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

Pharmaceutics

卷:14

Kevin O’Connor¹  Đorđe Veljović²  Aleksandar Pavic³  Jasmina Nikodinovic-Runic³  Ivana Malagurski³  Zoran Stojanovic⁴  Marina Pekmezovic⁵ 

[1] BiOrbic Bioeconomy SFI Research Centre, Belfield, D04 V1W Dublin, Ireland;

[2] Faculty of Technology and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia;

[3] Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11042 Belgrade, Serbia;

[4] Institute of Technical Sciences of the Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia;

[5] Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745 Jena, Germany;

关键词: polyene;    polyhydroxyalkanoate;    PHA;    formulation;    microsphere;    Candida albicans;   

DOI  :  10.3390/pharmaceutics14040696

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown