Biodistribution, metabolism, and in vivo gene expression of low molecular weight glycopeptide polyethylene glycol peptide DNA co-condensates.
The biodistribution, metabolism, cellular targeting, and gene expression of a nonviral peptide DNA gene delivery system was examined. (125)I-labeled plasmid DNA was condensed with low molecular weight peptide conjugates and dosed i.v. in mice to determine the influence of peptide DNA formulation parameters on specific gene targeting to hepatocytes. Optimal targeting to hepatocytes required the combined use of a triantennary glycopeptide (Tri-CWK(18)) and a polyethylene glycol-peptide (PEG-CWK(18)) to mediate specific recognition by the asialoglycoprotein receptor and to reduce nonspecific uptake by Kupffer cells. Tri-CWK(18)/PEG-CWK(18) DNA co-condensates were stabilized and protected from metabolism by glutaraldehyde crosslinking. An optimized formulation targeted 60% of the dose to the liver with 80% of the liver targeted DNA localized to hepatocytes. Glutaraldehyde crosslinking of DNA condensates reduced the liver elimination rate from a t((1/2)) of 0.8 to 3.6 h. An optimized gene delivery formulation produced detectable levels of human alpha1-antitrypsin in mouse serum which peaked at day 7 compared to no expression using control formulations. The results demonstrate the application of formulation optimization to improve the targeting selectivity and gene expression of a peptide DNA delivery system.
Collard
W T
WT
Divisions of Pharmaceutics and Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
Yang
Y
Y
Kwok
K Y
KY
Park
Y
Y
Rice
K G
KG
D000818:Animals; D004247:DNA / Q000737:chemistry / Q000235:genetics* / Q000493:pharmacokinetics; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008970:Molecular Weight; D010455:Peptides / Q000235:genetics* / Q000493:pharmacokinetics; D010957:Plasmids; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
D010455:Peptides; D011092:Polyethylene Glycols; D004247:DNA