T, Namatame N, Yamamoto Y, Hanai K, Kato T, Sano A, Ochiya T (2005) Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. Proc Natl Acad Sci 102:12177–12182

    Article  CAS  Google Scholar 

  143. Young S, Wong M, Tabata Y, Mikos AG (2005) Gelatin as a delivery vehicle for the controlled release of bioactive molecules. J Control Release 109:256–274

    Article  CAS  Google Scholar 

  144. Erbacher P, Zou S, Bettinger T, Steffan AM, Remy JS (1998) Chitosan-based vector/DNA complexes for gene delivery: biophysical characteristics and transfection ability 826. Pharm Res 15:1332–1339

    Article  CAS  Google Scholar 

  145. Park IK, Kim TH, Park YH, Shin BA, Choi ES, Chowdhury EH, Akaike T, Cho CS (2001) Galactosylated chitosan-graft-poly(ethylene glycol) as hepatocyte-targeting DNA carrier. J Control Release 76:349–362

    Article  CAS  Google Scholar 

  146. Thanou M, Florea BI, Geldof M, Junginger HE, Borchard G (2002) Quaternized chitosan oligomers as novel gene delivery vectors in epithelial cell lines. Biomaterials 23:153–159

    Article  CAS  Google Scholar 

  147. Germershaus O, Mao S, Sitterberg J, Bakowsky U, Kissel T (2008) Gene delivery using chitosan, trimethyl chitosan or polyethylenglycol-graft-trimethyl chitosan block copolymers: establishment of structure-activity relationships in vitro. J Control Release 125:145–154

    Article  CAS  Google Scholar 

  148. Chang KL, Higuchi Y, Kawakami S, Yamashita F, Hashida M (2010) Efficient gene transfection by histidine-modified chitosan through enhancement of endosomal escape. Bioconjugate Chem 21:1087–1095

    Article  CAS  Google Scholar 

  149. Lee D, Zhang W, Shirley SA, Kong X, Hellermann GR, Lockey RF, Mohapatra SS (2007) Thiolated chitosan/DNA nanocomplexes exhibit enhanced and sustained gene delivery. Pharm Res 24:157–167

    Article  CAS  Google Scholar 

  150. Pun SH, Bellocq NC, Liu A, Jensen G, Machemer T, Quijano E, Schluep T, Wen S, Engler H, Heidel J, Davis ME (2004) Cyclodextrin-modified polyethylenimine polymers for gene delivery. Bioconjugate Chem 15:831–840

    Article  CAS  Google Scholar 

  151. Pun SH, Davis ME (2002) Development of a nonviral gene delivery vehicle for systemic application. Bioconjugate Chem 13:630–639

    Article  CAS  Google Scholar 

  152. Ping Y, Hu Q, Tang G, Li J (2013) FGFR-targeted gene delivery mediated by supramolecular assembly between beta-cyclodextrin-crosslinked PEI and redox-sensitive PEG. Biomaterials 34:6482–6494

    Article  CAS  Google Scholar 

  153. Hwang SJ, Bellocq NC, Davis ME (2001) Effects of structure of beta-cyclodextrin-containing polymers on gene delivery. Bioconjugate Chem 12:280–290

    Article  CAS  Google Scholar 

  154. Bellocq NC, Pun SH, Jensen GS, Davis ME (2003) Transferrin-containing, cyclodextrin polymer-based particles for tumor-targeted gene delivery. Bioconjugate Chem 14:1122–1132

    Article  CAS  Google Scholar 

  155. Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ (2005) Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing’s sarcoma. Cancer Res 65:8984–8992

    Article  CAS  Google Scholar 

  156. Cryan SA, Holohan A, Donohue R, Darcy R, O’Driscoll CM (2004) Cell transfection with polycationic cyclodextrin vectors. Eur J Pharm Sci 21:625–633

    Article  CAS  Google Scholar 

  157. Ooya T, Choi HS, Yamashita A, Yui N, Sugaya Y, Kano A, Maruyama A, Akita H, Ito R, Kogure K, Harashima H (2006) Biocleavable polyrotaxane-plasmid DNA polyplex for enhanced gene delivery. J Am Chem Soc 128:3852–3853

    Article  CAS  Google Scholar 

  158. Wagner E, Kloeckner J (2006) Gene delivery using polymer therapeutics. Adv Polym Sci 192:135–173

    Article  CAS  Google Scholar 

  159. Knorr V, Russ V, Allmendinger L, Ogris M, Wagner E (2008) Acetal linked oligoethylenimines for use as pH-sensitive gene carriers. Bioconjugate Chem 19:1625–1634

    Article  CAS  Google Scholar 

  160. 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 25:2937–2945

    Article  CAS  Google Scholar 

  161. Kim YH, Park JH, Lee M, Park TG, Kim SW (2005) Polyethylenimine with acid-labile linkages as a biodegradable gene carrier. J Control Release 103:209–219

    Article  CAS  Google Scholar 

  162. Gosselin MA, Guo W, Lee RJ (2001) Efficient gene transfer using reversibly cross-linked low molecular weight polyethylenimine. Bioconjugate Chem 12:989–994

