Polyethylenimine-based non-viral gene delivery systems

U. Lungwitz1, M. Breunig1, T. Blunk1, A. Göpferich1
1Department of Pharmacy and Chemistry, Pharmaceutical Technology Unit, University of Regensburg, Regensburg, Germany

Tài liệu tham khảo

Ferrari, 1999, Polyethylenimine shows properties of interest for cystic fibrosis gene therapy, Biochim. Biophys. Acta, 1447, 219, 10.1016/S0167-4781(99)00153-0 Fajac, 1999, Sugar-mediated uptake of glycosylated polylysines and gene transfer into normal and cystic fibrosis airway epithelial cells, Hum. Gene Ther., 10, 395, 10.1089/10430349950018841 Olefsky, 2000, Diabetes: gene therapy for rats and mice, Nature (London), 408, 420, 10.1038/35044177 Song, 2004, Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice, Gene Ther., 11, 181, 10.1038/sj.gt.3302156 El Aneed, 2004, An overview of current delivery systems in cancer gene therapy, J. Controll. Rel., 94, 1, 10.1016/j.jconrel.2003.09.013 Merdan, 2002, Prospects for cationic polymers in gene and oligonucleotide therapy against cancer, Adv. Drug Deliv. Rev., 54, 715, 10.1016/S0169-409X(02)00046-7 Aigner, 2002, Delivery of unmodified bioactive ribozymes by an RNA-stabilizing polyethylenimine (LMW-PEI) efficiently down-regulates gene expression, Gene Ther., 9, 1700, 10.1038/sj.gt.3301839 Wall, 2003, Small RNA: can RNA interference be exploited for therapy?, Lancet, 362, 1401, 10.1016/S0140-6736(03)14637-5 Iwai, 2002, Polyethylenimine-mediated suicide gene transfer induces a therapeutic effect for hepatocellular carcinoma in vivo by using an Epstein–Barr virus-based plasmid vector*1, Biochem. Biophys. Res. Commun., 291, 48, 10.1006/bbrc.2002.6383 Lehrman, 1999, Virus treatment questioned after gene therapy death, Nature, 401, 517, 10.1038/43977 Liu, 2003, Molecular basis of the inflammatory response to adenovirus vectors, Gene Ther., 10, 935, 10.1038/sj.gt.3302036 Sun, 2003, Immune responses to adeno-associated virus and its recombinant vectors, Gene Ther., 10, 964, 10.1038/sj.gt.3302039 Donahue, 1992, Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer, J. Exp. Med., 176, 1125, 10.1084/jem.176.4.1125 Gore, 2003, Adverse effects of gene therapy: gene therapy can cause leukaemia: no shock, mild horror but a probe, Gene Ther., 10, 4, 10.1038/sj.gt.3301946 Mansouri, 2004, Chitosan–DNA nanoparticles as non-viral vectors in gene therapy: strategies to improve transfection efficacy, Eur. J. Pharm. Biopharm., 57, 1, 10.1016/S0939-6411(03)00155-3 Kumar, 2003, Cationic transfection lipids in gene therapy: successes, set-backs, challenges and promises, Curr. Med. Chem., 10, 1297, 10.2174/0929867033457458 Zhao, 2003, Polyphosphoesters in drug and gene delivery, Adv. Drug Deliv. Rev., 55, 483, 10.1016/S0169-409X(03)00040-1 Davis, 2002, Non-viral gene delivery systems, Curr. Opin. Biotechnol., 13, 128, 10.1016/S0958-1669(02)00294-X Boussif, 1995, A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine, Proc. Natl Acad. Sci. USA, 92, 7297, 10.1073/pnas.92.16.7297 Godbey, 1999, Poly(ethylenimine) and its role in gene delivery, J. Controll. Rel., 60, 149, 10.1016/S0168-3659(99)00090-5 Godbey, 2000, Poly(ethylenimine)-mediated gene delivery affects endothelial cell function and viability, Biomaterials, 22, 471, 10.1016/S0142-9612(00)00203-9 Helander, 1997, Polyethyleneimine is an effective permeabilizer of Gram-negative bacteria, Microbiology (Reading, UK), 143, 3193, 10.1099/00221287-143-10-3193 Mislick, 1996, Evidence for the role of proteoglycans in cation-mediated gene transfer, Proc. Natl Acad. Sci. USA, 93, 12349, 10.1073/pnas.93.22.12349 Labat-Moleur, 1996, An electron microscopy study into the mechanism of gene transfer with lipopolyamines, Gene Ther., 3, 1010 Behr, 1994, Gene transfer with synthetic cationic amphiphiles: prospects for gene therapy, Bioconjugate Chem., 5, 382, 10.1021/bc00029a002 Remy, 1998, Gene transfer with lipospermines and polyethylenimines, Adv. Drug Deliv. Rev., 30, 85, 10.1016/S0169-409X(97)00109-9 Godbey, 1999, Tracking the intracellular path of poly(ethylenimine)/DNA