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- Title
Hepatocyte-targeted in vivo gene expression by intravenous injection of plasmid DNA complexed with synthetic multi-functional gene delivery system.
- Authors
Nishikawa, M; Yamauchi, M; Morimoto, K; Ishida, E; Takakura, Y; Hashida, M
- Abstract
To achieve hepatocyte-targeted in vivo gene expression, a carrier that controls both the tissue and intracellular distribution of DNA was designed and synthesized. A cationic polymer, poly(L-ornithine) (pOrn), was modified first with galactose, then with a fusigenic peptide (mHA2) to obtain GalpOrn-mHA2. When applied with Gal-pOrn-mHA2 to asialoglycoprotein receptor-positive cells, fluorescein-labeled DNA showed a diffuse profile, suggesting the release of DNA from endosomes and/or lysosomes by the carrier. Then the biodistribution and gene expression after intravenous injection of DNA complexes (10 µg DNA per mouse) were examined. After injection of [[sup 32]P]DNA/Gal-pOrn-mHA2, about 60% of the radioactivity was recovered in the liver, mostly in parenchymal cells. A large amount (81 ng/g tissue) of transgene product (luciferase) was detected in the liver of mice injected with DNA/Gal-pOrn-mHA2, which was 280-fold greater than that obtained with DNA/DOTMA:Chol liposomes (50 µg DNA). Prior administration of galactosylated albumin reduced the gene expression to 1/100, indicating the asialoglycoprotein receptor-mediated gene transfer in liver parenchymal cells, ie hepatocytes. The luciferase activity in hepatocytes contributed more than 95% of the total activity in all the tissues examined. Thus, hepatocyte-targeted in vivo gene expression was achieved by the intravenous injection of DNA complex with the multifunctional gene carrier.
- Subjects
LIVER cells; GENE expression; PLASMIDS; GENE therapy
- Publication
Gene Therapy, 2000, Vol 7, Issue 7, p548
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3301140