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Cationic corticosteroid for nonviral gene delivery

Gene Therapy volume 11, pages 668–674 (2004)Cite this article

Abstract

Delivery of plasmid DNA for gene therapy often provokes an inflammatory response that reduces transgene expression. Cationic lipids for lipofection lack pharmacological activity despite the hydrophobicity of many drug candidates that could be exploited. We report a one-step synthesis of a water-soluble, dexamethasone–spermine (DS) cationic lipid that has potent gene transfer capability in confluent endothelial cells when used with the neutral lipid, dioleoylphosphatidylethanolamine (DOPE). In contrast, unconjugated mixtures of dexamethasone, spermine, and/or DOPE have essentially no gene transfer activity. DS retains partial corticosteroid character as quantified by the rapid translocation of glucocorticoid receptor to the nucleus and by dose-dependent transactivation from a glucocorticoid response element. DS has anti-inflammatory activity in vivo in the mouse thioglycollate model of inflammation. In a mouse lung model, DS:DOPE resulted in significantly less interferon-γ production at Day 1 and elevated transgene expression at Days 1 and 7 postintranasal instillation compared to DC-Chol:DOPE (sterol:DOPE:phosphate molar ratio of 1:1:1). Cationic pharmacophores such as DS represent a new approach to gene delivery and localized therapy.

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Acknowledgements

This work was supported by National Institutes of Health Grant 66565 and Cystic Fibrosis Foundation Grants D01IO and 5886. JG is an NSF Graduate Research Fellow and SLD is an established investigator of the American Heart Association. We graciously thank Dr Gordon Hager (Laboratory of Receptor Biology and Gene Expression, NIH) for the 3T3 cell line 3676, and Dr Haiching Ma for helpful discussions. We thank Dr Daniel Weiner (Division of Medical Genetics, U Penn.) for his help with the mouse studies.

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Authors and Affiliations

  1. Department of Bioengineering, 1024 Vagelos Research Laboratory, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA

    J A Gruneich, A Price & S L Diamond

  2. Department of Chemical and Biomolecular Engineering, 1024 Vagelos Research Laboratory, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA

    J Zhu & S L Diamond

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  1. J A Gruneich
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  2. A Price
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  3. J Zhu
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  4. S L Diamond
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Gruneich, J., Price, A., Zhu, J. et al. Cationic corticosteroid for nonviral gene delivery. Gene Ther 11, 668–674 (2004). https://doi.org/10.1038/sj.gt.3302214

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