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  • Title: Enhanced hepatocyte-selective in vivo gene expression by stabilized galactosylated liposome/plasmid DNA complex using sodium chloride for complex formation.
    Author: Fumoto S, Kawakami S, Ito Y, Shigeta K, Yamashita F, Hashida M.
    Journal: Mol Ther; 2004 Oct; 10(4):719-29. PubMed ID: 15451456.
    Abstract:
    In this study, we demonstrated that the presence of an essential amount of sodium chloride (NaCl) during the formation of cationic liposome/plasmid DNA complexes (lipoplexes) stabilizes the lipoplexes according to the surface charge regulation (SCR) theory. Fluorescence resonance energy transfer analysis revealed that cationic liposomes in an SCR lipoplex (5 and 10 mM NaCl solution in lipoplex) increased fusion. Also, aggregation of SCR lipoplexes was significantly delayed after exposure to saline (150 mM NaCl) as a model of physiological conditions. After intraportal administration, the hepatic transfection activity of galactosylated SCR lipoplexes (5 and 10 mM NaCl solution in lipoplex) was approximately 10- to 20-fold higher than that of galactosylated conventional lipoplexes in mice. The transfection activity in hepatocytes of galactosylated SCR lipoplexes was significantly higher than that of conventional lipoplexes, and preexposure to competitive asialoglycoprotein-receptor blocker significantly reduced the hepatic gene expression, suggesting that hepatocytes are responsible for high hepatic transgene expression of the galactosylated SCR lipoplexes. Pharmacokinetic studies both in situ and in vivo demonstrated a higher tissue binding affinity and a greater expanse of intrahepatic distribution by galactosylated SCR lipoplexes. Moreover, enhanced transfection activity of galactosylated SCR lipoplexes was observed in HepG2 cells, and investigation of confocal microscopic images showed that the release of plasmid DNA in the cell was markedly accelerated. These characteristics partly explain the mechanism of enhanced in vivo transfection efficacy by galactosylated SCR lipoplexes. Hence, information in this study will be valuable for the future use, design, and development of ligand-modified lipoplexes for in vivo applications.
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