    Article  CAS  Google Scholar 

  163. Yu H, Russ V, Wagner E (2009) Influence of the molecular weight of bioreducible oligoethylenimine conjugates on the polyplex transfection properties. AAPS J 11:445–455

    Article  CAS  Google Scholar 

  164. Forrest ML, Koerber JT, Pack DW (2003) A degradable polyethylenimine derivative with low toxicity for highly efficient gene delivery. Bioconjugate Chem 14:934–940

    Article  CAS  Google Scholar 

  165. Kloeckner J, Wagner E, Ogris M (2006) Degradable gene carriers based on oligomerized polyamines. Eur J Pharm Sci 29:414–425

    Article  CAS  Google Scholar 

  166. Chen L, Tian H, Chen J, Chen X, Huang Y, Jing X (2010) Multi-armed poly(l-glutamic acid)-graft-oligoethylenimine copolymers as efficient nonviral gene delivery vectors. J Gene Med 12:64–76

    Article  CAS  Google Scholar 

  167. Petersen H, Merdan T, Kunath K, Fischer D, Kissel T (2002) Poly(ethylenimine-co-l-lactamide-co-succinamide): a biodegradable polyethylenimine derivative with an advantageous pH-dependent hydrolytic degradation for gene delivery. Bioconjugate Chem 13:812–821

    Article  CAS  Google Scholar 

  168. Kloeckner J, Bruzzano S, Ogris M, Wagner E (2006) Gene carriers based on hexanediol diacrylate linked oligoethylenimine: effect of chemical structure of polymer on biological properties. Bioconjugate Chem 17:1339–1345

    Article  CAS  Google Scholar 

  169. Tarcha PJ, Pelisek J, Merdan T, Waters J, Cheung K, von Gersdorff K, Culmsee C, Wagner E (2007) Synthesis and characterization of chemically condensed oligoethylenimine containing beta-aminopropionamide linkages for siRNA delivery. Biomaterials 28:3731–3740

    Article  CAS  Google Scholar 

  170. Lim YB, Han SO, Kong HU, Lee Y, Park JS, Jeong B, Kim SW (2000) Biodegradable polyester, poly[alpha-(4-aminobutyl)-l-glycolic acid], as a non-toxic gene carrier. Pharm Res 17:811–816

    Article  CAS  Google Scholar 

  171. Lim YB, Kim SM, Suh H, Park JS (2002) Biodegradable, endosome disruptive, and cationic network-type polymer as a highly efficient and nontoxic gene delivery carrier. Bioconjugate Chem 13:952–957

    Article  CAS  Google Scholar 

  172. Akinc A, Anderson DG, Lynn DM, Langer R (2003) Synthesis of poly(beta-amino ester)s optimized for highly effective gene delivery. Bioconjugate Chem 14:979–988

    Article  CAS  Google Scholar 

  173. Lynn DM, Anderson DG, Putnam D, Langer R (2001) Accelerated discovery of synthetic transfection vectors: parallel synthesis and screening of a degradable polymer library. J Am Chem Soc 123:8155–8156

    Article  CAS  Google Scholar 

  174. Akinc A, Lynn DM, Anderson DG, Langer R (2003) Parallel synthesis and biophysical characterization of a degradable polymer library for gene delivery. J Am Chem Soc 125:5316–5323

    Article  CAS  Google Scholar 

  175. 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 Edit 42:3153–3158

    Article  CAS  Google Scholar 

  176. Akinc A, Zumbuehl A, Goldberg M, Leshchiner ES, Busini V, Hossain N, Bacallado SA, Nguyen DN, Fuller J, Alvarez R, Borodovsky A, Borland T, Constien R, de Fougerolles A, Dorkin JR, Narayanannair JK, Jayaraman M, John M, Koteliansky V, Manoharan M, Nechev L, Qin J, Racie T, Raitcheva D, Rajeev KG, Sah DW, Soutschek J, Toudjarska I, Vornlocher HP, Zimmermann TS, Langer R, Anderson DG (2008) A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat Biotechnol 26:561–569

    Article  CAS  Google Scholar 

  177. Love KT, Mahon KP, Levins CG, Whitehead KA, Querbes W, Dorkin JR, Qin J, Cantley W, Qin LL, Racie T, Frank-Kamenetsky M, Yip KN, Alvarez R, Sah DW, de Fougerolles A, Fitzgerald K, Koteliansky V, Akinc A, Langer R, Anderson DG (2010) Lipid-like materials for low-dose, in vivo gene silencing. Proc Natl Acad Sci 107:1864–1869

    Article  CAS  Google Scholar 

  178. Chen C-K, Law W-C, Aalinkeel R, Nair B, Kopwitthaya A, Mahajan SD, Reynolds JL, Zou J, Schwartz SA, Prasad PN, Cheng C (2012) Well-defined degradable cationic polylactide as nanocarrier for the delivery of siRNA to silence angiogenesis in prostate cancer. Adv Healthc Mater 1:751–761

