Cationic liposomal vectors incorporating a bolaamphiphile for oligonucleotide antimicrobials

Marianna Mamusa, Leopoldo Sitia, Francesco Barbero, Angels Ruyra, Teresa Díaz Calvo, Costanza Montis, Ana Gonzalez-Paredes, Grant N. Wheeler, Christopher J. Morris, Michael McArthur, Debora Berti

Research output: Contribution to journalArticle

17 Citations (Scopus)
13 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)1767–1777
Number of pages11
JournalBiochimica et Biophysica Acta (BBA) - Biomembranes
Volume1859
Issue number10
Early online date10 Jun 2017
DOIs
Publication statusPublished - Oct 2017

Keywords

  • Antimicrobial resistance
  • Cationic liposomes
  • Oligonucleotide therapeutics
  • Transfection
  • Small-angle x-ray scattering

Cite this