Design and development of polymers for gene delivery

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Felgner, P. L. et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc. Natl Acad. Sci. USA 84, 7413 (1987). This is the first report of gene delivery to mammalian cells using cationic lipids as the DNA carrier.

Koltover, I., Salditt, T., Radler, J. O. & Safinya, C. R. An inverted hexagonal phase of cationic liposome–DNA complexes related to DNA release and delivery. Science 281, 78–81 (1998). A key study that for the first time correlates the three-dimensional structures of lipoplexes with their transfection activity.

Zabner, J. Cationic lipids used in gene transfer. Adv. Drug Deliv. Rev. 27, 17–28 (1997).

Fillion, M. C. & Phillips, N. C. Major limitations in the use of cationic liposomes for DNA delivery. Int. J. Pharm. 162, 159–170 (1998).

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Hansma, H. G. et al. DNA condensation for gene therapy as monitored by atomic force microscopy. Nucleic Acids Res. 26, 2481–2487 (1998).

Lai, E. & van Zanten, J. H. Monitoring DNA/poly-L-lysine polyplex formation with time-resolved multiangle laser light scattering. Biophys. J. 80, 864–873 (2001).

Kabanov, A. V. et al. DNA interpolyelectrolyte complexes as a tool for efficient cell transformation. Biopolymers 31, 1437–1443 (1991).

Wadhwa, M. S., Collard, W. T., Adami, R. C., McKenzie, D. L. & Rice, K. G. Peptide-mediated gene delivery: influence of peptide structure on gene expression. Bioconjug. Chem. 8, 81–88 (1997).

Plank, C., Tang, M. X., Wolfe, A. R. & Szoka, F. C. Branched cationic peptides for gene delivery: role of type and number of cationic residues in formation and in vitro activity of DNA polyplexes. Hum. Gene Ther. 10, 319–332 (1999).

Schaffer, D. V., Fidelman, N. A., Dan, N. & Lauffenburger, D. A. Vector unpacking as a potential barrier for receptor-mediated polyplex gene delivery. Biotechnol. Bioeng. 67, 598–606 (2000). The first direct investigation of the effects of polymer–DNA interaction strength on gene-delivery efficiency.

Wolfert, M. A. et al. Polyelectrolyte vectors for gene delivery: influence of cationic polymer on biophysical properties of complexes formed with DNA. Bioconjug. Chem. 10, 993–1004 (1999).

Zelphati, O. & Szoka, F. C. Mechanism of oligonucleotide release from cationic liposomes. Proc. Natl Acad. Sci. USA 93, 11493–11498 (1996).

Dash, P. R., Read, M. L., Barrett, L. B., Wolfert, M. A. & Seymour, L. W. Factors affecting blood clearance and in vivo distribution of polyelectrolyte complexes for gene delivery. Gene Ther. 6, 643–650 (1999).

Ogris, M., Brunner, S., Schuller, S., Kircheis, R. & Wagner, E. PEGylated DNA/transferrin–PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery. Gene Ther. 6, 595–605 (1999).

Toncheva, V. et al. Novel vectors for gene delivery formed by self-assembly of DNA with poly(L-lysine) grafted with hydrophilic polymers. Biochim. Biophys. Acta 1380, 354–368 (1998).

Oupicky, D. et al. Steric stabilization of poly-L-lysine/DNA complexes by the covalent attachment of semitelechelic poly[N-(2-hydroxypropyl)methacrylamide]. Bioconjug. Chem. 11, 492–501 (2000).

Dash, P. R. et al. Decreased binding to proteins and cells of polymeric gene delivery vectors surface modified with a multivalent hydrophilic polymer and retargeting through attachment of transferrin. J. Biol. Chem. 275, 3793–3802 (2000).

Howard, K. A. et al. Influence of cationic polymers on the biophysical properties of polyelectrolyte complexes formed by self-assembly with DNA. Biochim. Biophys. Acta 1475, 245–255 (2000).

Wang, W., Tetley, L. & Uchegbu, I. F. The level of hydrophobic substitution and the molecular weight of amphiphilic poly-L-lysine-based polymers strongly affects their assembly into polymeric bilayer vesicles. J. Colloid. Int. Sci. 237, 200–207 (2001).

Erbacher, P. et al. Gene transfer by DNA/glycosylated polylysine complexes into human blood monocyte-derived macrophages. Hum. Gene Ther. 7, 721–729 (1996).

