کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2487865 | 1556515 | 2010 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Crossâlinked low molecular weight glycopeptideâmediated gene delivery: Relationship between DNA metabolic stability and the level of transient gene expression in vivo
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
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چکیده انگلیسی
DNA coâcondensates were formed by reacting [125I]DNA with an admixture of a highâmannose glycopeptide (Man9âCWK18) and either of two poly(ethylene glycol) peptides (PEGâVSâCWK18 or PEGâSSâCWK18) followed by crossâlinking with 6-50 mol equiv of glutaraldehyde. [125I]DNA coâcondensates were administered intravenously in mice to determine the influence of peptide DNA formulation parameters on specific targeting to Kupffer cells. Optimal targeting to Kupffer cells required the combined use of 50 mol % Man9âCWK18 and PEGâCWK18 to mediate specific recognition by the mannose receptor to Kupffer cells. The cellular uptake of crossâlinked Man9âCWK18/PEGâCWK18 DNA coâcondensates was receptor mediated since Kupffer cell targeting was inhibited by preâadministration of Manâbovine serum albumin (BSA) but not BSA. An optimized formulation targeted 60% of the dose to the liver, with 80% of the liverâtargeted DNA localized to Kupffer cells. Crossâlinking with either 6, 15, or 50 mol equiv of glutaraldehyde led to a corresponding decrease in the metabolism rate of DNA in liver as measured by halfâliveâ of 4, 6, and 39 h, respectively. Tail vein dosing of 50 μg of DNA coâcondensates crossâlinked with 6 mol equiv of glutaraldehyde produced detectable levels of human α1âantitrypsin in blood after 12 h, which peaked at day six and persisted for 10 days. The level of human α1âantitrypsin was elevated twoâfold each day when dosing with DNA coâcondensates crossâlinked with 15 mol equiv of glutaraldehyde, revealing a correlation between the metabolic stability of the DNA in liver and level of gene expression. In addition to possessing greater metabolic stability, DNA coâcondensates crossâlinked with 50 mol equiv of glutaraldehyde, but lacking a targeting ligand, avoided rapid liver uptake and possessed a prolonged pharmacokinetic halfâlife, providing insight into a means to target DNA condensates to peripheral tissues. © 2001 WileyâLiss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:2010-2022, 2001
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 90, Issue 12, December 2001, Pages 2010-2022
Journal: Journal of Pharmaceutical Sciences - Volume 90, Issue 12, December 2001, Pages 2010-2022
نویسندگان
Yongsheng Yang, Youmie Park, Shouchin Man, Yahong Liu, Kevin G. Rice,