Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver.
Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver.
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作者：
开发了一类新型的PEG化聚吖啶肽，其在小鼠肝脏中介导有效的刺激基因转移。聚吖啶肽（Acr-X）n-Cys-PEG具有2-6个由Lys、Arg、Leu或Glu间隔的Lys-吖啶（Acr）重复序列，用聚乙二醇（PEG 5000 Da）进行Cys衍生，并作为体内基因转移剂进行评价。结果表明，（Acr-Lys）6-Cys-PEG能与质粒DNA（pGL 3）高亲和力结合，稳定DNA，使其不被DNA酶代谢，延长DNA在循环中的药代动力学半衰期达2小时。尾静脉剂量的聚乙二醇化聚吖啶肽pGL 3复合物（50 μl中1 μg），随后在DNA给药后5-60 min的时间范围内刺激流体动力学剂量的生理盐水，导致肝脏中高水平的荧光素酶表达，相当于直接流体动力学剂量1 μg pGL 3介导的水平。这些结果确立了聚乙二醇化聚吖啶肽作为一类新的和有前途的基因递送肽的独特性质，其促进与质粒DNA的可逆结合，在体内保护其免受DNA酶的影响，从而延长循环半衰期，并将转染感受态DNA释放到肝脏中，以介导流体动力学增强后的高水平基因表达。
A novel class of PEGylated polyacridine peptides was developed that mediate potent stimulated gene transfer in the liver of mice. Polyacridine peptides, (Acr-X)n-Cys-PEG, possessing 2–6 repeats of Lys-acridine (Acr) spaced by either Lys, Arg, Leu or Glu, were Cys derivatized with polyethylene glycol (PEG 5000 Da) and evaluated as in vivo gene transfer agents. An optimal peptide of (Acr-Lys)6-Cys-PEG was able to bind to plasmid DNA (pGL3) with high affinity by polyintercalation, stabilize DNA from metabolism by DNAse and extend the pharmacokinetic half-life of DNA in the circulation for up to 2 hrs. A tail vein dose of PEGylated polyacridine peptide pGL3 polyplexes (1 μg in 50 μl), followed by a stimulatory hydrodynamic dose of normal saline at times ranging from 5–60 min post-DNA administration, led to a high level of luciferase expression in the liver, equivalent to levels mediated by direct hydrodynamic dosing of 1 μg of pGL3. The results establish the unique properties of PEGylated polyacridine peptides as a new and promising class of gene delivery peptides that facilitate reversible binding to plasmid DNA, protecting it from DNase in vivo resulting in an extended circulatory half-life, and release of transfection-competent DNA into the liver to mediate a high-level of gene expression upon hydrodynamic boost.
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影响因子：
5.1
作者：
Dash, PR;Read, ML;Seymour, LW
通讯作者：
Seymour, LW
影响因子：
3.5
作者：
Boeckle, S;von Gersdorff, K;Ogris, M
通讯作者：
Ogris, M
DOI：
10.1006/bbrc.2001.5418
发表时间：
2001-08-24
影响因子：
3.1
作者：
Guillaume, CR;Delepine, P;Claude, F
通讯作者：
Claude, F
影响因子：
5.1
作者：
Li, S;Rizzo, MA;Huang, L
通讯作者：
Huang, L
DOI：
10.1073/pnas.95.4.1427
发表时间：
1998-02-17
影响因子：
11.1
作者：
Blessing, T;Remy, JS;Behr, JP
通讯作者：
Behr, JP