Nishikawa, M., Takemura, S., Takakura, Y. & Hashida, M. Targeted delivery of plasmid DNA to hepatocytes in vivo optimization of the pharmacokinetics of plasmid DNA galactosylated poly(L-lysine) complexes by controlling their physicochemical properties. J. Pharm. Exp. Ther. 287, 408–415 (1998).

Kircheis, R. et al. Polyethylenimine/DNA complexes shielded by transferrin target gene expression to tumors after systemic application. Gene Ther. 8, 28–40 (2001).

Mishra, S., Webster, P. & Davis, M. E. PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur. J. Cell Biol. 83, 97–111 (2004).

Erbacher, P., Roche, A. C., Monsigny, M. & Midoux, P. Glycosylated polylysine/DNA complexes: gene transfer efficiency in relation with the size and the sugar substitution level of glycosylated polylysines and with the plasmid size. Bioconjug. Chem. 6, 401–410 (1995).

Ferkol, T., Perales, J. C., Mularo, F. & Hanson, R. W. Receptor-mediated gene transfer into macrophages. Proc. Natl Acad. Sci. USA 93, 101–105 (1996).

Zanta, M. -A., Boussif, O., Adib, A. & Behr, J. -P. In vitro gene delivery to hepatocytes with galactosylated polyethylenimine. Bioconjug. Chem. 8, 839–844 (1997).

Bettinger, T., Remy, J. S. & Erbacher, P. Size reduction of galactosylated PEI/DNA complexes improves lectin-mediated gene transfer into hepatocytes. Bioconjug. Chem. 10, 558–561 (1999).

Leamon, C. P., Weigl, D. & Hendren, R. W. Folate copolymer-mediated transfection of cultured cells. Bioconjug. Chem. 10, 947–957 (1999).

Wu, G. Y. & Wu, C. H. Receptor-mediated in vitro gene transformation by a soluble DNA carrier system. J. Biol. Chem. 262, 4429–4432 (1987).

Wu, G. Y. & Wu, C. H. Receptor-mediated gene delivery and expression in vivo. J. Biol. Chem. 263, 14621–14624 (1988).

Wu, C. H., Wilson, J. M. & Wu, G. Y. Targeting genes: delivery and persistent expression of a foreign gene driven by mammalian regulatory elements in vivo. J. Biol. Chem. 264, 16985–16987 (1989).

Wu, G. Y. et al. Receptor-mediated gene delivery in vivo. J. Biol. Chem. 266, 14338–14342 (1991).

Cotten, M. et al. 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. USA 87, 4033–4037 (1990). References 55–59 were the first reports of targeted gene delivery to specific cells using a polymer-based carrier.

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

Zenke, M. et al. Receptor-mediated endocytosis of transferrin-polycation conjugates: an efficient way to introduce DNA into hematopoietic cells. Proc. Natl Acad. Sci. USA 87, 3655–3659 (1990).

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

Schaffer, D. V., Neve, R. L. & Lauffenburger, D. A. Use of the green fluorescent protein as a quantitative reporter of epidermal growth factor receptor-mediated gene delivery. Tissue Eng. 3, 53–63 (1997).

Schaffer, D. V. in Chemical Engineering 125 (Massachusetts Institute of Technology, Cambridge, Massachusetts, 1998).

Kircheis, R. et al. Coupling of cell-binding ligands to polyethylenimine for targeted gene delivery. Gene Ther. 4, 409–418 (1997).

Harbottle, R. P. et al. An RGD-oligolysine peptide: a prototype construct for integrin-mediated gene delivery. Hum. Gene Ther. 9, 1037–1047 (1998).

Schaffer, D. V. & Lauffenburger, D. A. Optimization of cell surface binding enhances efficiency and specificity of molecular conjugate gene delivery. J. Biol. Chem. 273, 28004–28009 (1998).

Tseng, W. C., Haselton, F. R. & Giorgio, T. D. Transfection by cationic liposomes using simultaneous single cell measurements of plasmid delivery and transgene expression. J. Biol. Chem. 272, 25641–25647 (1997).

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Mislick, K. A. & Baldeschwieler, J. D. Evidence for the role of proteoglycans in cation-mediated gene transfer. Proc. Natl Acad. Sci. USA 93, 12349–12354 (1996).

