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Polyethylene glycol (PEG)ylated 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 acridine-modified lysine (Acr) in (Acr-Lys)(6)-Cys-PEG(5kDa) stabilizes a 1-μg pGL3 dose for up to 1 h 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. In this study, we report that increasing the spacing of Acr with either four or five Lys residues markedly increases the stability of PEGylated polyacridine peptide polyplexes in the circulation allowing maximal HD-stimulated expression for up to 5 h 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 h. This structure-activity relationship study defines the PEGylated polyacridine peptide requirements for maintaining fully transfection competent plasmid DNA in the circulation for 5 h and provides an understanding as to why polyplexes or lipoplexes prepared with polyethylenimine, chitosan or Lipofectamine are inactive within 5 min following intravenous dosing.

High-affinity PEGylated polyacridine peptide polyplexes mediate potent in vivo gene expression