期刊
GENE THERAPY
卷 18, 期 1, 页码 23-37出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2010.117
关键词
gene delivery; DNA pharmacokinetics; peptide; gene expression; biodistribution
类别
资金
- NIH [DK066212]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK066212] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM067795, R01GM087653, R01GM097093] Funding Source: NIH RePORTER
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-polyethylene glycol (PEG), possessing 2-6 repeats of Lys-acridine (Acr) spaced by either Lys, Arg, Leu or Glu, were Cys derivatized with PEG (PEG(5000 kDa)) 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 h. A tail vein dose of PEGylated polyacridine peptide pGL3 polyplexes (1 mu g in 50 mu l), followed by a stimulatory hydrodynamic dose of normal saline at times ranging from 5 to 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 mu g 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. Gene Therapy (2011) 18, 23-37; doi: 10.1038/gt.2010.117; published online 19 August 2010
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