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Vol. 39, No. 1, 2007
Issue release date: March 2007

Development of Gene Vectors for Pinpoint Targeting to Human Hepatocytes by Cationically Modified Polymer Complexes

Chiba N. · Ueda M. · Shimada T. · Jinno H. · Watanabe J. · Ishihara K. · Kitajima M.
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Abstract

We developed a vector that might enable gene therapy of metabolic liver disease or hepatoma. Here we demonstrate the use of cationically modified biocompatible phospholipid polymer conjugated with hepatitis B surface (HBs) antigen for the specific transfer of genes into human hepatocytes. Poly(2-methacryloyloxyethyl phosphorylcholine (MPC)- co-N,N-dimethylaminoethyl methacrylate (DMAEMA)-co- p-nitrophenylcarbonyloxyethyl methacrylate(NPMA))(polyMDN) was prepared as a frame of vector. The specific expression of sFlt-1 or GFP by polyMDN conjugated with HBs containing plasmid (plasmid/polyMDN-HBs), polyMDN containing plasmid (plasmid/polyMDN), plasmid only and PBS were assessed in tumor cells (HepG2 or WiDr) in vitro and in vivo. The histological findings, organ weight changes, and degree of liver dysfunction were examined in the mice administered by several reagents. The sFlt-1 and GFP expression was observed only in the HepG2 cells transfected with sFlt-1 or GFP/polyMDN-HBs. None of the side effects mentioned above was observed. In conclusion, these results suggest that polyMDN-HBs is a human hepatocyte-specific gene delivery vector that might not have serious side effects.



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References

  1. Mulligan R: The basic science of gene therapy. Science 1993;260:926–932.
  2. Neurath AR, Kent SB, Strick N, Parker K: Identification and chemical synthesis of a host cell receptor binding site on hepatitis B virus. Cell 1986;46:429–436.
  3. Le Seyec J, Chouteau P, Cannie I, Guguen-Guillouzo C, Gripon P: Infection process of the hepatitis B virus depends on the presence of a defined sequence in the pre-S1 domain. J Virol 1999;73:2052–2057.
  4. Takei K, Konno T, Watanabe J, Ishihara K: Regulation of enzyme-substrate complexation by a substrate conjugated with a phospholipid polymer. Biomacromolecules 2004;5:858–862.
  5. Kimura M, Fukumoto K, Watanabe J, Takai M, Ishihara K: Spontaneously forming hydrogel from water-soluble random- and block-type phospholipid polymers. Biomaterials 2005;26:6853–6862.
  6. Kitagawa T, Iwase R, Ishihara K, Yamaoka T, Murakami A: Facilitated disassembly of polyplexes composed of self-assembling amphiphilic polycations enhances the gene transfer efficacy. Chem Lett 2005;11:1478–1479.