complexes for gene delivery, Proc. Natl Acad. Sci. USA, 96, 5177, 10.1073/pnas.96.9.5177 Remy-Kristensen, 2001, Role of endocytosis in the transfection of L929 fibroblasts by polyethylenimine/DNA complexes, Biochim. Biophys. Acta, 1514, 21, 10.1016/S0005-2736(01)00359-5 Ogris, 2000, A versatile assay to study cellular uptake of gene transfer complexes by flow cytometry, Biochim. Biophys. Acta (BBA)—Gen. Subjects, 1474, 237, 10.1016/S0304-4165(00)00018-0 Bieber, 2002, Intracellular route and transcriptional competence of polyethylenimine–DNA complexes, J. Controll. Rel., 82, 441, 10.1016/S0168-3659(02)00129-3 Mellman, 1996, Endocytosis and molecular sorting, Annu. Rev. Cell Dev. Biol., 12, 575, 10.1146/annurev.cellbio.12.1.575 Brunner, 2000, Cell cycle dependence of gene transfer by lipoplex, polyplex and recombinant adenovirus, Gene Ther., 7, 401, 10.1038/sj.gt.3301102 Frankel, 1988, Cellular uptake of the tat protein from human immunodeficiency virus, Cell, 55, 1189, 10.1016/0092-8674(88)90263-2 Elliott, 1997, Intercellular trafficking and protein delivery by a herpesvirus structural protein, Cell, 88, 223, 10.1016/S0092-8674(00)81843-7 Ho, 2001, Synthetic protein transduction domains: enhanced transduction potential in vitro and in vivo, Cancer Res., 61, 474 Gebhart, 2001, Evaluation of polyplexes as gene transfer agents, J. Controll. Rel., 73, 401, 10.1016/S0168-3659(01)00357-1 Bandyopadhyay, 1999, Nucleotide exchange in genomic DNA of rat hepatocytes using RNA/DNA oligonucleotides. Targeted delivery of liposomes and polyethyleneimine to the asialoglycoprotein receptor, J. Biol. Chem., 274, 10163, 10.1074/jbc.274.15.10163 von Harpe, 2000, Characterization of commercially available and synthesized polyethylenimines for gene delivery, J. Controll. Rel., 69, 309, 10.1016/S0168-3659(00)00317-5 Kunath, 2003, Low-molecular-weight polyethylenimine as a non-viral vector for DNA delivery: comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecular-weight polyethylenimine, J. Controll. Rel., 89, 113, 10.1016/S0168-3659(03)00076-2 Fischer, 1999, A novel non-viral vector for DNA delivery based on low molecular weight, branched polyethylenimine: effect of molecular weight on transfection efficiency and cytotoxicity, Pharm. Res., 16, 1273, 10.1023/A:1014861900478 Jones, 1944, The polymerization of ethylenimine, J. Org. Chem., 9, 125, 10.1021/jo01184a002 Dick, 1970, Characterization of polyethylenimine, J. Macromol. Sci. Chem., 4, 1301, 10.1080/00222337008081731 Godbey, 1999, Size matters: molecular weight affects the efficiency of poly(ethylenimine) as a gene delivery vehicle, J. Biomed. Mater. Res., 45, 268, 10.1002/(SICI)1097-4636(19990605)45:3<268::AID-JBM15>3.0.CO;2-Q Turunen, 1999, Efficient adventitial gene delivery to rabbit carotid artery with cationic polymer–plasmid complexes, Gene Ther., 6, 6, 10.1038/sj.gt.3300800 Suh, 1994, Ionization of poly(ethylenimine) and poly(allylamine) at various pH's, Bioorg. Chem., 22, 318, 10.1006/bioo.1994.1025 Oh, 2002, Polyethylenimine-mediated cellular uptake, nucleus trafficking and expression of cytokine plasmid DNA, Gene Ther., 9, 1627, 10.1038/sj.gt.3301735 Ogris, 1998, The size of DNA/transferrin–PEI complexes is an important factor for gene expression in cultured cells, Gene Ther., 5, 1425, 10.1038/sj.gt.3300745 Clamme, 2003, Intracellular dynamics of the gene delivery vehicle polyethylenimine during transfection: investigation by two-photon fluorescence correlation spectroscopy, Biochim. Biophys. Acta, 1617, 52, 10.1016/j.bbamem.2003.09.002 Regnstroem, 2003, PEI—a potent, but not harmless, mucosal immuno-stimulator of mixed T-helper cell response and FasL-mediated cell death in mice, Gene Ther., 10, 1575, 10.1038/sj.gt.3302054 Gharwan, 2003, Non-viral gene transfer into fetal mouse livers (a comparison between the cationic polymer PEI and naked DNA), Gene Ther., 10, 810, 10.1038/sj.gt.3301954 Wightman, 2001, Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo, J. Gene Med., 3, 362, 10.1002/jgm.187 Brunner, 2002, Overcoming