    Article  CAS  Google Scholar 

  179. Chen CK, Jones CH, Mistriotis P, Yu Y, Ma XN, Ravikrishnan A, Jiang M, Andreadis ST, Pfeifer BA, Cheng C (2013) Poly(ethylene glycol)-block-cationic polylactide nanocomplexes of differing charge density for gene delivery. Biomaterials 34:9688–9699

    Article  CAS  Google Scholar 

  180. Chen CK, Law WC, Aalinkeel R, Yu Y, Nair B, Wu JC, Mahajan S, Reynolds JL, Li YK, Lai CK, Tzanakakis ES, Schwartz SA, Prasad PN, Cheng C (2014) Biodegradable cationic polymeric nanocapsules for overcoming multidrug resistance and enabling drug-gene co-delivery to cancer cells. Nanoscale 6:1567–1572

    Article  CAS  Google Scholar 

  181. Miyata K, Oba M, Nakanishi M, Fukushima S, Yamasaki Y, Koyama H, Nishiyama N, Kataoka K (2008) Polyplexes from poly(aspartamide) bearing 1,2-diaminoethane side chains induce pH-selective, endosomal membrane destabilization with amplified transfection and negligible cytotoxicity. J Am Chem Soc 130:16287–16294

    Article  CAS  Google Scholar 

  182. Uchida H, Miyata K, Oba M, Ishii T, Suma T, Itaka K, Nishiyama N, Kataoka K (2011) Odd-even effect of repeating aminoethylene units in the side chain of N-substituted polyaspartamides on gene transfection profiles. J Am Chem Soc 133:15524–15532

    Article  CAS  Google Scholar 

  183. Uchida H, Itaka K, Nomoto T, Ishii T, Suma T, Ikegami M, Miyata K, Oba M, Nishiyama N, Kataoka K (2014) Modulated protonation of side chain aminoethylene repeats in N-substituted polyaspartamides promotes mRNA transfection. J Am Chem Soc 136:12396–12405

    Article  CAS  Google Scholar 

  184. Christensen LV, Chang CW, Kim WJ, Kim SW, Zhong Z, Lin C, Engbersen JF, Feijen J (2006) Reducible poly(amido ethylenimine)s designed for triggered intracellular gene delivery. Bioconjugate Chem 17:1233–1240

    Article  CAS  Google Scholar 

  185. Hoon JJ, Christensen LV, Yockman JW, Zhong Z, Engbersen JF, Jong KW, Feijen J, Wan KS (2007) Reducible poly(amido ethylenimine) directed to enhance RNA interference. Biomaterials 28:1912–1917

    Article  CAS  Google Scholar 

  186. Wang XL, Jensen R, Lu ZR (2007) A novel environment-sensitive biodegradable polydisulfide with protonatable pendants for nucleic acid delivery. J Control Release 120:250–258

    Article  CAS  Google Scholar 

  187. Zintchenko A, Philipp A, Dehshahri A, Wagner E (2008) Simple modifications of branched PEI lead to highly efficient siRNA carriers with low toxicity. Bioconjugate Chem 19:1448–1455

    Article  CAS  Google Scholar 

  188. Creusat G, Rinaldi AS, Weiss E, Elbaghdadi R, Remy JS, Mulherkar R, Zuber G (2010) Proton sponge trick for pH-sensitive disassembly of polyethylenimine-based siRNA delivery systems. Bioconjugate Chem 21:994–1002

    Article  CAS  Google Scholar 

  189. Creusat G, Thomann JS, Maglott A, Pons B, Dontenwill M, Guerin E, Frisch B, Zuber G (2012) Pyridylthiourea-grafted polyethylenimine offers an effective assistance to siRNA-mediated gene silencing in vitro and in vivo. J Control Release 157:418–426

    Article  CAS  Google Scholar 

  190. Blessing T, Kursa M, Holzhauser R, Kircheis R, Wagner E (2001) Different strategies for formation of pegylated EGF-conjugated PEI/DNA complexes for targeted gene delivery. Bioconjugate Chem 12:529–537

    Article  CAS  Google Scholar 

  191. Merdan T, Kunath K, Petersen H, Bakowsky U, Voigt KH, Kopecek J, Kissel T (2005) PEGylation of poly(ethylene imine) affects stability of complexes with plasmid DNA under in vivo conditions in a dose-dependent manner after intravenous injection into mice. Bioconjugate Chem 16:785–792

    Article  CAS  Google Scholar 

  192. Miteva M, Kirkbride KC, Kilchrist KV, Werfel TA, Li HM, Nelson CE, Gupta MK, Giorgio TD, Duvall CL (2015) Tuning PEGylation of mixed micelles to overcome intracellular and systemic siRNA delivery barriers. Biomaterials 38:97–107

    Article  CAS  Google Scholar 

  193. Reineke TM, Davis ME (2003) Structural effects of carbohydrate-containing polycations on gene delivery. 2. Charge center type. Bioconjugate Chem 14:255–261