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  7. Sakaki S, Tsuchida M, Iwasaki Y, Ishihara K: A water-soluble phospholipid polymer as a new biocompatible synthetic DNA carrier. Bull Chem Soc Jpn 2004;77:2283–2288.
  8. Wu GY, Wu CH: Receptor-mediated gene delivery and expression in vivo. J Biol Chem 1988;263:14621–14624.
  9. Midoux P, Menedes C, Legrand A, Raimond J, Mayer R, Monsigny M, et al: Specific gene transfer mediated by lactosylated poly-L-lysine into hepatoma cells. Nucl Acids Res 1993;21:871–878.
  10. Perales JC, Ferkol T, Beegen H, Ratnoff OD, Hanson RW: Gene transfer in vivo: Sustained expression and regulation of genes introduced into the liver by receptor-mediated uptake. Proc Natl Acad Sci USA 1994;91:4086–4090.
  11. Kircheis R, Schuller S, Brunner S, Ogris M, Heider KH, Zauner W, et al: Polycation-based DNA complexes for tumor-targeted gene delivery in vivo. J Gene Med 1999;1:111–120.
  12. Ferkol T, Kaetzel CS, Davis PB: Gene transfer into respiratory epithelial cells by targeting the polymeric immunoglobulin receptor. J Clin Invest 1993;92:2394–2400.
  13. Li S, Tan Y, Viroonchatapan E, Pitt BR, Huang L: Targeted gene delivery to pulmonary endothelium by anti-PECAM antibody. Am J Physiol 2000;278:L504–L511.
  14. Ross GF, Morris RE, Ciraolo G, Huelsman K, Bruno M, Whitsett JA, et al: Surfactant protein A-polylysine conjugates for delivery of DNA to airway cells in culture. Hum Gene Ther 1995;6:31–40.
  15. Wagner E, Plank C, Zatloukal K, Cotten M, Birnstiel ML: Influenza virus hemagglutinin HA-2 N-terminal fusogenic peptides augment gene transfer by transferring-polylysine-DNA complexes: Toward a synthetic virus-like gene transfer vehicle. Proc Natl Acad Sci USA 1992;89:7934–7938.
  16. Nishikawa M, Yamauchi M, Morimoto K, Ishida E, Takakura Y, Hashida M: Hepatocyte-targeted in vivo gene expression by intravenous injection of plasmid DNA complexed with synthetic multi-functional gene delivery system. Gene Ther 2000;7:548–555.
  17. Marshal E: Viral vectors still pack surprises. Science 2001;294:1640.
  18. Ishikawa H, Nakata K, Mawatari F, Ueki T, Tsuruta S, Ido A, et al: Utilization of variant-type of human α-fetoprotein promoter in gene therapy targeting for hepatocellular carcinoma. Gene Ther 1999;6:465–470.
  19. Protzer U, Nassal M, Chiang PW, Kirschfink M, Schaller H: Interferon gene transfer by a hepatitis B virus vector efficiently suppresses wild-type virus infection. Proc Natl Acad Sci USA 1999;96:10818–10823.
  20. Carman WF, Zanetti AR, Karayiannis P, Waters J, Manzillo G, Tanzi E, et al: Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990;336:325–329.
  21. Chlou HL, Lee TS, Kuo J, Mau YC, Ho MS: Altered antigenicity of ‘a’ determinant variants of hepatitis B virus. J Gen Virol 1997;78:2639–2645.
  22. Zhou X, Huang L: DNA transfection mediated by cationic liposomes containing lipopolylysine: characterization and mechanism of action. Biochim Biophys Acta 1994;1189:195–203.
  23. Yang JP, Huang L: Overcoming the inhibitory effect of serum on lipofection by increasing the charge ratio of cationic liposome to DNA. Gene Ther 1997;4:950–960.
  24. Li S, Rizzo MA, Bhattacharya S, Huang L: Characterization of cationic lipid-protamine-DNA (LPD) complexes for intravenous gene delivery. Gene Ther 1998;5:930–937.
  25. Litzinger DC, Brown JM, Wala I, Kaufman SA, Van GY, Farrell CL, et al: Fate of cationic liposomes and their complex with oligonucleotide in vivo. Biochim Biophys Acta 1996;1281:139–149.
  26. Mahato RI, Kawabata K, Takamura Y, Hashida M: In vivo disposition characteristics of plasmid DNA complexed with cationic liposomes. J Drug Target 1995;3:149–157.
  27. 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 Pharmacol Exp Ther 1998;287:408–415.
  28. Finsinger D, Remy J-S, Erbacher P, Koch C, Plank C: Protective copolymers for nonviral gene vectors: synthesis, vector characterization and application in gene delivery. Gene Ther 2000;7:1183–1192.
  29. Collard WT, Yang Y, Kwok KY, Park Y, Rice KG: Biodistribution, metabolism, and in vivo gene expression of low molecular weight glycopeptide polyethylene glycol peptide DNA co-condensates. J Pharm Sci 2000;89:499–512.
  30. Monck MA, Mori A, Lee D, Tam P, Wheeler JJ, Cullis PR, et al: Stabilized plasmid-lipid particles: pharmacokinetics and plasmid delivery to distal tumors following intravenous injection. J Drug Target 2000;7:439–452.
  31. Li S, Wu SP, Whitmore M, Loeffert EJ, Wang L, Watkins SC, et al: Effect of immune response on gene transfer to the lung via systemic administration of cationic lipidic vectors. Am J Physiol 1999;276:L796–L804.
  32. Yew NS, Wang KX, Przybylska M, Bagley RG, Stedman M, Marshall J, et al: Contribution of plasmid DNA to inflammation in the lung after administration of cationic lipid:pDNA complexes. Hum Gene Ther 1999;10:223–234.
  33. Tousignant JD, Gates AL, Ingram LA, Johnson CL, Nietupski JB, Cheng SH, et al: Comprehensive analysis of the acute toxicities induced by systemic administration of cationic lipid:plasmid DNA complexes in mice. Hum Gene Ther 2000;11:2493–2513.
  34. Yoshida J, Mizuno M, Yagi K: Efficinet transfaction of human interferon-β gene to human glioma cells by means of cationic multilamellar liposomes coupled with a monoclonal antibody. J Neurooncol 1994;19:269–274.
  35. Luten J, van Steenis JH, van Someren R, Kemmink J, Schuurmans-Nieuwenbroek NM, et al: Water-soluble biodegradable cationic polyphosphazenes for gene delivery. J Control Release. 2003;89:489–497.

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