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High-Affinity PEGylated Polyacridine Peptide Polyplexes Mediate Potent In Vivo Gene Expression
Journal article   Open access   Peer reviewed

High-Affinity PEGylated Polyacridine Peptide Polyplexes Mediate Potent In Vivo Gene Expression

Koby Kizzire, Sanjib Khargharia and Kevin G Rice
Gene therapy, Vol.20(4), pp.407-416
04/2013
DOI: 10.1038/gt.2012.47
PMCID: PMC3665005
PMID: 22786534
url
https://doi.org/10.1038/gt.2012.47View
Published (Version of record) Open Access

Abstract

PEGylated polyacridine peptides bind to plasmid DNA with high affinity to form unique polyplexes that possess a long circulatory half-life and are hydrodynamically (HD)-stimulated to produce efficient gene expression in the liver of mice. We previously demonstrated that (Acr-Lys) 6 -Cys-PEG 5kDa stabilizes a 1 μg pGL3 dose for up to 1 hr in the circulation, resulting in HD-stimulated (saline only) gene expression in the liver, equivalent in magnitude to direct-HD dosing of 1 μg of pGL3 (Fernandez C.A. et al. Gene Therapy 2011). In the present study we report that increasing the spacing of Acr with either 4 or 5 Lys residues, dramatically increases the stability of PEGylated polyacridine peptide polyplexes in the circulation allowing maximal HD-stimulated expression for up to 5 hrs post-DNA administration. Co-administration of a decoy dose of 9 μg of non-expressing DNA polyplex with 1 μg of pGL3 polyplex further extended the HD-stimulated expression to 9 hrs. This structure-activity relationship study defines the PEGylated polyacridine peptide requirements for maintaining fully transfection competent plasmid DNA in the circulation for 5 hrs and provides an understanding as to why polyplexes or lipoplexes prepared with PEI, chitosan or Lipofectamine are inactive within 5 min following i.v. dosing.
 gene delivery pharmacokinetics peptide hydrodynamics liver

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