    Article  CAS  Google Scholar 

  194. Carlisle RC, Etrych T, Briggs SS, Preece JA, Ulbrich K, Seymour LW (2004) Polymer-coated polyethylenimine/DNA complexes designed for triggered activation by intracellular reduction. J Gene Med 6:337–344

    Article  CAS  Google Scholar 

  195. Ito T, Yoshihara C, Hamada K, Koyama Y (2010) DNA/polyethyleneimine/hyaluronic acid small complex particles and tumor suppression in mice. Biomaterials 31:2912–2918

    Article  CAS  Google Scholar 

  196. Hornof M, de la FM, Hallikainen M, Tammi RH, Urtti A (2008) Low molecular weight hyaluronan shielding of DNA/PEI polyplexes facilitates CD44 receptor mediated uptake in human corneal epithelial cells. J Gene Med 10:70–80

    Article  CAS  Google Scholar 

  197. Noga M, Edinger D, Rodl W, Wagner E, Winter G, Besheer A (2012) Controlled shielding and deshielding of gene delivery polyplexes using hydroxyethyl starch (HES) and alpha-amylase. J Control Release 159:92–103

    Article  CAS  Google Scholar 

  198. Heller P, Birke A, Huesmann D, Weber B, Fischer K, Reske-Kunz A, Bros M, Barz M (2014) Introducing PeptoPlexes: polylysine-block-polysarcosine based polyplexes for transfection of HEK 293T cells. Macromol Biosci 14:1380–1395

    Article  CAS  Google Scholar 

  199. Davis PB, Cooper MJ (2007) Vectors for airway gene delivery. AAPS J 9:E11–E17

    Article  Google Scholar 

  200. Schottler S, Becker G, Winzen S, Steinbach T, Mohr K, Landfester K, Mailander V, Wurm FR (2016) Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. Nat Nanotechnol 11:372–377

    Article  CAS  Google Scholar 

  201. Kukowska-Latallo JF, Raczka E, Quintana A, Chen C, Rymaszewski M, Baker JR Jr (2000) Intravascular and endobronchial DNA delivery to murine lung tissue using a novel, nonviral vector 999. Hum Gene Ther 11:1385–1395

    Article  CAS  Google Scholar 

  202. Okuda T, Sugiyama A, Niidome T, Aoyagi H (2004) Characters of dendritic poly(-lysine) analogues with the terminal lysines replaced with arginines and histidines as gene carriers in vitro. Biomaterials 25:537–544

    Article  CAS  Google Scholar 

  203. Schatzlein AG, Zinselmeyer BH, Elouzi A, Dufes C, Chim YTA, Roberts CJ, Davies MC, Munro A, Gray AI, Uchegbu IF (2005) Preferential liver gene expression with polypropylenimine dendrimers. J Control Release 101:247–258

    Article  CAS  Google Scholar 

  204. Kadlecova Z, Rajendra Y, Matasci M, Baldi L, Hacker DL, Wurm FM, Klok HA (2013) DNA delivery with hyperbranched polylysine: a comparative study with linear and dendritic polylysine. J Control Release 169:276–288

    Article  CAS  Google Scholar 

  205. Koppu S, Oh YJ, Edrada-Ebel R, Blatchford DR, Tetley L, Tate RJ, Dufes C (2010) Tumor regression after systemic administration of a novel tumor-targeted gene delivery system carrying a therapeutic plasmid DNA. J Control Release 143:215–221

    Article  CAS  Google Scholar 

  206. Fischer W, Calderon M, Schulz A, Andreou I, Weber M, Haag R (2010) Dendritic polyglycerols with oligoamine shells show low toxicity and high siRNA transfection efficiency in vitro. Bioconjugate Chem 21:1744–1752

    Article  CAS  Google Scholar 

  207. Frohlich T, Edinger D, Russ V, Wagner E (2012) Stabilization of polyplexes via polymer crosslinking for efficient siRNA delivery. Eur J Pharm Sci 47:914–920

    Article  CAS  Google Scholar 

  208. Russ V, Frohlich T, Li Y, Halama A, Ogris M, Wagner E (2010) Improved in vivo gene transfer into tumor tissue by stabilization of pseudodendritic oligoethylenimine-based polyplexes. J Gene Med 12:180–193

    CAS  Google Scholar 

  209. Klutz K, Russ V, Willhauck MJ, Wunderlich N, Zach C, Gildehaus FJ, Goke B, Wagner E, Ogris M, Spitzweg C (2009) Targeted radioiodine therapy of neuroblastoma tumors following systemic nonviral delivery of the sodium iodide symporter gene. Clin Cancer Res 15:6079–6086

    Article  CAS  Google Scholar 

  210. Russ V, Elfberg H, Thoma C, Kloeckner J, Ogris M, Wagner E (2008) Novel degradable oligoethylenimine acrylate ester-based pseudodendrimers for in vitro and in vivo gene transfer. Gene Ther 15:18–29

    Article  CAS  Google Scholar 

  211. Russ V, Gunther M, Halama A, Ogris M, Wagner E (2008) Oligoethylenimine-grafted polypropylenimine dendrimers as degradable and biocompatible synthetic vectors for gene delivery. J Control Release 132:131–140

