Biodistribution, metabolism, and in vivo gene expression of low molecular weight glycopeptide polyethylene glycol peptide DNA co-condensates
✍ Scribed by Wendy T. Collard; Yongsheng Yang; Kai Y. Kwok; Youmie Park; Kevin G. Rice
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 454 KB
- Volume
- 89
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
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 ␣1-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.