Projects per year
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 language | English |
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Pages (from-to) | 1767–1777 |
Number of pages | 11 |
Journal | Biochimica et Biophysica Acta-Biomembranes |
Volume | 1859 |
Issue number | 10 |
Early online date | 10 Jun 2017 |
DOIs | |
Publication status | Published - Oct 2017 |
Keywords
- Antimicrobial resistance
- Cationic liposomes
- Oligonucleotide therapeutics
- Transfection
- Small-angle x-ray scattering
Profiles
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Michael McArthur
- Norwich Medical School - Professor of Nanomedicine
- Metabolic Health - Member
- Gastroenterology and Gut Biology - Member
Person: Research Group Member, Research Centre Member, Academic, Teaching & Research
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Grant Wheeler
- School of Biological Sciences - Professor
- Cells and Tissues - Member
- Wheeler Group - Group Leader
Person: Group Lead, Research Group Member, Academic, Teaching & Research
Projects
- 1 Finished
-
DNA-TRAP Delivery of Nucleic Acid-Based Theraputics for the TReatment of Antibiotic-Resistant Pathogens.
Morris, C., Baldelli Bombelli, F., McArthur, M., Wheeler, G., Giorgetti, M., Ruiz Estrada, G., Ruyra Ripoll, A., Saide, K. & Sitia, L.
1/10/13 → 30/09/17
Project: Research
Research output
- 25 Citations (Scopus)
- 1 Article
-
Antimicrobial nanoplexes meet model bacterial membranes: the key role of Cardiolipin
Marín-Menéndez, A., Montis, C., Díaz-Calvo, T., Carta, D., Hatzixanthis, K., Morris, C. J., McArthur, M. & Berti, D., 25 Jan 2017, In: Scientific Reports. 7, 41242.Research output: Contribution to journal › Article › peer-review
Open AccessFile42 Citations (Scopus)27 Downloads (Pure)