Regional hydrodynamic gene delivery to the rat liver with physiological volumes of DNA solution

X H Zhang, X B Dong, G J Sawyer, L Collins, J W Fabre

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43 Citations (Scopus)

Abstract

Background The major barrier to the clinical application of hydrodynamic gene delivery to the liver is the large volume of fluid required using standard protocols. Regional hydrodynamic gene delivery via branches of the portal vein has not previously been reported, and we have evaluated this approach in a rat model. Methods The pGL3 plasmid with the luciferase reporter gene was used at 50 mug/ml in isotonic solutions, and was administered with a syringe pump for precise control of the hydrodynamic conditions evaluated. Gene expression was individually measured in six anatomically distinct liver lobes. The effect of systemic chloroquine to promote endocytic escape and a (Lys) 16-containing peptide to condense the DNA into similar to100-nm nanoparticles was also evaluated. Results Hydrodynamic conditions for excellent gene delivery were obtained by using 3-ml volumes (similar to12 ml/kg) of isotonic DNA solution delivered at 24 ml/min to the right lateral lobe (similar to20% of the liver mass). Under these conditions, >95% of gene delivery usually occurred in the targeted right lateral lobe. Outflow obstruction was essential for gene delivery, both at optimal and at very low levels of hydrodynamic gene delivery. The use of systemic chloroquine to promote endocytic escape did not augment hydrodynamic gene delivery, while condensation of DNA in non-ionic isotonic solutions (5% dextrose) to nanoparticles of similar to100 nm completely abolished gene delivery. Conclusions Regional hydrodynamic gene delivery via a branch of the portal vein offers a physiological model of liver gene therapy, for experimental and clinical application. Copyright (C) 2004 John Wiley Sons, Ltd.
Original languageEnglish
Pages (from-to)693 - 703
Number of pages11
JournalJOURNAL OF GENE MEDICINE
Volume6
Issue number6
DOIs
Publication statusPublished - Jun 2004

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