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- Title
Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver.
- Authors
Fernandez, C A; Baumhover, N J; Duskey, J T; Khargharia, S; Kizzire, K; Ericson, M D; Rice, K G
- Abstract
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 (PEG5000 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 μg in 50 μl), 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 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.
- Subjects
POLYETHYLENE glycol; GENE expression; GENE therapy; GENETIC transformation; METABOLISM; LABORATORY mice; ACRIDINE; PHARMACOKINETICS; DRUG delivery systems
- Publication
Gene Therapy, 2011, Vol 18, Issue 1, p23
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/gt.2010.117