the nuclear barrier: cell cycle independent non-viral gene transfer with linear polyethylenimine or electroporation, Mol. Ther., 5, 80, 10.1006/mthe.2001.0509 Wiseman, 2003, A comparison of linear and branched polyethylenimine (PEI) with DCChol/DOPE liposomes for gene delivery to epithelial cells in vitro and in vivo, Gene Ther., 10, 1654, 10.1038/sj.gt.3302050 Weyts, 1988, New synthesis of linear poly(ethylenimine), Polym. Bull. (Berlin), 19, 13, 10.1007/BF00255018 Saegusa, 1972, Isomerization polymerization of 2-oxazoline. I. Preparation of unsubstituted 2-oxazoline polymer, Polym. J. (Tokyo), 3, 35, 10.1295/polymj.3.35 Saegusa, 1972, Isomerization polymerization of 2-oxazoline. IV. Kinetic study of 2-methyl-2-oxazoline polymerization, Macromolecules, 5, 359, 10.1021/ma60028a005 Brissault, 2003, Synthesis of linear polyethylenimine derivatives for DNA transfection, Bioconjugate Chem., 14, 581, 10.1021/bc0200529 Jeong, 2001, DNA transfection using linear poly(ethylenimine) prepared by controlled acid hydrolysis of poly(2-ethyl-2-oxazoline), J. Controll. Rel., 73, 391, 10.1016/S0168-3659(01)00310-8 Goula, 1998, Size, diffusibility and transfection performance of linear PEI/DNA complexes in the mouse central nervous system, Gene Ther., 5, 712, 10.1038/sj.gt.3300635 Blessing, 2001, Different strategies for formation of pegylated EGF-conjugated PEI/DNA complexes for targeted gene delivery, Bioconjugate Chem., 12, 529, 10.1021/bc0001488 Zou, 2000, Systemic linear polyethylenimine (L-PEI)-mediated gene delivery in the mouse, J. Gene Med., 2, 128, 10.1002/(SICI)1521-2254(200003/04)2:2<128::AID-JGM95>3.0.CO;2-W Klemm, 1998, Effects of polyethyleneimine on endocytosis and lysosome stability, Biochem. Pharmacol., 56, 41, 10.1016/S0006-2952(98)00098-7 Zhang, 2000, High-generation polycationic dendrimers are unusually effective at disrupting anionic vesicles: membrane bending model, Bioconjugate Chem., 11, 805, 10.1021/bc000018z Forrest, 2002, On the kinetics of polyplex endocytic trafficking: implications for gene delivery vector design, Mol. Ther., 6, 57, 10.1006/mthe.2002.0631 Kichler, 2001, Polyethylenimine-mediated gene delivery: a mechanistic study, J. Gene Med., 3, 135, 10.1002/jgm.173 Merdan, 2002, Intracellular processing of poly(ethylene imine)/ribozyme complexes can be observed in living cells by using confocal laser scanning microscopy and inhibitor experiments, Pharm. Res., 19, 140, 10.1023/A:1014212630566 Wattiaux, 2000, Endosomes, lysosomes: their implication in gene transfer, Adv. Drug Deliv. Rev., 41, 201, 10.1016/S0169-409X(99)00066-6 Russell, 2000, Update on adenovirus and its vectors, J. Gen. Virol., 81, 2573, 10.1099/0022-1317-81-11-2573 Bischof, 1999, Transient transfection of mammary epithelial cells with a PEI/DNA/adenovirus system, Biol. Chem., 380, 269, 10.1515/BC.1999.036 Baker, 1997, Polyethylenimine (PEI) is a simple, inexpensive and effective reagent for condensing and linking plasmid DNA to adenovirus for gene delivery, Gene Ther., 4, 773, 10.1038/sj.gt.3300471 Gottschalk, 1996, A novel DNA–peptide complex for efficient gene transfer and expression in mammalian cells, Gene Ther., 3, 448 Smith, 1998, Synthetic peptide-based DNA complexes for non-viral gene delivery, Adv. Drug Deliv. Rev., 30, 115, 10.1016/S0169-409X(97)00111-7 Lear, 1987, Membrane binding and conformational properties of peptides representing the NH2 terminus of influenza HA-2, J. Biol. Chem., 262, 6500, 10.1016/S0021-9258(18)48270-1 Plank, 1994, The influence of endosome-disruptive peptides on gene transfer using synthetic virus-like gene transfer systems, J. Biol. Chem., 269, 12918, 10.1016/S0021-9258(18)99963-1 Wolfert, 1998, Chloroquine and amphipathic peptide helixes show synergistic transfection in vitro, Gene Ther., 5, 409, 10.1038/sj.gt.3300606 Wagner, 1999, Application of membrane-active peptides for non-viral gene delivery, Adv. Drug Deliv. Rev., 38, 279, 10.1016/S0169-409X(99)00033-2 Subbarao, 1987, pH-dependent bilayer destabilization by an amphipathic peptide, Biochemistry, 