Influence of disease stage on polyethylenimine-mediated plasmid DNA delivery in murine hepatitis.
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 (CCl(4)). Plasmid DNA (pDNA) encoding firefly luciferase was used as the model reporter gene. We determined luciferase activity in various organs of CCl(4)-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 CCl(4) injection), whereas the complexes induced gene expression in the liver at the liver regeneration stage (48 h after CCl(4) injection). Significant differences in gene expressions between CCl(4)-treated mice and control mice vanished in most organs at the hepatitis subsidence stage (168 h after CCl(4) injection), indicating that the influence of hepatitis induced by CCl(4) was reversible with PEI-mediated gene delivery. Our findings demonstrated that murine hepatitis induced by CCl(4) 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.
Sasaki
Hitoshi
H
Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. sasaki@net.nagasaki-u.ac.jp
Yoshida
Shohei
S
Kitahara
Takashi
T
Yoshioka
Takashi
T
Nakagawa
Hiroo
H
Nakamura
Tadahiro
T
Ichikawa
Nobuhiro
N
Nishida
Koyo
K
Nakamura
Junzo
J
Nakashima
Mikiro
M