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

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

Cristiano, R. J., Smith, L. c. & Woo, S. L. C. Hepatic gene therapy: adenovirus enhancement of receptor-mediated gene delivery and expression in primary hepatocytes. Proc. Natl Acad. Sci. USA 90, 2122–2126 (1993).

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

Cotten, M. et al. 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. USA 89, 6094–6098 (1992).

Wagner, E., Plank, C., Zatloukal, K., Cotten, M. & Birnstiel, M. L. 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. USA 89, 7934–7938 (1992).

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

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

Midoux, P. et al. Specific gene transfer mediated by lactosylated poly-L-lysine into hepatoma cells. Nucleic Acids Res. 21, 871–878 (1993).

Wyman, T. B. et al. Design, synthesis, and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers. Biochemistry 36, 3008–3017 (1997).

Lee, H., Jeong, J. H. & Park, T. G. A new gene delivery formulation of polyethylenimine/DNA complexes coated with PEG conjugated fusogenic peptide. J. Control. Release 76, 183–192 (2001).

Vaysse, L., Burgelin, I., Merlio, J. P. & Arveiler, B. Improved transfection using epithelial cell line-selected ligands and fusogenic peptides. Biochim. Biophys. Acta 1475, 369–376 (2000).

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Lukacs, G. L. et al. Size-dependent DNA mobility in cytoplasm and nucleus. J. Biol. Chem. 275, 1625–1629 (2000). This is an important paper demonstrating that plasmid DNA is too large to diffuse through the cytosol and, as a result, some form of active transport or mixing must be responsible for transport of DNA to the nuclear membrane.

Lechardaeur, D. et al. Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer. Gene Ther. 6, 482–497 (1999).

Suh, J., Wirtz, D. & Hanes, J. Efficient active transport of gene nanocarriers to the cell nucleus. Proc. Natl Acad. Sci. USA 100, 3878–3882 (2003).

Subramanian, A., Ranganathan, P. & Diamond, S. L. Nuclear targeting peptide scaffolds for lipofection of nondividing mammalian cells. Nat. Biotechnol. 17, 873–877 (1999).

Brunner, S. et al. Cell cycle dependence of gene transfer by lipoplex, polyplex and recombinant adenovirus. Gene Ther. 7, 401–407 (2000).

Chan, C. K. & Jans, D. A. Enhancement of polylysine-mediated transferrinfection by nuclear localization sequences: polylysine does not function as a nuclear localization sequence. Hum. Gene Ther. 10, 1695–1702 (1999).

Chan, C. K., Senden, T. & Jans, D. A. Supramolecular structure and nuclear targeting efficiency determine the enhancement of transfection by modified polylysines. Gene Ther. 7, 1690–1697 (2000).

Sebestyén, M. G. et al. DNA vector chemistry: the covalent attachment of signal peptides to plasmid DNA. Nature Biotechnol. 16, 80–85 (1998).

Brandén, L. J., Mohamed, A. J. & Smith, C. I. E. A peptide nucleic acid-nuclear localization signal fusion that mediates nuclear transport of DNA. Nature Biotechnol. 17, 784–787 (1999).

Ciolina, C. et al. Coupling of nuclear localization signals to plasmid DNA and specific interaction of the conjugates with importin α. Bioconjug. Chem. 10, 46–55 (1999).

Bremner, K. H., Seymour, L. W., Logan, A. & Read, M. L. Factors influencing the ability of nuclear localization sequence peptides to enhance nonviral gene delivery. Bioconjug. Chem. 15, 152–161 (2004).

Wilson, G., Dean, B. S., Wang, G. & Dean, D. A. DNA vector chemistry: the covalent attachment of signal peptides to plasmid DNA. J. Biol. Chem. 16, 80–85 (1998).

Erbacher, P., Roche, A. C., Monsigny, M. & Midoux, P. The reduction of the positive charges of polylysine by partial gluconoylation increases the transfection efficiency of polylysine/DNA complexes. Biochim. Biophys. Acta 1324, 27–36 (1997).

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Perales, J. C., Ferkol, T., Geegen, H., Ratnoff, O. D. & Hanson, R. W. Gene transfer in vivo: sustained expression and regulation of genes introduced into the liver by receptor-targeted uptake. Proc. Natl Acad. Sci. USA 91, 4086–4090 (1994).

Wadhwa, M. S., Knoell, D. L., Young, A. P. & Rice, K. G. Targeted gene delivery with a low molecular weight glycopeptide carrier. Bioconjug. Chem. 6, 283–291 (1995).