    Article  CAS  Google Scholar 

  212. Leng Q, Scaria P, Zhu J, Ambulos N, Campbell P, Mixson AJ (2005) Highly branched HK peptides are effective carriers of siRNA. J Gene Med 7:977–986

    Article  CAS  Google Scholar 

  213. Stevenson M, Ramos-Perez V, Singh S, Soliman M, Preece JA, Briggs SS, Read ML, Seymour LW (2008) Delivery of siRNA mediated by histidine-containing reducible polycations. J Control Release 130:46–56

    Article  CAS  Google Scholar 

  214. Leng Q, Mixson AJ (2005) Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo. Cancer Gene Ther 12:682–690

    Article  CAS  Google Scholar 

  215. Hartmann L, Börner HG (2009) Precision polymers: monodisperse, monomer-sequence-defined segments to target future demands of polymers in medicine. Adv Mater 21:3425–3431

    Article  CAS  Google Scholar 

  216. Hartmann L, Krause E, Antonietti M, Borner HG (2006) Solid-phase supported polymer synthesis of sequence-defined, multifunctional poly(amidoamines). Biomacromolecules 7:1239–1244

    Article  CAS  Google Scholar 

  217. Schaffert D, Badgujar N, Wagner E (2011) Novel Fmoc-polyamino acids for solid-phase synthesis of defined polyamidoamines. Org Lett 13:1586–1589

    Article  CAS  Google Scholar 

  218. Salcher EE, Kos P, Frohlich T, Badgujar N, Scheible M, Wagner E (2012) Sequence-defined four-arm oligo(ethanamino)amides for pDNA and siRNA delivery: impact of building blocks on efficacy. J Control Release 164:380–386

    Article  CAS  Google Scholar 

  219. Schaffert D, Troiber C, Wagner E (2012) New sequence-defined polyaminoamides with tailored endosomolytic properties for plasmid DNA delivery. Bioconjugate Chem 23:1157–1165

    Article  CAS  Google Scholar 

  220. Schaffert D, Troiber C, Salcher EE, Frohlich T, Martin I, Badgujar N, Dohmen C, Edinger D, Klager R, Maiwald G, Farkasova K, Seeber S, Jahn-Hofmann K, Hadwiger P, Wagner E (2011) Solid-phase synthesis of sequence-defined T-, i-, and U-shape polymers for pDNA and siRNA delivery. Angew Chem Int Edit 50:8986–8989

    Article  CAS  Google Scholar 

  221. Scholz C, Kos P, Leclercq L, Jin X, Cottet H, Wagner E (2014) Correlation of length of linear oligo(ethanamino) amides with gene transfer and cytotoxicity. ChemMedChem 9:2104–2110

    Article  CAS  Google Scholar 

  222. Felgner PL, Barenholz Y, Behr JP, Cheng SH, Cullis P, Huang L, Jessee JA, Seymour L, Szoka F, Thierry AR, Wagner E, Wu G (1997) Nomenclature for synthetic gene delivery systems. Hum Gene Ther 8:511–512

    Article  CAS  Google Scholar 

  223. Plank C, Zelphati O, Mykhaylyk O (2011) Magnetically enhanced nucleic acid delivery. Ten years of magnetofection-progress and prospects. Adv Drug Deliver Rev 63:1300–1331

    Article  CAS  Google Scholar 

  224. Scherer F, Anton M, Schillinger U, Henke J, Bergemann C, Kruger A, Gansbacher B, Plank C (2002) Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo. Gene Ther 9:102–109

    Article  CAS  Google Scholar 

  225. Huttinger C, Hirschberger J, Jahnke A, Kostlin R, Brill T, Plank C, Kuchenhoff H, Krieger S, Schillinger U (2008) Neoadjuvant gene delivery of feline granulocyte-macrophage colony-stimulating factor using magnetofection for the treatment of feline fibrosarcomas: a phase I trial. J Gene Med 10:655–667

    Article  CAS  Google Scholar 

  226. Bates K, Kostarelos K (2013) Carbon nanotubes as vectors for gene therapy: past achievements, present challenges and future goals. Adv Drug Deliver Rev 65:2023–2033

    Article  CAS  Google Scholar 

  227. Feng L, Yang X, Shi X, Tan X, Peng R, Wang J, Liu Z (2013) Polyethylene glycol and polyethylenimine dual-functionalized nano-graphene oxide for photothermally enhanced gene delivery. Small 9:1989–1997

    Article  CAS  Google Scholar 

  228. Kim H, Namgung R, Singha K, Oh IK, Kim WJ (2011) Graphene oxide-polyethylenimine nanoconstruct as a gene delivery vector and bioimaging tool. Bioconjugate Chem 22:2558–2567

    Article  CAS  Google Scholar 

  229. Paul A, Hasan A, Kindi HA, Gaharwar AK, Rao VT, Nikkhah M, Shin SR, Krafft D, Dokmeci MR, Shum-Tim D, Khademhosseini A (2014) Injectable graphene oxide/hydrogel-based angiogenic gene delivery system for vasculogenesis and cardiac repair. ACS Nano 8:8050–8062

    Article  CAS  Google Scholar 

  230. Qin SY, Feng J, Rong L, Jia HZ, Chen S, Liu XJ, Luo GF, Zhuo RX, Zhang XZ (2014) Theranostic GO-based nanohybrid for tumor induced imaging and potential combinational tumor therapy. Small 10:599–608

    Article  CAS  Google Scholar 

  231. Zhang LM, Wang ZL, Lu ZX, Shen H, Huang J, Zhao QH, Liu M, He NY, Zhang ZJ (2013) PEGylated reduced graphene oxide as a superior ssRNA delivery system. J Mater Chem B 1:749–755

    Article  CAS  Google Scholar 

  232. Kim H, Kim WJ (2014) Photothermally controlled gene delivery by reduced graphene oxide-polyethylenimine nanocomposite. Small 10:117–126

    Article  CAS  Google Scholar 

  233. Hsieh TY, Huang WC, Kang YD, Chu CY, Liao WL, Chen YY, Chen SY (2016) Neurotensin-conjugated reduced graphene oxide with multi-stage near-infrared-triggered synergic targeted neuron gene transfection in vitro and in vivo for neurodegenerative disease therapy. Adv Healthc Mater 5:3016–3026

    Article  CAS  Google Scholar 

  234. Kim HJ, Takemoto H, Yi Y, Zheng M, Maeda Y, Chaya H, Hayashi K, Mi P, Pittella F, Christie RJ, Toh K, Matsumoto Y, Nishiyama N, Miyata K, Kataoka K (2014) Precise engineering of siRNA delivery vehicles to tumors using polyion complexes and gold nanoparticles. ACS Nano 8:8979–8991

    Article  CAS  Google Scholar 

  235. Yi Y, Kim HJ, Mi P, Zheng M, Takemoto H, Toh K, Kim BS, Hayashi K, Naito M, Matsumoto Y, Miyata K, Kataoka K (2016) Targeted systemic delivery of siRNA to cervical cancer model using cyclic RGD-installed unimer polyion complex-assembled gold nanoparticles. J Control Release 244:247–256

    Article  CAS  Google Scholar 

  236. Moller K, Muller K, Engelke H, Brauchle C, Wagner E, Bein T (2016) Highly efficient siRNA delivery from core-shell mesoporous silica nanoparticles with multifunctional polymer caps. Nanoscale 8:4007–4019

    Article  CAS  Google Scholar 

  237. Pittella F, Cabral H, Maeda Y, Mi P, Watanabe S, Takemoto H, Kim HJ, Nishiyama N, Miyata K, Kataoka K (2014) Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles. J Control Release 178:18–24

    Article  CAS  Google Scholar 

  238. Zuber G, Dauty E, Nothisen M, Belguise P, Behr JP (2001) Towards synthetic viruses. Adv Drug Deliver Rev 52:245–253

    Article  CAS  Google Scholar 

  239. Wagner E (2004) Strategies to improve DNA polyplexes for in vivo gene transfer: will “artificial viruses” be the answer? Pharm Res 21:8–14

    Article  CAS  Google Scholar 

  240. 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–E742

    Article  CAS  Google Scholar 

  241. Murthy N, Campbell J, Fausto N, Hoffman AS, Stayton PS (2003) Bioinspired pH-responsive polymers for the intracellular delivery of biomolecular drugs. Bioconjugate Chem 14:412–419

    Article  CAS  Google Scholar 

  242. Wagner E (2007) Programmed drug delivery: nanosystems for tumor targeting. Expert Opin Biol Th 7:587–593

    Article  CAS  Google Scholar 

  243. Kursa M, Walker GF, Roessler V, Ogris M, Roedl W, Kircheis R, Wagner E (2003) Novel shielded transferrin-polyethylene glycol-polyethylenimine/DNA complexes for systemic tumor-targeted gene transfer. Bioconjugate Chem 14:222–231

    Article  CAS  Google Scholar 

  244. Kircheis R, Kichler A, Wallner G, Kursa M, Ogris M, Felzmann T, Buchberger M, Wagner E (1997) Coupling of cell-binding ligands to polyethylenimine for targeted gene delivery. Gene Ther 4:409–418

    Article  CAS  Google Scholar 

  245. Murthy N, Campbell J, Fausto N, Hoffman AS, Stayton PS (2003) Design and synthesis of pH-responsive polymeric carriers that target uptake and enhance the intracellular delivery of oligonucleotides. J Control Release 89:365–374

    Article  CAS  Google Scholar 

  246. Knorr V, Allmendinger L, Walker GF, Paintner FF, Wagner E (2007) An acetal-based PEGylation reagent for pH-sensitive shielding of DNA polyplexes. Bioconjugate Chem 18:1218–1225

    Article  CAS  Google Scholar 

  247. Beckert L, Kostka L, Kessel E, Krhac Levacic A, Kostkova H, Etrych T, Lachelt U, Wagner E (2016) Acid-labile pHPMA modification of four-arm oligoaminoamide pDNA polyplexes balances shielding and gene transfer activity in vitro and in vivo. Eur J Pharm Biopharm 105:85–96

