Journal article
Metabolically Stabilized Long-Circulating PEGylated Polyacridine Peptide Polyplexes Mediate Hydrodynamically Stimulated Gene Expression in Liver
Gene therapy, Vol.18(1), pp.23-37
08/19/2010
DOI: 10.1038/gt.2010.117
PMCID: PMC2990782
PMID: 20720577
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-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.
Details
- Title: Subtitle
- Metabolically Stabilized Long-Circulating PEGylated Polyacridine Peptide Polyplexes Mediate Hydrodynamically Stimulated Gene Expression in Liver
- Creators
- Christian A. Fernandez - University of IowaNicholas J. Baumhover - University of IowaJason T. Duskey - University of IowaSanjib Khargharia - University of IowaKoby Kizzire - University of IowaMark D. EricsonKevin G. Rice
- Resource Type
- Journal article
- Publication Details
- Gene therapy, Vol.18(1), pp.23-37
- DOI
- 10.1038/gt.2010.117
- PMID
- 20720577
- PMCID
- PMC2990782
- NLM abbreviation
- Gene Ther
- ISSN
- 0969-7128
- eISSN
- 1476-5462
- Language
- English
- Date published
- 08/19/2010
- Academic Unit
- Radiology; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984365898202771
Metrics
9 Record Views