26, 2964, 10.1021/bi00385a002 Parente, 1988, pH-dependent fusion of phosphatidylcholine small vesicles. Induction by a synthetic amphipathic peptide, J. Biol. Chem., 263, 4724, 10.1016/S0021-9258(18)68843-X Fattal, 1994, Pore-forming peptides induce rapid phospholipid flip–flop in membranes, Biochemistry, 33, 6721, 10.1021/bi00187a044 Nicol, 1999, Orientation of the pore-forming peptide GALA in POPC vesicles determined by a BODIPY-avidin/biotin binding assay, Biophys. J., 76, 2121, 10.1016/S0006-3495(99)77368-6 Kircheis, 1997, Coupling of cell-binding ligands to polyethylenimine for targeted gene delivery, Gene Ther., 4, 409, 10.1038/sj.gt.3300418 Lee, 2001, A new gene delivery formulation of polyethylenimine/DNA complexes coated with PEG-conjugated fusogenic peptide, J. Controll. Rel., 76, 183, 10.1016/S0168-3659(01)00426-6 Wyman, 1997, Design, synthesis, and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers, Biochemistry, 36, 3008, 10.1021/bi9618474 Felgner, 1997, Nomenclature for synthetic gene delivery systems, Hum. Gene Ther., 8, 511, 10.1089/hum.1997.8.5-511 Pouton, 1998, Polycation–DNA complexes for gene delivery: a comparison of the biopharmaceutical properties of cationic polypeptides and cationic lipids, J. Controll. Rel., 53, 289, 10.1016/S0168-3659(98)00015-7 Erbacher, 1996, Putative role of chloroquine in gene transfer into a human hepatoma cell line by DNA/lactosylated polylysine complexes, Exp. Cell Res., 225, 186, 10.1006/excr.1996.0169 Dean, 1997, Import of plasmid DNA into the nucleus is sequence specific, Exp. Cell Res., 230, 293, 10.1006/excr.1996.3427 Lukacs, 2000, Size-dependent DNA mobility in cytoplasm and nucleus, J. Biol. Chem., 275, 1625, 10.1074/jbc.275.3.1625 Lechardeur, 1999, Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer, Gene Ther., 6, 482, 10.1038/sj.gt.3300867 Pollard, 2001, Ca2+-sensitive cytosolic nucleases prevent efficient delivery to the nucleus of injected plasmids, J. Gene Med., 3, 153, 10.1002/jgm.160 Pollard, 1998, Polyethylenimine but not cationic lipids promotes transgene delivery to the nucleus in mammalian cells, J. Biol. Chem., 273, 7507, 10.1074/jbc.273.13.7507 Talcott, 1999, Getting across the nuclear pore complex, Trends Cell Biol., 9, 312, 10.1016/S0962-8924(99)01608-6 Bottger, 1998, Acid nuclear extracts as mediators of gene transfer and expression, Biochim. Biophys. Acta, 1395, 78, 10.1016/S0167-4781(97)00128-0 Feldherr, 1991, Signal-mediated nuclear transport in proliferating and growth-arrested BALB/c 3T3 cells, J. Cell Biol., 115, 933, 10.1083/jcb.115.4.933 Kreiss, 1999, Plasmid DNA size does not affect the physicochemical properties of lipoplexes but modulates gene transfer efficiency, Nucl. Acids Res., 27, 3792, 10.1093/nar/27.19.3792 Walker, 2004, The effects of plasmid copy number and sequence context upon transfection efficiency, J. Controll. Rel., 94, 245, 10.1016/j.jconrel.2003.10.003 Adam, 1994, Identification of cytosolic factors required for nuclear location sequence-mediated binding to the nuclear envelope, J. Cell Biol., 125, 547, 10.1083/jcb.125.3.547 Radu, 1995, Identification of a protein complex that is required for nuclear protein import and mediates docking of import substrate to distinct nucleoporins, Proc. Natl Acad. Sci. USA, 92, 1769, 10.1073/pnas.92.5.1769 Moroianu, 1995, Previously identified protein of uncertain function is karyopherin a and together with karyopherin b docks import substrate at nuclear pore complexes, Proc. Natl Acad. Sci. USA, 92, 2008, 10.1073/pnas.92.6.2008 Wozniak, 1998, Karyopherins and kissing cousins, Trends Cell Biol., 8, 184, 10.1016/S0962-8924(98)01248-3 Cartier, 2002, Utilization of synthetic peptides containing nuclear localization signals for non-viral gene transfer systems, Gene Ther., 9, 157, 10.1038/sj.gt.3301635 Moore, 1994, Purification of a Ran-interacting protein that is required for protein import into the nucleus, Proc. Natl Acad. Sci. USA, 91, 10212, 10.1073/pnas.91.21.10212 Melchior, 1993, Inhibition of nuclear protein import by