In vitro and in vivo effects of polyethylene glycol (PEG)-modified lipid in DOTAP/cholesterol-mediated gene transfection

Torben Gjetting, Nicolai Skovbjerg Arildsen, Camilla Laulund Christensen, Thomas Tuxen Poulsen, Jack A. Roth, Vagn Neerup Handlos, Hans Skovgaard Poulsen

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Background: DOTAP/cholesterol-based lipoplexes are successfully used for delivery of plasmid DNA in vivo especially to the lungs, although low systemic stability and circulation have been reported. To achieve the aim of discovering the best method for systemic delivery of DNA to disseminated tumors we evaluated the potential of formulating DOTAP/cholesterol lipoplexes with a polyethylene glycol (PEG)-modified lipid, giving the benefit of the shielding and stabilizing properties of PEG in the bloodstream. Method: A direct comparison of properties in vitro and in vivo of 4 different DOTAP/cholesterol-based lipoplexes containing 0%, 2%, 4%, and 10% PEG was performed using reporter gene activity and radioactive tracer lipid markers to monitor biodistribution. Results: We found that 10% PEGylation of lipoplexes caused reduced retention in lung and heart tissues of nude mice compared to nonPEGylated lipoplexes, however no significant delivery to xenograft flank tumors was observed. Although PEGylated and nonPEGylated lipoplexes were delivered to cells the ability to mediate successful transfection is hampered upon PEGylation, presumably due to a changed uptake mechanism and intracellular processing. Conclusion: The eminent in vivo transfection potency of DOTAP/cholesterol-based lipoplexes is well established for expression in lung tumors, but it is unsuitable for expression in non first pass organs such as xenograft flank tumors in mice even after addition of a PEG-lipid in the formulation.

Original languageEnglish (US)
Pages (from-to)371-383
Number of pages13
JournalInternational journal of nanomedicine
Volume5
Issue number1
StatePublished - Dec 1 2010

Keywords

  • Biodistribution
  • DOTAP
  • Gene delivery
  • Lung cancer
  • Polyethylene glycol (PEG)
  • Xenograft tumor model

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Gjetting, T., Arildsen, N. S., Christensen, C. L., Poulsen, T. T., Roth, J. A., Handlos, V. N., & Poulsen, H. S. (2010). In vitro and in vivo effects of polyethylene glycol (PEG)-modified lipid in DOTAP/cholesterol-mediated gene transfection. International journal of nanomedicine, 5(1), 371-383.