Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Hydroporation as the mechanism of hydrodynamic delivery

Gene Therapy volume 11, pages 675–682 (2004)Cite this article

Abstract

We have reported that a rapid tail vein injection of a large volume of plasmid DNA solution into a mouse results in high level of transgene expression in the liver. Gene transfer efficiency of this hydrodynamics-based procedure is determined by the combined effect of a large volume and high injection speed. Here, we show that the hydrodynamic injection induces a transient irregularity of heart function, a sharp increase in venous pressure, an enlargement of liver fenestrae, and enhancement of membrane permeability of the hepatocytes. At the cellular level, our results suggest that hepatic delivery by the hydrodynamic injection is accomplished by the generation of membrane pores in the hepatocytes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Liu F, Song YK, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Therapy 1999; 6: 1258–1266.

    Article  CAS  Google Scholar 

  2. Zhang G, Budker V, Wolff JA . High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum Gene Ther 1999; 10: 1735–1737.

    Article  CAS  Google Scholar 

  3. Liu D, Knapp JE . Hydrodynamics-based gene delivery. Curr Opin Mol Ther 2001; 3: 192–197.

    CAS  PubMed  Google Scholar 

  4. Herweijer H, Wolff JA . Progress and prospects: naked DNA gene transfer and therapy. Gene Therapy 2003; 10: 453–458.

    Article  CAS  Google Scholar 

  5. Ehrhardt A et al. Optimization of cis-acting elements for gene expression from nonviral vectors in vivo. Hum Gene Ther 2003; 14: 215–225.

    Article  CAS  Google Scholar 

  6. Kramer MG et al. In vitro and in vivo comparative study of chimeric liver-specific promoters. Mol Ther 2003; 7: 375–385.

    Article  CAS  Google Scholar 

  7. Rivera IR, Kim J, Kemper B . Transcriptional analysis in vivo of the hepatic genes, Cyp2b9 and Cyp2b10, by intravenous administration of plasmid DNA in mice. Biochim Biophys Acta 2003; 1619: 254–262.

    Article  Google Scholar 

  8. Yant SR et al. Somatic integration and long-term transgene expression in normal and haemophilic mice using a DNA transposon system. Nat Genet 2000; 25: 35–41.

    Article  CAS  Google Scholar 

  9. Alino SF, Crespo A, Dasi F . Long-term therapeutic levels of human alpha-1 antitrypsin in plasma after hydrodynamic injection of nonviral DNA. Gene Therapy 2003; 10: 1672–1679.

    Article  CAS  Google Scholar 

  10. McCaffrey AP et al. RNA interference in adult mice. Nature 2002; 418: 38–39.

    Article  CAS  Google Scholar 

  11. Lewis DL et al. Efficient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat Genet 2002; 32: 107–108.

    Article  CAS  Google Scholar 

  12. Song E et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 2003; 9: 347–351.

    Article  CAS  Google Scholar 

  13. Chang JH, Sigal LJ, Lerro A, Taylor J . Replication of the human hepatitis delta virus genome is initiated in mouse hepatocytes following intravenous injection of naked DNA or RNA sequence. J Virol 2001; 75: 3469–3473.

    Article  CAS  Google Scholar 

  14. Yang PL, Althage A, Chung J, Chisari FV . Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection. Proc Natl Acad Sci USA 2002; 99: 13825–13830.

    Article  CAS  Google Scholar 

  15. Gumucio JJ, Berkowitz CM, Webster ST, Thornton AJ . Structure and functional organization of the liver. In: Kaplowitz N (ed). Liver and Billiary Diseases. Williams and Wilkins: Baltimore, MD, 1996, pp 3–19.

    Google Scholar 

  16. Wisse E et al. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 1985; 5: 683–692.

    Article  CAS  Google Scholar 

  17. Fraser R et al. High perfusion pressure damages the sieving ability of sinusoidal endothelium in rat liver. Br J Exp Pathol 1980; 61: 222–228.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Matsuda R, Nishikawa A, Tanaka H . Visualization of dystrophic muscle fibers in mdx mouse by vital staining with Evans Blue: evidence of apoptosis in dystrophin-deficient muscle. J Biochem (Tokyo) 1995; 118: 959–964.

