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Article

Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model

1
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11042 Belgrade, Serbia
2
Institute of Technical Sciences of the Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia
3
Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745 Jena, Germany
4
Faculty of Technology and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia
5
BiOrbic Bioeconomy SFI Research Centre, Belfield, D04 V1W Dublin, Ireland
6
School of Biomolecular and Biomedical Sciences, University College Dublin, Belfield, D04 V1W Dublin, Ireland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Juan José Torrado
Pharmaceutics 2022, 14(4), 696; https://doi.org/10.3390/pharmaceutics14040696
Received: 22 February 2022 / Revised: 18 March 2022 / Accepted: 18 March 2022 / Published: 24 March 2022
(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)
Immobilizing antifungal polyenes such as nystatin (Nys) and amphotericin B (AmB) into biodegradable formulations is advantageous compared to free drug administration providing sustained release, reduced dosing due to localized targeting and overall reduced systemic drug toxicity. In this study, we encapsulated Nys and AmB in medium chain length polyhydroxyalkanoates (mcl-PHA) microspheres (7–8 µm in diameter). The obtained formulations have been validated for antifungal activity in vitro against a panel of pathogenic fungi including species of Candida, Aspergillus, Microsporum and Trichophyton genera and toxicity and efficacy in vivo using the zebrafish model of disseminated candidiasis. While free polyenes, especially AmB, were highly toxic to zebrafish embryos at the effective (MIC) doses, after their loading into mcl-PHA microspheres, inner organ toxicity and teratogenicity associated with both drugs were not observed, even at 100 × MIC doses. The obtained mcl-PHA/polyene formulations have successfully eradicated C. albicans infection and showed an improved therapeutic profile in zebrafish by enhancing infected embryos survival. This approach is contributing to the antifungal arsenal as polyenes, although the first broad-spectrum antifungals on the market are still the gold standard for treatment of fungal infections. View Full-Text
Keywords: polyene; polyhydroxyalkanoate; PHA; formulation; microsphere; Candida albicans; zebrafish polyene; polyhydroxyalkanoate; PHA; formulation; microsphere; Candida albicans; zebrafish
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MDPI and ACS Style

Pavic, A.; Stojanovic, Z.; Pekmezovic, M.; Veljović, Đ.; O’Connor, K.; Malagurski, I.; Nikodinovic-Runic, J. Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model. Pharmaceutics 2022, 14, 696. https://doi.org/10.3390/pharmaceutics14040696

AMA Style

Pavic A, Stojanovic Z, Pekmezovic M, Veljović Đ, O’Connor K, Malagurski I, Nikodinovic-Runic J. Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model. Pharmaceutics. 2022; 14(4):696. https://doi.org/10.3390/pharmaceutics14040696

Chicago/Turabian Style

Pavic, Aleksandar, Zoran Stojanovic, Marina Pekmezovic, Đorđe Veljović, Kevin O’Connor, Ivana Malagurski, and Jasmina Nikodinovic-Runic. 2022. "Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model" Pharmaceutics 14, no. 4: 696. https://doi.org/10.3390/pharmaceutics14040696

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