Analysis of hepatic disposition of native and galactosylated polyethylenimine complexed with plasmid DNA in perfused rat liver.
We studied the intrahepatic disposition characteristics of galactosylated polyethylenimine (Gal-PEI)/plasmid DNA (pDNA) complexes using rat liver perfusion experiment. After intraportal administration, transfection activity in liver of Gal-PEI complexes was approximately 26-fold higher than that of native PEI complexes. To evaluate the relationship between hepatic gene expression and disposition profiles, hepatic disposition of Gal-PEI complexes were pharmacokinetically analyzed by use of perfused rat liver, which enables uptake characteristics intrinsic to the liver to be elucidated. Moment analysis revealed that both complexes exhibited very high single-pass extraction. To characterize each kinetic process in hepatic uptake of Gal-PEI complexes, their outflow profiles were analyzed based on a two-compartment dispersion model. Consequently, the tissue binding affinity of Gal-PEI complexes was 3.0-fold larger than that of native PEI complexes, suggesting the increasing of hepatic binding affinity much enhanced the hepatic gene transfection efficiency. In contrast, galactosylation of PEI did not affected internalization (and/or sequestration) rate.
Fumoto
Shintaro
S
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Kawakami
Shigeru
S
Ishizuka
Masako
M
Nishikawa
Makiya
M
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M