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 (PEG 5000 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 g in 50 l), 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 g 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. © 2011 Macmillan Publishers Limited All rights reserved.

Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver / Fernandez, C. A.; Baumhover, N. J.; Duskey, J. T.; Khargharia, S.; Kizzire, K.; Ericson, M. D.; Rice, K. G.. - In: GENE THERAPY. - ISSN 0969-7128. - 18:1(2011), pp. 23-37. [10.1038/gt.2010.117]

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

Duskey J. T.;
2011

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 (PEG 5000 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 g in 50 l), 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 g 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. © 2011 Macmillan Publishers Limited All rights reserved.
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Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver / Fernandez, C. A.; Baumhover, N. J.; Duskey, J. T.; Khargharia, S.; Kizzire, K.; Ericson, M. D.; Rice, K. G.. - In: GENE THERAPY. - ISSN 0969-7128. - 18:1(2011), pp. 23-37. [10.1038/gt.2010.117]
Fernandez, C. A.; Baumhover, N. J.; Duskey, J. T.; Khargharia, S.; Kizzire, K.; Ericson, M. D.; Rice, K. G.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1205664
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