Hashida, M., Takemura, S., Nishikawa, M. & Takakura, Y. Targeted delivery of plasmid DNA complexed with galactosylated poly(L-lysine). Adv. Drug Deliv. Rev. 53, 301–310 (1998).

Suh, W., Chung, J. -K., Park, S. -H. & Kim, S. W. Anti-JL1 antibody-conjugated poly(L-lysine) for targeted gene delivery to leukemia T cells. J. Control. Release 72, 171–178 (2001).

Boussif, O. et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc. Natl Acad. Sci. USA 92, 7297–7301 (1995). The first report of polyethylenimine as a gene-delivery vector.

Diebold, S. S., Kursa, M., Wagner, E., Cotten, M. & Zenke, M. Mannose polyethylenimine conjugates for targeted DNA delivery into dendritic cells. J. Biol. Chem. 274, 19087–19094 (1999).

Kircheis, R., Blessing, R., Brunner, S., Wightman, L. & Wagner, E. Tumor targeting with surface-shielded ligand–polycation DNA complexes. J. Control. Release 72, 165–170 (2001).

Wojda, U. & Miller, J. L. Targeted transfer of polyethylenimine–avidin–DNA bioconjugates to hematopoietic cells using biotinylated monoclonal antibodies. J. Pharm. Sci. 89, 674–681 (2000).

Abdallah, B. et al. A powerful nonviral vector for in vivo gene transfer into the adult mammalian brain: polyethylenimine. Hum. Gene Ther. 7, 1947–1954 (1996).

Goula, D. et al. Size, diffusibility and transfection performance of linear PEI/DNA complexes in the mouse central nervous system. Gene Ther. 5, 712–717 (1998).

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Goula, D. et al. Polyethylenimine-based intravenous delivery of transgenes to mouse lung. Gene Ther. 5, 1291–1295 (1998).

Ferrari, S. et al. Polyethylenimine shows properties of interest for cystic fibrosis gene therapy. Biochim. Biophys. Acta 1447, 219–225 (1999).

Coll, J. L. et al. In vivo delivery to tumors of DNA complexed with linear polyethylenimine. Hum. Gene Ther. 10, 1659–1666 (1999).

Behr, J. -P. The proton sponge: a trick to enter cells the viruses did not exploit. Chimia 51, 34–36 (1997). This review paper provides the first clear description of the proton-sponge hypothesis.

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Forrest, M. L., Meister, G. E., Koerber, J. T. & Pack, D. W. Partial acetylation of polyethylenimine enhances in vitro gene delivery. Pharm. Res. 21, 365–371 (2004).

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Tanaka, S. et al. Targeted killing of carcinoembryonic antigen (CEA)-producing cholangiocarcinoma cells by polyamido amine dendrimer-mediated transfer of an Epstein-Barr virus (EBV)-based plasmid vector carrying the CEA promoter. Cancer Gene Ther. 7, 1241–1249 (2000).

Rudolph, C., Lausier, J., Naundorf, S., Muller, R. H. & Rosenecker, J. In vivo gene delivery to the lung using polyethylenimine and fractured polyamidoamine dendrimers. J. Gene Med. 2, 269–278 (2000).

Harada, Y. et al. Highly efficient suicide gene expression in hepatocellular carcinoma cells by Epstein–Barr virus-based plasmid vectors combined with polyamidoamine dendrimer. Cancer Gene Ther. 7, 27–36 (2000).

Marayuma-Tabata, H. et al. Effective suicide gene therapy in vivo by EBV-based plasmid vector coupled with polyamidoamine dendrimer. Gene Ther. 7, 53–60 (2000).

Tang, M. X., Redemann, C. T. & Szoka, F. C. In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjug. Chem. 7, 703–714 (1996).

Tang, M. X. & Szoka, F. C. The influence of polymer structure on the interactions of cationic polymers with DNA and morphology of the resulting complexes. Gene Ther. 4, 823–832 (1997).

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

Ihm, J. -E. et al. High transfection efficiency of poly(4-vinylimidazole) as a new gene carrier. Bioconjug. Chem. 14, 707–708 (2003).

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

Pichon, C., Roufai, M. B., Monsigny, M. & Midoux, P. Histidylated oligolysines increase the transmembrane passage and the biological activity of antisense oligonucleotides. Nucleic Acids Res. 28, 504–512 (2000).

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