Cationic liposomal vectors incorporating a bolaamphiphile for oligonucleotide antimicrobials

Mamusa, Marianna, Sitia, Leopoldo, Barbero, Francesco, Ruyra, Angels, Díaz Calvo, Teresa, Montis, Costanza, Gonzalez-Paredes, Ana, Wheeler, Grant N., Morris, Christopher J., McArthur, Michael and Berti, Debora (2017) Cationic liposomal vectors incorporating a bolaamphiphile for oligonucleotide antimicrobials. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1859 (10). 1767–1777. ISSN 0005-2736

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Abstract

Antibacterial resistance has become a serious crisis for world health over the last few decades, so that new therapeutic approaches are strongly needed to face the threat of resistant infections. Transcription factor decoys (TFD) are a promising new class of antimicrobial oligonucleotides with proven in vivo activity when combined with a bolaamphiphilic cationic molecule, 12-bis-THA. These two molecular species form stable nanoplexes which, however, present very scarce colloidal stability in physiological media, which poses the challenge of drug formulation and delivery. In this work, we reformulated the 12-bis-THA/TFD nanoplexes in a liposomal carrier, which retains the ability to protect the oligonucleotide therapeutic from degradation and deliver it across the bacterial cell wall. We performed a physical-chemical study to investigate how the incorporation of 12-bis-THA and TFD affects the structure of POPC- and POPC/DOPE liposomes. Analysis was performed using dynamic light scattering (DLS), ζ-potential measurements, small-angle x-ray scattering (SAXS), and steady-state fluorescence spectroscopy to better understand the structure of the liposomal formulations containing the 12-bis-THA/TFD complexes. Oligonucleotide delivery to model Escherichia coli bacteria was assessed by means of confocal scanning laser microscopy (CLSM), evidencing the requirement of a fusogenic helper lipid for transfection. Preliminary biological assessments suggested the necessity of further development by modulation of 12-bis-THA concentration in order to optimize its therapeutic index, i.e. the ratio of antibacterial activity to the observed cytotoxicity. In summary, POPC/DOPE/12-bis-THA liposomes appear as promising formulations for TFD delivery.

Item Type: Article
Uncontrolled Keywords: antimicrobial resistance,cationic liposomes,oligonucleotide therapeutics,transfection,small-angle x-ray scattering
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Science > School of Pharmacy
Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Chemistry
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Depositing User: Pure Connector
Date Deposited: 14 Jun 2017 05:06
Last Modified: 17 Mar 2020 23:29
URI: https://ueaeprints.uea.ac.uk/id/eprint/63747
DOI: 10.1016/j.bbamem.2017.06.006

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