By a News Reporter-Staff News Editor at Gene Therapy Weekly -- Investigators publish new report on Pharmacokinetics. According to news originating from Iowa City, Iowa, by NewsRx correspondents, research stated, "The pharmacokinetics (PK), biodistribution and metabolism of non-viral gene delivery systems administered systemically are directly related to in vivo efficacy. The magnitude of luciferase expression in the liver of mice following a tail vein dose of a polyplex, composed of 1 mu g of pGL3 in complex with a polyethylene glycol (PEG) polyacridine peptide, followed by a delayed hydrodynamic (HD) stimulation (1-9 h), depends on the HD stimulation delay time and the structure of the polyacridine peptide."
Our news journalists obtained a quote from the research from the University of Iowa, "As demonstrated in the present study, the PEG length and the type of chemical linkage joining PEG to the polyacridine peptide dramatically influence the in vivo gene transfer efficiency. To understand how PEG length, linkage and location influence gene transfer efficiency, detailed PK, biodistribution and HD-stimulated gene expression experiments were performed on polyplexes prepared with an optimized polyacridine peptide modified through a single terminal Cys or Pen (penicillamine) with a PEG chain of average length of 2, 5, 10, 20, or 30 kDa. The chemical linkage was examined by attaching PEG(5 kDa) to the polyacridine peptide through a thiol-thiol (SS), thiol-maleimide (SM), thiol-vinylsulfone (SV), thiol-acetamide (SA), penicillamine-thiol-maleimide (PM) or penicillamine-thiol-thiol (PS). The influence of PEG location was analyzed by attaching PEG(5 kDa) to the polyacridine peptide through a C-terminal, N-terminal, or a middle Cys residue. The results established rapid metabolism of polyplexes containing SV and SA chemical linkages that leads to a decreased polyplex PK half-life and a complete loss of HD-stimulated gene expression at delay times of 5 h. Conversely, polyplexes containing PM, PS, and SM chemical linkages were metabolically stable, allowing robust HD-stimulated expression at delay times up to 5 h post-polyplex administration. The location of PEG(5 kDa) within the polyacridine peptide exerted only a minor influence on the gene transfer of polyplexes. However, varying the PEG length from 2, 5, 10, 20, or 30 kDa dramatically altered polyplex biodistribution, with a 30 kDa PEG maximally blocking liver uptake to 13% of dose, while maintaining the ability to mediate HD-stimulated gene expression."
According to the news editors, the research concluded: "The combination of results establishes important relationships between PEGylated polyacridine peptide structure, physical properties, in vivo metabolism, PK and biodistribution resulting in an optimal PEG length and linkage that leads to a robust HD-stimulated gene expression in mice."
For more information on this research see: PEG length and chemical linkage controls polyacridine peptide DNA polyplex pharmacokinetics, biodistribution, metabolic stability and in vivo gene expression. Journal of Controlled Release, 2013;170(3):325-333. Journal of Controlled Release can be contacted at: Elsevier Science Bv, PO Box 211, 1000 Ae Amsterdam, Netherlands. (Elsevier - www.elsevier.com; Journal of Controlled Release - www.elsevier.com/wps/product/cws_home/502690)
The news correspondents report that additional information may be obtained from S. Khargharia, University of Iowa, Coll Pharm, Div Med & Nat Prod Chem, Iowa City, IA 52242, United States. Additional authors for this research include K. Kizzire, M.D. Ericson, N.J. Baumhover and K.G. Rice (see also Pharmacokinetics).
Keywords for this news article include: Biotechnology, Pharmaceuticals, Drugs, Iowa City, Metabolism, Gene Therapy, United States, Penicillamine, Bioengineering, Pharmacokinetics, Sulfur Amino Acids, North and Central America
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