    Article  CAS  Google Scholar 

  19. Lechardeur D et al. Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer. Gene Therapy 1999; 6: 482–497.

    Article  CAS  Google Scholar 

  20. Zabner J et al. Cellular and molecular barriers to gene transfer by a cationic lipid. J Biol Chem 1995; 270: 18997–19007.

    Article  CAS  Google Scholar 

  21. Dean DA . Import of plasmid DNA into the nucleus is sequence-specific. Exp Cell Res 1997; 230: 293–302.

    Article  CAS  Google Scholar 

  22. Dean DA, Dean BS, Muller S, Smith LC . Sequence requirements for plasmid nuclear entry. Exp Cell Res 1999; 253: 713–722.

    Article  CAS  Google Scholar 

  23. Zhang G, Song YK, Liu D . Long-term expression of human alpha 1-antitrypsin gene in mouse liver achieved by intravenous administration of plasmid DNA using a hydrodynamics-based procedure. Gene Therapy 2000; 7: 1344–1349.

    Article  CAS  Google Scholar 

  24. Kobayashi N et al. Hepatic uptake and gene expression mechanisms following intravenous administration of plasmid DNA by conventional and hydrodynamics-based procedure. J Pharmacol Exp Ther 2001; 297: 853–860.

    CAS  PubMed  Google Scholar 

  25. Liu D, Zhang G . Hepatic delivery of nucleic acids using hydrodynamics-based procedure. In: Mahato RI and Kim SW (ed). Pharmaceutical Perspectives of Nucleic Acid-Based Therapeutics. Taylor & Francis Inc.: London and New York, 2002, pp 455–468.

    Chapter  Google Scholar 

  26. Budker V et al. Hypothesis: naked plasmid DNA is taken up by cells in vivo by a receptor-mediated process. J Genet Med 2000; 2: 76–88.

    CAS  Google Scholar 

  27. Hofman CR et al. Efficient in vivo gene transfer by PCR amplified fragment with reduced inflammatory activity. Gene Therapy 2001; 8: 71–74.

    Article  CAS  Google Scholar 

  28. Zhang G et al. Efficient expression of naked DNA delivered intraarterially to limb muscles of nonhuman primates. Hum Gene Ther 2001; 12: 427–438.

    Article  CAS  Google Scholar 

  29. Maruyama H et al. Kidney-targeted naked DNA transfer by retrograde renal vein injection in rats. Hum Gene Ther 2002; 13: 455–468.

    Article  CAS  Google Scholar 

  30. Eastman SJ et al. Development of catheter-based procedures for transducing the rabbit liver with plasmid DNA. Hum Gene Ther 2002; 13: 2065–2077.

    Article  CAS  Google Scholar 

  31. Wolf P . The radioiodination of RNA and DNA to high specific activities. Methods Cell Biol 1976; 13: 121–152.

    Article  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge that the term ‘hydroporation’ was originally proposed by Dr Ning-Sun Yang at the Institute of BioAgricultural Sciences, Academia Sinica, Taipei, Taiwan. This work was supported in part by grants from NIH CA72529 to D Liu, HL60652 to X Gao, and HL59956, HL71643 to D Dean.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    G Zhang, X Gao, R Vollmer & D Liu

  2. Division of Pathology, NSABP Foundation, Inc., Four Allegheny Center, Pittsburgh, PA, USA

    Y K Song

  3. Cell Biology and Physiology, Center for Biologic Imagine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    D B Stolz

  4. Division of Pulmonary and Critical Care Medicine, College of Medicine, Northwestern University, Chicago, IL, USA

    J Z Gasiorowski & D A Dean

Authors
  1. G Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y K Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Vollmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D B Stolz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Z Gasiorowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D A Dean
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, G., Gao, X., Song, Y. et al. Hydroporation as the mechanism of hydrodynamic delivery. Gene Ther 11, 675–682 (2004). https://doi.org/10.1038/sj.gt.3302210

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302210

Keywords

This article is cited by

Search

Advanced search

Quick links