Non-linear pharmacodynamics in a non-viral gene delivery system: positive non-linear relationship between dose and transfection efficiency.

A remarkable non-linearity was found between dose and transfection activities of non-viral gene delivery systems, such as a Lipofectamine/DNA complex and an octaarginine-modified multifunctional envelope-type nano device (R8-MEND). We measured the nuclear delivery of pDNA to distinguish the non-linearity in intracellular pharmacokinetics or pharmacodynamics after transfection with R8-MEND at different doses. A remarkable positive non-linearity was found in the pharmacodynamics when the dose was increased. Even dummy pDNA enhanced the efficiency of transcription and/or translation per pDNA in the nucleus, but empty liposomes did not. These results suggest the importance of controlled pharmacodynamics as well as the importance of intracellular pharmacokinetics for the rational design of non-viral gene delivery systems.

[1]  N. Caplen,et al.  In vitro liposome-mediated DNA transfection of epithelial cell lines using the cationic liposome DC-Chol/DOPE. , 1995, Gene therapy.

[2]  D. Escande,et al.  Polyethylenimine but Not Cationic Lipids Promotes Transgene Delivery to the Nucleus in Mammalian Cells* , 1998, The Journal of Biological Chemistry.

[3]  N. Landsberger,et al.  Molecular Mechanisms of Gene Silencing Mediated by DNA Methylation , 2002, Molecular and Cellular Biology.

[4]  C. Hsieh,et al.  DNA Methylation Has a Local Effect on Transcription and Histone Acetylation , 2002, Molecular and Cellular Biology.

[5]  Joseph Zabner,et al.  Cellular and Molecular Barriers to Gene Transfer by a Cationic Lipid (*) , 1995, The Journal of Biological Chemistry.

[6]  F. Booy,et al.  Characterisation of LMD virus-like nanoparticles self-assembled from cationic liposomes, adenovirus core peptide μ (mu) and plasmid DNA , 2002, Gene Therapy.

[7]  Shiroh Futaki,et al.  Development of a non-viral multifunctional envelope-type nano device by a novel lipid film hydration method. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[8]  H Akita,et al.  Quantitative three-dimensional analysis of the intracellular trafficking of plasmid DNA transfected by a nonviral gene delivery system using confocal laser scanning microscopy. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[9]  H Harashima,et al.  Stearylated arginine-rich peptides: a new class of transfection systems. , 2001, Bioconjugate chemistry.

[10]  Yasuo Shinohara,et al.  Quantitative Analysis of Correlation Between Number of Nuclear Plasmids and Gene Expression Activity After Transfection with Cationic Liposomes , 2002, Pharmaceutical Research.

[11]  Hideyoshi Harashima,et al.  Pharmacokinetic and pharmacodynamic considerations in gene therapy. , 2003, Drug discovery today.