Pharmacokinetics and in vivo gene transfer of plasmid DNA complexed with mannosylated poly(L-lysine) in mice.
To achieve mannose receptor-mediated, cell-specific, in vivo gene transfer by intravenous injection of plasmid DNA, mannosylated poly(L-lysine) (Man-PLL) was synthesized as a carrier molecule, and mixed with a plasmid DNA encoding chloramphenicol acetyltransferase (CAT) gene to form DNA/Man-PLL complex. The particle size and zeta potential of DNA/Man-PLL (prepared at 1:0.7 on a weight basis) were determined to be 220 nm and +12 mV, respectively. The pharmacokinetics of the DNA/Man-PLL complex was assessed in mice using 32P-labeled DNA ([32P]DNA). After intravenous injection of [32P]DNA/Man-PLL, the radioactivity in plasma fell rapidly and was recovered mainly in the liver nonparenchymal cells. The amount in the liver reached more than 80% of the dose. Radioactivity observed in kidney, lung, and spleen was very low compared to that in the liver. Then, the in vivo gene expression after intravenous injection of DNA/Man-PLL was examined by a CAT assay. Highest CAT activity was detected in the liver, but no activity was detected in the lung, kidney, and spleen. These results clearly indicate that a cell-specific gene delivery system can be developed by regulating the biodistribution of DNA/carrier complex through the control of its physicochemical properties.
Nishikawa
M
M
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Takemura
S
S
Yamashita
F
F
Takakura
Y
Y
Meijer
D K
DK
Hashida
M
M
Swart
P J
PJ
D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D007275:Injections, Intravenous; D008297:Male; D008358:Mannose / Q000737:chemistry*; D008657:Metabolic Clearance Rate; D051379:Mice; D010761:Phosphorus Radioisotopes; D010957:Plasmids; D011107:Polylysine / Q000737:chemistry*; D014018:Tissue Distribution
D010761:Phosphorus Radioisotopes; D011107:Polylysine; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase; D008358:Mannose