non-hydrolyzable analogs of GTP and identification of the small GTPase Ran/TC4 as an essential transport factor, J. Cell Biol., 123, 1649, 10.1083/jcb.123.6.1649 Hebert, 2003, Improvement of exogenous DNA nuclear importation by nuclear localization signal-bearing vectors: a promising way for non-viral gene therapy?, Biol. Cell, 95, 59, 10.1016/S0248-4900(03)00007-8 Nakanishi, 2001, Nuclear targeting of DNA, Eur. J. Pharm. Sci., 13, 17, 10.1016/S0928-0987(00)00203-7 Dowty, 1995, Plasmid DNA entry into postmitotic nuclei of primary rat myotubes, Proc. Natl Acad. Sci. USA, 92, 4572, 10.1073/pnas.92.10.4572 Schwartz, 1999, Synthetic DNA-compacting peptides derived from human sequence enhance cationic lipid-mediated gene transfer in vitro and in vivo, Gene Ther., 6, 282, 10.1038/sj.gt.3300795 Chan, 2001, Enhancement of MSH receptor- and GAL4-mediated gene transfer by switching the nuclear import pathway, Gene Ther., 8, 166, 10.1038/sj.gt.3301366 Nagasaki, 2003, Can nuclear localization signals enhance nuclear localization of plasmid DNA?, Bioconjugate Chem., 14, 282, 10.1021/bc025602h Morris, 1997, A new peptide vector for efficient delivery of oligonucleotides into mammalian cells, Nucl. Acids Res., 25, 2730, 10.1093/nar/25.14.2730 Chan, 1999, Enhancement of polylysine-mediated transferrinfection by nuclear localization sequences: polylysine does not function as a nuclear localization sequence, Hum. Gene Ther., 10, 1695, 10.1089/10430349950017699 Chan, 2000, Supramolecular structure and nuclear targeting efficiency determine the enhancement of transfection by modified polylysines, Gene Ther., 7, 1690, 10.1038/sj.gt.3301275 Fontes, 2000, Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-alpha, J. Mol. Biol., 297, 1183, 10.1006/jmbi.2000.3642 Vaysse, 2002, Proteolipidic vectors for gene transfer to the lung, Biochem. Biophys. Res. Commun., 290, 1489, 10.1006/bbrc.2002.6343 Fritz, 1996, Gene transfer into mammalian cells using histone-condensed plasmid DNA, Hum. Gene Ther., 7, 1395, 10.1089/hum.1996.7.12-1395 Namiki, 1998, Gene transduction for disseminated intraperitoneal tumor using cationic liposomes containing non-histone chromatin proteins: cationic liposomal gene therapy of carcinomatosa, Gene Ther., 5, 240, 10.1038/sj.gt.3300577 Chan, 1998, Mutual exclusivity of DNA binding and nuclear localization signal recognition by the yeast transcription factor GAL4: implications for non-viral DNA delivery, Gene Ther., 5, 1204, 10.1038/sj.gt.3300708 Siomi, 1995, A nuclear localization domain in the hnRNP A1 protein, J. Cell Biol., 129, 551, 10.1083/jcb.129.3.551 Nakielny, 1996, Transportin: nuclear transport receptor of a novel nuclear protein import pathway, Exp. Cell Res., 229, 261, 10.1006/excr.1996.0369 Dean, 1999, Sequence requirements for plasmid nuclear import, Exp. Cell Res., 253, 713, 10.1006/excr.1999.4716 Li, 2001, Muscle-specific enhancement of gene expression by incorporation of SV40 enhancer in the expression plasmid, Gene Ther., 8, 494, 10.1038/sj.gt.3301419 Young, 2003, Effect of a DNA nuclear targeting sequence on gene transfer and expression of plasmids in the intact vasculature, Gene Ther., 10, 1465, 10.1038/sj.gt.3302021 Vacik, 1999, Cell-specific nuclear import of plasmid DNA, Gene Ther., 6, 1006, 10.1038/sj.gt.3300924 Mesika, 2001, A regulated, NF[kappa]B-assisted import of plasmid DNA into mammalian cell nuclei, Mol. Ther., 3, 653, 10.1006/mthe.2001.0312 Dworetzky, 1988, The effects of variations in the number and sequence of targeting signals on nuclear uptake, J. Cell Biol., 107, 1279, 10.1083/jcb.107.4.1279 Rebuffat, 2002, Gene delivery by a steroid-peptide nucleic acid conjugate, Fed. Am. Soc. Exp. Boil. J., 16, 1426 Brisson, 1999, Subcellular trafficking of the cytoplasmic expression system, Hum. Gene Ther., 10, 2601, 10.1089/10430349950016645 Zanta, 1999, Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus, Proc. Natl Acad. Sci. USA, 96, 91, 10.1073/pnas.96.1.91 Carlisle, 2001, Adenovirus hexon protein enhances nuclear delivery and increases transgene expression of polyethylenimine/plasmid DNA vectors, Mol. Ther., 4, 473, 10.1006/mthe.2001.0472 Itaka, 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, 10.1002/jgm.470 Ludtke, 2002, The effect of cell division on the cellular dynamics of microinjected DNA and dextran, Mol. Ther., 5, 579, 10.1006/mthe.2002.0581 Coonrod, 1997, On the mechanism of DNA transfection: efficient gene transfer without viruses, Gene Ther., 4, 1313, 10.1038/sj.gt.3300536 Ogris, 2003, Tumor-targeted gene therapy: strategies for the preparation of ligand–polyethylene glycol–polyethylenimine/DNA complexes, J. Controll. Rel., 91, 173, 10.1016/S0168-3659(03)00230-X Kursa, 2003, Novel shielded transferrin–polyethylene glycol–polyethylenimine/DNA complexes for systemic tumor-targeted gene transfer, Bioconjugate Chem., 14, 222, 10.1021/bc0256087 Plank, 1996, Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery, Hum. Gene Ther., 7, 1437, 10.1089/hum.1996.7.12-1437 Ahn, 2002, Biodegradable poly(ethylenimine) for plasmid DNA delivery, J. Controll. Rel., 80, 273, 10.1016/S0168-3659(01)00547-8 Vinogradov, 1998, Self-assembly of polyamine–poly(ethylene glycol) copolymers with phosphorothioate oligonucleotides, Bioconjugate Chem., 9, 805, 10.1021/bc980048q Tang, 2003, Polyethylene glycol modified polyethylenimine for improved CNS gene transfer: effects of PEGylation extent, Biomaterials, 24, 2351, 10.1016/S0142-9612(03)00029-2 Nguyen, 2000, Evaluation of polyether–polyethylenimine graft copolymers as gene transfer agents, Gene Ther., 7, 126, 10.1038/sj.gt.3301052 Ogris, 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, 10.1038/sj.gt.3300900 Petersen, 2002, Polyethylenimine-graft-poly(ethylene glycol) copolymers: influence of copolymer block structure on DNA complexation and biological activities as gene delivery system, Bioconjugate Chem., 13, 845, 10.1021/bc025529v Petersen, 2002, Synthesis, characterization, and biocompatibility of polyethylenimine-graft-poly(ethylene glycol) block copolymers, Macromolecules, 35, 6867, 10.1021/ma012060a Kircheis, 1999, Polycation-based DNA complexes for tumor-targeted gene delivery in vivo, J. Gene Med., 1, 111, 10.1002/(SICI)1521-2254(199903/04)1:2<111::AID-JGM22>3.0.CO;2-Y Ochietti, 2002, Inducing neutrophil recruitment in the liver of ICAM-1-deficient mice using polyethyleneimine grafted with Pluronic P123 as an organ-specific carrier for transgenic ICAM-1, Gene Ther., 9, 939, 10.1038/sj.gt.3301716 Trubetskoy, 2003, Recharging cationic DNA complexes with highly charged polyanions for in vitro and in vivo gene delivery, Gene Ther., 10, 261, 10.1038/sj.gt.3301888 Oupicky, 2002, Importance of lateral and steric stabilization of polyelectrolyte gene delivery vectors for extended systemic circulation, Mol. Ther., 5, 463, 10.1006/mthe.2002.0568 Carlisle, 2004, Polymer-coated polyethylenimine/DNA complexes designed for triggered activation by intracellular reduction, J. Gene Med., 6, 337, 10.1002/jgm.525 Tseng, 2003, Improved stability of polycationic vector by dextran-grafted branched polyethylenimine, Biomacromolecules, 4, 1277, 10.1021/bm034083y Tiyaboonchai, 2003, Formulation and characterization of DNA–polyethylenimine–dextran sulfate nanoparticles, Eur. J. Pharm. Sci., 19, 191, 10.1016/S0928-0987(03)00102-7 Kircheis, 2001, Polyethylenimine/DNA complexes shielded by transferrin target gene expression to tumors after systemic application, Gene Ther., 8, 28, 10.1038/sj.gt.3301351 Rhaese, 2003, Human serum albumin–polyethylenimine nanoparticles for gene delivery, J. Controll. Rel., 92, 199, 10.1016/S0168-3659(03)00302-X Ruponen, 2003, Extracellular and intracellular barriers in non-viral gene delivery*1, J. Controll. Rel., 93, 213, 10.1016/j.jconrel.2003.08.004 Oupicky, 2001, Triggered intracellular activation of disulfide crosslinked polyelectrolyte gene delivery complexes with extended systemic circulation in vivo, Gene Ther., 8, 713, 10.1038/sj.gt.3301446 Kichler, 2002, Intranasal gene delivery with a polyethylenimine–PEG conjugate, J. Controll. Rel., 81, 379, 10.1016/S0168-3659(02)00080-9 Shi, 2003, Repeated intrathecal administration of plasmid DNA complexed with polyethylene glycol-grafted polyethylenimine led to prolonged transgene expression in the spinal cord, Gene Ther., 10, 1179, 10.1038/sj.gt.3301970 Kunath, 2003, Integrin targeting using RGD–PEI conjugates for in vitro gene transfer, J. Gene Med., 5, 588, 10.1002/jgm.382 Woodle, 2001, Sterically stabilized polyplex: ligand-mediated activity, J. Controll. Rel., 74, 309, 10.1016/S0168-3659(01)00339-X Wolfert, 1999, Polyelectrolyte vectors for gene delivery: influence of cationic polymer on biophysical properties of complexes formed with DNA, Bioconjugate Chem., 10, 993, 10.1021/bc990025r Ernst, 1999, Interaction of liposomal and polycationic transfection complexes with pulmonary surfactant, J. Gene Med., 1, 331, 10.1002/(SICI)1521-2254(199909/10)1:5<331::AID-JGM60>3.0.CO;2-8 Jobe, 1996, Surfactant enhances adenovirus-mediated gene expression in rabbit lungs, Gene Ther., 3, 775 Freeman, 1996, The influence of sodium glycocholate and other additives on the in vivo transfection of plasmid DNA in the lungs, Pharm. Res., 13, 202, 10.1023/A:1016078728202 Rudolph, 2002, Non-viral gene delivery to the lung with copolymer-protected and transferrin-modified polyethylenimine, Biochim. Biophys. Acta (BBA)—Gen. Subjects, 1573, 75, 10.1016/S0304-4165(02)00334-3 Gautam, 2001, Transgene expression in mouse airway epithelium by aerosol gene therapy with PEI–DNA complexes, Mol. Ther., 3, 551, 10.1006/mthe.2001.0300 Aoki, 2001, Polyethylenimine-mediated gene transfer into pancreatic tumor dissemination in the murine peritoneal cavity, Gene Ther., 8, 508, 10.1038/sj.gt.3301435 Coll, 1999, In vivo delivery to tumors of DNA complexed with linear polyethylenimine, Hum. Gene Ther., 10, 1659, 10.1089/10430349950017662 Lemkine, 2002, Preferential transfection of adult mouse neural stem cells and their immediate progeny in vivo with polyethylenimine, Mol. Cell. Neurosci., 19, 165, 10.1006/mcne.2001.1084 Abdallah, 1996, A powerful non-viral vector for in vivo gene transfer into the adult mammalian brain: polyethylenimine, Hum. Gene Ther., 7, 1947, 10.1089/hum.1996.7.16-1947 Wang, 2001, Transgene expression in the brain stem effected by intramuscular injection of polyethylenimine/DNA complexes, Mol. Ther., 3, 658, 10.1006/mthe.2001.0324 Liu, 1997, Factors influencing the efficiency of cationic liposome-mediated intravenous gene delivery, Nat. Biotechnol., 15, 167, 10.1038/nbt0297-167 Goula, 1998, Polyethylenimine-based intravenous delivery of transgenes to mouse lung, Gene Ther., 5, 1291, 10.1038/sj.gt.3300717 Koshkina, 2003, Biodistribution and pharmacokinetics of aerosol and intravenously administered DNA–polyethyleneimine complexes: optimization of pulmonary delivery and retention, Mol. Ther., 8, 249, 10.1016/S1525-0016(03)00177-1 Bragonzi, 2000, Biodistribution and transgene expression with non-viral cationic vector/DNA complexes in the lungs, Gene Ther., 7, 1753, 10.1038/sj.gt.3301282 Furgeson, 2002, Novel water insoluble lipoparticulates for gene delivery, Pharm. Res., 19, 382, 10.1023/A:1015166806366 Furgeson, 2003, Modified linear polyethylenimine–cholesterol conjugates for DNA complexation, Bioconjugate Chem., 14, 840, 10.1021/bc0340565 Stockert, 1995, The asialoglycoprotein receptor: relationships between structure, function, and expression, Physiol. Rev., 75, 591, 10.1152/physrev.1995.75.3.591 Morimoto, 2003, Molecular weight-dependent gene transfection activity of unmodified and galactosylated polyethyleneimine on hepatoma cells and mouse liver, Mol. Ther., 7, 254, 10.1016/S1525-0016(02)00053-9 Sagara, 2002, A new synthesis of galactose–poly(ethylene glycol)–polyethylenimine for gene delivery to hepatocytes, J. Controll. Rel., 79, 271, 10.1016/S0168-3659(01)00555-7 Bettinger, 1999, Size reduction of galactosylated PEI/DNA complexes improves lectin-mediated gene transfer into hepatocytes, Bioconjugate Chem., 10, 558, 10.1021/bc990006h Zanta, 1997, In vitro gene delivery to hepatocytes with galactosylated polyethylenimine, Bioconjugate Chem., 8, 839, 10.1021/bc970098f Kunath, 2003, Galactose-PEI–DNA complexes for targeted gene delivery: degree of substitution affects complex size and transfection efficiency, J. Controll. Rel., 88, 159, 10.1016/S0168-3659(02)00458-3 Choi, 1998, Lactose–poly(ethylene glycol)-grafted poly-l-lysine as hepatoma cell-tapgeted gene carrier, Bioconjugate Chem., 9, 708, 10.1021/bc980017v Choi, 1999, Characterization of a targeted gene carrier, lactose–polyethylene glycol-grafted poly-l-lysine and its complex with plasmid DNA, Hum. Gene Ther., 10, 2657, 10.1089/10430349950016690 Wu, 1987, Receptor-mediated in vitro gene transformation by a soluble DNA carrier system, J. Biol. Chem., 262, 4429, 10.1016/S0021-9258(18)61209-8 Cristiano, 1993, Hepatic gene therapy: efficient gene delivery and expression in primary hepatocytes utilizing a conjugated adenovirus–DNA complex, Proc. Natl Acad. Sci. USA, 90, 11548, 10.1073/pnas.90.24.11548 Diebold, 1999, Efficient gene delivery into human dendritic cells by adenovirus polyethylenimine and mannose polyethylenimine transfection, Hum. Gene Ther., 10, 775, 10.1089/10430349950018535 Avrameas, 1996, Expression of a mannose/fucose membrane lectin on human dendritic cells, Eur. J. Immunol., 26, 394, 10.1002/eji.1830260219 Banchereau, 1998, Dendritic cells and the control of immunity, Nature (London), 392, 245, 10.1038/32588 Van den Eynde, 1997, Tumor antigens recognized by T lymphocytes, Int. J. Clin. Lab. Res., 27, 81, 10.1007/BF02912440 Song, 1997, Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity, J. Exp. Med., 186, 1247, 10.1084/jem.186.8.1247 Specht, 1997, Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases, J. Exp. Med., 186, 1213, 10.1084/jem.186.8.1213 Kircheis, 2001, Tumor targeting with surface-shielded ligand–polycation DNA complexes, J. Controll. Rel., 72, 165, 10.1016/S0168-3659(01)00272-3 Smrekar, 2003, Tissue-dependent factors affect gene delivery to tumors in vivo, Gene Ther., 10, 1079, 10.1038/sj.gt.3301965 Hildebrandt, 2003, Optical imaging of transferrin targeted PEI/DNA complexes in living subjects, Gene Ther., 10, 758, 10.1038/sj.gt.3301939 Kim, 1999, The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis, Exp. Cell Res., 253, 78, 10.1006/excr.1999.4706 Lu, 2002, Folate-mediated delivery of macromolecular anticancer therapeutic agents, Adv. Drug Deliv. Rev., 54, 675, 10.1016/S0169-409X(02)00042-X Guo, 2001, Efficient gene delivery via non-covalent complexes of folic acid and polyethylenimine, J. Controll. Rel., 77, 131, 10.1016/S0168-3659(01)00456-4 Guo, 1999, Receptor-targeted gene delivery via folate-conjugated polyethylenimine [online computer file], PharmScience, 1 Benns, 2002, Optimization of factors influencing the transfection efficiency of folate–PEG–folate-graft-polyethylenimine, J. Controll. Rel., 79, 255, 10.1016/S0168-3659(01)00513-2 Hynes, 1992, Integrins: versatility, modulation, and signaling in cell adhesion, Cell, 69, 11, 10.1016/0092-8674(92)90115-S Springer, 1990, Adhesion receptors of the immune system, Nature, 346, 425, 10.1038/346425a0 Pierschbacher, 1984, Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule, Nature, 309, 30, 10.1038/309030a0 Panetti, 1995, Alpha v beta 5 integrin receptor-mediated endocytosis of vitronectin is protein kinase C-dependent, J. Biol. Chem., 270, 18593, 10.1074/jbc.270.31.18593 Wickham, 1993, Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment, Cell, 73, 309, 10.1016/0092-8674(93)90231-E Erbacher, 1999, Gene transfer with synthetic virus-like particles via the integrin-mediated endocytosis pathway, Gene Ther., 6, 138, 10.1038/sj.gt.3300783 O'Neill, 2001, Receptor-mediated gene delivery to human peripheral blood mononuclear cells using anti-CD3 antibody coupled to polyethylenimine, Gene Ther., 8, 362, 10.1038/sj.gt.3301407 Merdan, 2003, Pegylated polyethylenimine-Fab' antibody fragment conjugates for targeted gene delivery to human ovarian carcinoma cells, Bioconjugate Chem., 14, 989, 10.1021/bc0340767