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Asymmetrical N4,N9-Diacyl Spermines: SAR Studies of Nonviral Lipopolyamine Vectors for Efficient siRNA Delivery with Silencing of EGFP Reporter Gene


Reference:

Blagbrough, I. S., Metwally, A. A. and Ghonaim, H. M., 2012. Asymmetrical N4,N9-Diacyl Spermines: SAR Studies of Nonviral Lipopolyamine Vectors for Efficient siRNA Delivery with Silencing of EGFP Reporter Gene. Molecular Pharmaceutics, 9 (7), pp. 1853-1861.

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    Official URL:

    http://dx.doi.org/10.1021/mp200428d

    Abstract

    Our aim is to study the effects of varying the two acyl moieties in synthesized N4,N9-diacyl spermines on siRNA formulations and their delivery efficiency in cell lines. Six novel asymmetrical lipopolyamines, [N4-cholesteryloxy-3-carbonyl-N9-oleoyl-, N4-decanoyl-N9-oleoyl-, N4-decanoyl-N9-stearoyl-, N4-lithocholoyl-N9-oleoyl-, N4-myristoleoyl-N9-myristoyl-, and N4-oleoyl-N9-stearoyl]-1,12-diamino-4,9-diazadodecane, were assessed for their abilities to bind to siRNA, studied using a RiboGreen intercalation assay, and to form nanoparticles. Their siRNA delivery efficiencies were quantified in FEK4 primary skin cells and in an immortalized cancer cell line (HtTA) using a fluorescein-tagged siRNA, and compared with formulations of N4,N9-dioleoyl-1,12-diamino-4,9-diazadodecane and of a leading transfecting agent, TransIT-TKO. Transfection was measured in terms of siRNA delivery and silencing of EGFP reporter gene in HeLa cells. By incorporating two different acyl moieties, changing their length and oxidation level in a controlled manner, we show efficient fluorescein-tagged siRNA formulation, delivery, and knock-down of EGFP reporter gene. N4-Oleoyl-N9-stearoyl spermine and N4-myristoleoyl-N9-myristoyl spermine are effective siRNA delivery vectors typically resulting in 89% cell delivery and gene silencing to 34% in the presence of serum, comparable with the results obtained with TransIT-TKO; adding a second lipid chain is better than incorporating a steroid moiety.

    Details

    Item Type Articles
    CreatorsBlagbrough, I. S., Metwally, A. A. and Ghonaim, H. M.
    DOI10.1021/mp200428d
    DepartmentsFaculty of Science > Pharmacy & Pharmacology
    Publisher StatementBlagbrough_Mol_Pharm_2012_9_1853.pdf: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/mp200428d
    RefereedYes
    StatusPublished
    ID Code30485

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