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Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver

Gene Therapy volume 18, pages 23–37 (2011)Cite this article

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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.

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Acknowledgements

The authors gratefully acknowledge support from NIH Grant DK066212.

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Authors and Affiliations

  1. Divisions of Pharmaceutics and Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, IA, USA

    C A Fernandez, N J Baumhover, J T Duskey, S Khargharia, K Kizzire, M D Ericson & K G Rice

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  1. C A Fernandez
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Correspondence to K G Rice.

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Fernandez, C., Baumhover, N., Duskey, J. et al. Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver. Gene Ther 18, 23–37 (2011). https://doi.org/10.1038/gt.2010.117

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