Physicochemical and pharmacokinetic characteristics of plasmid DNA/cationic liposome complexes.
The objectives of this study were (i) to characterize the plasmid DNA encoding the chloramphenicol acetyltransferase reporter gene (pCAT) complexed with cationic liposomes (Lipofectin and LipofectACE) in terms of particle size and zeta potential, (ii) to compare pharmacokinetic characteristics, and (iii) to study the hepatic uptake mechanisms. DNA/LipofectACE complexes showed a negative zeta potential of -36 mV at 1:5 w/w ratio, but a positive zeta potential of (19 mV at 1:10 w/w ratio. Lipofectin samples showed a positive zeta potential) of 21-28 mV at these ratios. These preparations showed a wide particle size distribution ranging from 600 to 1200 nm. Following intravenous injection of 1:10 w/w ratio [32P]pCAT/liposome complexes at a dose of 0.1 mg DNA/kg into the tail vein of mice, radioactivity was rapidly eliminated from the plasma and almost 50-60% of the dose was taken up by the liver within 5 min after administration. Plasmid DNA/liposome complexes were predominantly taken up by the liver nonparenchymal cells. The hepatic uptake was inhibited by preceding administration of dextran sulfate (DS), but not by polycytidic acid (poly[C]) and polyinosinic acid (poly[I]), suggesting the involvement of a phagocytic process. We suggest that these complexes are preferentially taken up by the liver nonparenchymal cells mainly via Kupffer cell phagocytosis.
Mahato
R I
RI
Department of Drug Delivery Research, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Kawabata
K
K
Nomura
T
T
Takakura
Y
Y
Hashida
M
M
D000818:Animals; D002412:Cations; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000493:pharmacokinetics*; D015316:Genetic Therapy; D008081:Liposomes; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010316:Particle Size; D010761:Phosphorus Radioisotopes; D010957:Plasmids; D014018:Tissue Distribution
D002412:Cations; D008081:Liposomes; D010761:Phosphorus Radioisotopes; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase