Influence of disease stage on polyethylenimine-mediated plasmid DNA delivery in murine hepatitis

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In order to determine the influence of hepatic disease-stage on polyethylenimine-mediated gene delivery, we investigated branched and linear polyethylenimine (B-PEI, L-PEI)-mediated plasmid DNA delivery with time in murine hepatitis induced by a subcutaneous injection of tetrachloro carbon (CCl4). Plasmid DNA (pDNA) encoding firefly luciferase was used as the model reporter gene. We determined luciferase activity in various organs of CCl4-treated mice and control mice after an intravenous administration of B-PEI and L-PEI/pDNA complexes. Both B-PEI and L-PEI/pDNA complexes showed significantly lower gene expression in the liver, spleen, and lung at the stage of severe hepatitis (18 h after CCl4 injection), whereas the complexes induced gene expression in the liver at the liver regeneration stage (48 h after CCl4 injection). Significant differences in gene expressions between CCl4-treated mice and control mice vanished in most organs at the hepatitis subsidence stage (168 h after CCl4 injection), indicating that the influence of hepatitis induced by CCl4 was reversible with PEI-mediated gene delivery. Our findings demonstrated that murine hepatitis induced by CCl4 could influence polyethylenimine-mediated plasmid DNA delivery according to the disease stage. These results indicate the necessity of considering the timing and dose of gene therapy according to the disease stage.

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