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Azithromycin-liposomes as a novel approach for localized therapy of cervicovaginal bacterial infections

Authors Vanić Ž, Rukavina Z, Manner S, Fallarero A, Uzelac L, Kralj M, Amidžić Klarić D, Bogdanov A, Raffai T, Virok DP, Filipović-Grčić J, Škalko-Basnet N

Received 9 April 2019

Accepted for publication 25 June 2019

Published 30 July 2019 Volume 2019:14 Pages 5957—5976


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Thomas J. Webster

Željka Vanić,1 Zora Rukavina,1 Suvi Manner,2 Adyary Fallarero,3 Lidija Uzelac,4 Marijeta Kralj,4 Daniela Amidžić Klarić,1 Anita Bogdanov,5 Tímea Raffai,5 Dezső Peter Virok,5 Jelena Filipović-Grčić,1 Nataša Škalko-Basnet6

1Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; 2Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi and University of Helsinki, 20520 Turku, Finland; 3Division of Pharmaceutical Biosciences, Pharmaceutical Biology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland; 4Department of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; 5Department of Medical Microbiology and Immunobiology, University of Szeged, 6720 Szeged, Hungary; 6Drug Transport and Delivery Research Group, Department of Pharmacy, Faculty of Health Sciences, University of Tromsø the Arctic University of Norway, 5037 Tromsø, Norway

Background: Efficient localized cervicovaginal antibacterial therapy, enabling the delivery of antibiotic to the site of action at lower doses while escaping systemic drug effects and reducing the risk of developing microbial resistance, is attracting considerable attention. Liposomes have been shown to allow sustained drug release into vaginal mucosa and improve delivery of antibiotics to bacterial cells and biofilms. Azithromycin (AZI), a potent broad-spectrum macrolide antibiotic, has not yet been investigated for localized therapy of cervicovaginal infections, although it is administered orally for the treatment of sexually transmitted diseases. Encapsulation of AZI in liposomes could improve its solubility, antibacterial activity, and allow the prolonged drug release in the cervicovaginal tissue, while avoiding systemic side effects.
Purpose: The objective of this study was to develop AZI-liposomes and explore their potentials for treating cervicovaginal infections.
Methods: AZI-liposomes that differed in bilayer elasticity/rigidity and surface charge were prepared and evaluated under simulated cervicovaginal conditions to yield optimized liposomes, which were assessed for antibacterial activity against several planktonic and biofilm-forming Escherichia coli strains and intracellular Chlamydia trachomatis, ex vivo AZI vaginal deposition/penetration, and in vitro cytotoxicity toward cervical cells.
Results: Negatively charged liposomes with rigid bilayers (CL-3), propylene glycol liposomes (PGL-2) and deformable propylene glycol liposomes (DPGL-2) were efficient against planktonic E. coli ATCC 700928 and K-12. CL-3 was superior for preventing the formation of E. coli ATCC 700928 and K-12 biofilms, with IC50 values (concentrations that inhibit biofilm viability by 50%) up to 8-fold lower than those of the control (free AZI). DPGL-2 was the most promising for eradication of already formed E. coli biofilms and for treating C. trachomatis infections. All AZI-liposomes were biocompatible with cervical cells and improved localization of the drug inside vaginal tissue compared with the control.
Conclusion: The performed studies confirm the potentials of AZI-liposomes for localized cervicovaginal therapy.

Keywords: vaginal drug delivery, biofilm, Escherichia coli, Chlamydia trachomatis, cervical cells, biocompatibility

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