PEGylated DNA/transferrin-PEI complexes:: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery

被引:1010
作者
Ogris, M
Brunner, S
Schüller, S
Kircheis, R
Wagner, E
机构
[1] Univ Vienna, Inst Biochem, Bioctr, A-1030 Vienna, Austria
[2] Boehringer Ingelheim R&D Vienna, Vienna, Austria
基金
奥地利科学基金会;
关键词
in vivo gene transfer; polyethylenimine; polyethylene glycol; erythrocyte interaction; plasma interaction;
D O I
10.1038/sj.gt.3300900
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We investigated the in vitro and in vivo properties of DNA/transferrin-polyethylenimine (800 kDa) complexes before and after covalent coupling of poly(ethylene glycol) (PEG). Upon incubation with plasma, the positively charged non-PEGylated DNA complexes form aggregates. Plasma proteins such as IgM, fibrinogen, fibronectin and complement C3 were found to bind to non-PEGylated DNA complexes. At DNA concentrations relevant for in vivo gene delivery a strong aggregation of erythrocytes was also observed PEGylation of the complexes strongly reduces plasma protein binding and erythrocyte aggregation. Furthermore, PEGylated complex size was stabilized and had a reduced surface charge. Prolonged circulation in the blood of the PEGylated complexes was also observed when injected intravenously. In tumor bearing mice, application of non-PEGylated complexes through the tail vein resulted in reporter gene expression in fail and lung, but severe toxicity was observed in some mice. in contrast, PEGylated complexes mediated reporter gene transfer to the tumor without significant toxicity.
引用
收藏
页码:595 / 605
页数:11
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