    Article  CAS  Google Scholar 

  248. Wagner E (2008) Converging paths of viral and non-viral vector engineering. Mol Ther 16:1–2

    Article  CAS  Google Scholar 

  249. Xu PS, Li SY, Li Q, Van Kirk EA, Ren J, Murdoch WJ, Zhang ZJ, Radosz M, Shen YQ (2008) Virion-mimicking nanocapsules from pH-controlled hierarchical self-assembly for gene delivery. Angew Chem Int Edit 47:1260–1264

    Article  CAS  Google Scholar 

  250. Wolff JA, Rozema DB (2008) Breaking the bonds: non-viral vectors become chemically dynamic. Mol Ther 16:8–15

    Article  CAS  Google Scholar 

  251. Meyer M, Philipp A, Oskuee R, Schmidt C, Wagner E (2008) Breathing life into polycations: functionalization with pH-responsive endosomolytic peptides and polyethylene glycol enables siRNA delivery. J Am Chem Soc 130:3272–3273

    Article  CAS  Google Scholar 

  252. Meyer M, Dohmen C, Philipp A, Kiener D, Maiwald G, Scheu C, Ogris M, Wagner E (2009) Synthesis and biological evaluation of a bioresponsive and endosomolytic siRNA-polymer conjugate. Mol Pharm 6:752–762

    Article  CAS  Google Scholar 

  253. Cheng Y, Yumul RC, Pun SH (2016) Virus-inspired polymer for efficient in vitro and in vivo gene delivery. Angew Chem Int Edit 55:12013–12017

    Article  CAS  Google Scholar 

  254. Butun V, Armes SP, Billingham NC (2001) Synthesis and aqueous solution properties of near-monodisperse tertiary amine methacrylate homopolymers and diblock copolymers. Polymer 42:5993–6008

    Article  CAS  Google Scholar 

  255. Wang D, Wang T, Liu J, Yu H, Jiao S, Feng B, Zhou F, Fu Y, Yin Q, Zhang P, Zhang Z, Zhou Z, Li Y (2016) Acid-activatable versatile micelleplexes for PD-L1 blockade-enhanced cancer photodynamic immunotherapy. Nano Lett 16:5503–5513

    Article  CAS  Google Scholar 

  256. Alfarouk KO, Muddathir AK, Shayoub MEA (2011) Tumor Acidity as Evolutionary Spite. Cancers 3:408–414

    Article  Google Scholar 

  257. Cardone RA, Casavola V, Reshkin SJ (2005) The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer 5:786–795

    Article  CAS  Google Scholar 

  258. Sun CY, Shen S, Xu CF, Li HJ, Liu Y, Cao ZT, Yang XZ, Xia JX, Wang J (2015) Tumor acidity-sensitive polymeric vector for active targeted siRNA delivery. J Am Chem Soc 137:15217–15224

    Article  CAS  Google Scholar 

  259. Choi S, Lee KD (2008) Enhanced gene delivery using disulfide-crosslinked low molecular weight polyethylenimine with listeriolysin o-polyethylenimine disulfide conjugate. J Control Release 131:70–76

    Article  CAS  Google Scholar 

  260. Klein PM, Wagner E (2014) Bioreducible polycations as shuttles for therapeutic nucleic acid and protein transfection. Antioxid Redox Sign 21:804–817

    Article  CAS  Google Scholar 

  261. Klein PM, Reinhard S, Lee DJ, Muller K, Ponader D, Hartmann L, Wagner E (2016) Precise redox-sensitive cleavage sites for improved bioactivity of siRNA lipopolyplexes. Nanoscale 8:18098–18104

    Article  CAS  Google Scholar 

  262. McKenzie DL, Kwok KY, Rice KG (2000) A potent new class of reductively activated peptide gene delivery agents. J Biol Chem 275:9970–9977

    Article  CAS  Google Scholar 

  263. Read ML, Bremner KH, Oupicky D, Green NK, Searle PF, Seymour LW (2003) Vectors based on reducible polycations facilitate intracellular release of nucleic acids. J Gene Med 5:232–245

    Article  CAS  Google Scholar 

  264. Chen X, Bai Y, Zaro JL, Shen WC (2010) Design of an in vivo cleavable disulfide linker in recombinant fusion proteins. Biotechniques 49:513–518

    Article  CAS  Google Scholar 

  265. Brulisauer L, Kathriner N, Prenrecaj M, Gauthier MA, Leroux JC (2012) Tracking the bioreduction of disulfide-containing cationic dendrimers. Angew Chem Int Edit 51:12454–12458

    Article  CAS  Google Scholar 

  266. Cerritelli S, Velluto D, Hubbell JA (2007) PEG-SS-PPS: reduction-sensitive disulfide block copolymer vesicles for intracellular drug delivery. Biomacromolecules 8:1966–1972

