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Development of lipopolyplexes for gene delivery: a comparison of the effects of differing modes of targeting peptide display on the structure and transfection activities of lipopolyplexes

Bofinger, Robin; Zaw-Thin, May; Mitchell, Nicholas J.; Patrick, P. Stephen; Stowe, Cassandra; Gomez-Ramirez, Ana; Hailes, Helen C.; Kalber, Tammy L.; Tabor, Alethea B.

Authors

Robin Bofinger

May Zaw-Thin

P. Stephen Patrick

Cassandra Stowe

Ana Gomez-Ramirez

Helen C. Hailes

Tammy L. Kalber

Alethea B. Tabor



Abstract

The design, synthesis and formulation of non‐viral gene delivery vectors is an area of renewed research interest. Amongst the most efficient non‐viral gene delivery systems are lipopolyplexes, in which cationic peptides are co‐formulated with plasmid DNA and lipids. One advantage of lipopolyplex vectors is that they have the potential to be targeted to specific cell types by attaching peptide targeting ligands on the surface, thus increasing both the transfection efficiency and selectivity for disease targets such as cancer cells. In this paper, we have investigated two different modes of displaying cell‐specific peptide targeting ligands at the surface of lipopolyplexes. Lipopolyplexes formulated with bimodal peptides, with both receptor binding and DNA condensing sequences, were compared with lipopolyplexes with the peptide targeting ligand directly conjugated to one of the lipids. Three EGFR targeting peptide sequences were studied, together with a range of lipid formulations and maleimide lipid structures. The biophysical properties of the lipopolyplexes and their transfection efficiencies in a basal‐like breast cancer cell line were investigated using plasmid DNA bearing genes for the expression of firefly luciferase and green fluorescent protein. Fluorescence quenching experiments were also used to probe the macromolecular organisation of the peptide and pDNA components of the lipopolyplexes. We demonstrated that both approaches to lipopolyplex targeting give reasonable transfection efficiencies, and the transfection efficiency of each lipopolyplex formulation is highly dependent on the sequence of the targeting peptide. To achieve maximum therapeutic efficiency, different peptide targeting sequences and lipopolyplex architectures should be investigated for each target cell type.

Journal Article Type Article
Publication Date Oct 16, 2018
Journal Journal of Peptide Science
Print ISSN 1075-2617
Publisher Wiley
Peer Reviewed Peer Reviewed
Pages e3131
APA6 Citation Bofinger, R., Zaw-Thin, M., Mitchell, N. J., Patrick, P. S., Stowe, C., Gomez-Ramirez, A., …Tabor, A. B. (2018). Development of lipopolyplexes for gene delivery: a comparison of the effects of differing modes of targeting peptide display on the structure and transfection activities of lipopolyplexes. Journal of Peptide Science, (e3131). doi:10.1002/psc.3131. ISSN 1075-2617
DOI https://doi.org/10.1002/psc.3131
Keywords Organic Chemistry; Molecular Medicine; Biochemistry; Molecular Biology; Pharmacology; Structural Biology; Drug Discovery; General Medicine
Publisher URL https://onlinelibrary.wiley.com/doi/abs/10.1002/psc.3131

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