Abstract
The purpose of this study was to evaluate the cytokine response induced by linear and branched polyethylenimine (PEI)/plasmid DNA (pDNA) complex (polyplex) in relation to the ratio of PEI nitrogen and DNA phosphate (N/P ratio) of the polyplex, dose of pDNA, and structure and molecular weight of PEI, which are important for transfection efficacy of PEI polyplex. As a control, a N-[1-(2, 3-dioleyloxy) propyl]-n,n,n-trimethylammonium chloride/cholesterol liposome/pDNA complex (lipoplex) was selected for its high transfection efficacy in vivo. The concentration of proinflammatory cytokines such as tumor necrosis factor (TNF)-α were much lower after the administration of polyplex than lipoplex irrespective of the N/P ratio, dose of pDNA, or structure and molecular weight of PEI, although these factors affected the transfection efficacy in vivo. We demonstrated that the amount of activated nuclear factor-κB, which contributes substantially to the production of cytokines, was comparable with the control (no treatment) level, and significantly less than that obtained with lipoplex. Although the production of proinflammatory cytokines (TNF-α, interferon-γ, and interleukin-12) was reduced on the administration of the linear PEI polyplex, serum alanine aminotransferase levels were significantly enhanced by pDNA in a dose-dependent manner, suggesting that such hepatic damage is not induced by proinflammatory cytokines.
Footnotes
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This work was supported in part by Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by Health and Labor Sciences Research Grants for Research on Advanced Medical Technology from the Ministry of Health, Labor, and Welfare of Japan.
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doi:10.1124/jpet.105.100669.
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ABBREVIATIONS: PEI, polyethylenimine; pDNA, plasmid DNA; lipoplex, cationic liposome/pDNA complex; NFκB, nuclear factor κB; TNF, tumor necrosis factor; IFN, interferon; IL, interleukin; N/P ratio, the ratio of PEI nitrogen and DNA phosphate; polyplex, PEI/pDNA complex; DOTMA, N-[1-(2, 3-dioleyloxy) propyl]-n,n,n-trimethylammonium chloride; –:+, charge ratio; ALT, alanine aminotransferase.
- Received December 26, 2005.
- Accepted March 3, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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