    Article  CAS  Google Scholar 

  267. Sun H, Guo B, Cheng R, Meng F, Liu H, Zhong Z (2009) Biodegradable micelles with sheddable poly(ethylene glycol) shells for triggered intracellular release of doxorubicin. Biomaterials 30:6358–6366

    Article  CAS  Google Scholar 

  268. Zhu CH, Zheng M, Meng FH, Mickler FM, Ruthardt N, Zhu XL, Zhong ZY (2012) Reversibly shielded DNA polyplexes based on bioreducible PDMAEMA-SS-PEG-SS-PDMAEMA triblock copolymers mediate markedly enhanced nonviral gene transfection. Biomacromolecules 13:769–778

    Article  CAS  Google Scholar 

  269. Zanta MA, Belguise VP, Behr JP (1999) Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus. Proc Natl Acad Sci 96:91–96

    Article  CAS  Google Scholar 

  270. van der Aa MA, Koning GA, d’Oliveira C, Oosting RS, Wilschut KJ, Hennink WE, Crommelin DJ (2005) An NLS peptide covalently linked to linear DNA does not enhance transfection efficiency of cationic polymer based gene delivery systems. J Gene Med 7:208–217

    Article  CAS  Google Scholar 

  271. Remaut K, Symens N, Lucas B, Demeester J, De Smedt SC (2014) Cell division responsive peptides for optimized plasmid DNA delivery: the mitotic window of opportunity? J Control Release 179:1–9

    Article  CAS  Google Scholar 

  272. Andersen H, Parhamifar L, Hunter AC, Shahin V, Moghimi SM (2016) AFM visualization of sub-50 nm polyplex disposition to the nuclear pore complex without compromising the integrity of the nuclear envelope. J Control Release 244:24–29

    Article  CAS  Google Scholar 

  273. Martin I, Dohmen C, Mas-Moruno C, Troiber C, Kos P, Schaffert D, Lachelt U, Teixido M, Günther M, Kessler H, Giralt E, Wagner E (2012) Solid-phase-assisted synthesis of targeting peptide-PEG-oligo(ethane amino)amides for receptor-mediated gene delivery. Org Biomol Chem 10:3258–3268

    Article  CAS  Google Scholar 

  274. Lachelt U, Wittmann V, Muller K, Edinger D, Kos P, Hohn M, Wagner E (2014) Synthetic polyglutamylation of dual-functional MTX ligands for enhanced combined cytotoxicity of poly(I:C) nanoplexes. Mol Pharm 11:2631–2639

    Article  CAS  Google Scholar 

  275. Zhang CY, Kos P, Muller K, Schrimpf W, Troiber C, Lachelt U, Scholz C, Lamb DC, Wagner E (2014) Native chemical ligation for conversion of sequence-defined oligomers into targeted pDNA and siRNA carriers. J Control Release 180:42–50

    Article  CAS  Google Scholar 

  276. Fröhlich T, Edinger D, Kläger R, Troiber C, Salcher E, Badgujar N, Martin I, Schaffert D, Cengizeroglu A, Hadwiger P, Vornlocher HP, Wagner E (2012) Structure-activity relationships of siRNA carriers based on sequence-defined oligo (ethane amino) amides. J Control Release 160:532–541

    Article  CAS  Google Scholar 

  277. Troiber C, Edinger D, Kos P, Schreiner L, Klager R, Herrmann A, Wagner E (2013) Stabilizing effect of tyrosine trimers on pDNA and siRNA polyplexes. Biomaterials 34:1624–1633

    Article  CAS  Google Scholar 

  278. Whitehead KA, Dorkin JR, Vegas AJ, Chang PH, Veiseh O, Matthews J, Fenton OS, Zhang Y, Olejnik KT, Yesilyurt V, Chen D, Barros S, Klebanov B, Novobrantseva T, Langer R, Anderson DG (2014) Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity. Nat Commun 5:4277

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Peng Zhang appreciates receiving China Scholarship Council fellowships as support to his PhD studies at Ludwig-Maximilians-Universität München, Germany. We also acknowledge the financial support by the DFG Excellence Cluster Nanosystems Initiative Munich (NIM) and SinoGermanCenter Grant GZ995.

Author information

Authors and Affiliations

  1. Pharmaceutical Biotechnology, Center for System-Based Drug Research Ludwig-Maximilians-Universität, 81377, Munich, Germany

    Peng Zhang & Ernst Wagner

  2. Nanosystems Initiative Munich (NIM), 80799, Munich, Germany

    Peng Zhang & Ernst Wagner

  3. Center for NanoScience (CeNS), Ludwig-Maximilians-Universität, 80799, Munich, Germany

    Ernst Wagner

Authors
  1. Peng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ernst Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peng Zhang.

Additional information

This article is part of the Topical Collection “Polymeric Gene Delivery Systems”; edited by Yiyun Cheng.

Communicated by: Yiyun Cheng.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, P., Wagner, E. History of Polymeric Gene Delivery Systems. Top Curr Chem (Z) 375, 26 (2017). https://doi.org/10.1007/s41061-017-0112-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s41061-017-0112-0

Keywords

Search

Navigation