Journal
PHARMACEUTICS
Volume 14, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics14040696
Keywords
polyene; polyhydroxyalkanoate; PHA; formulation; microsphere; Candida albicans; zebrafish
Categories
Funding
- Ministry of Education, Science and Technological Development of the Republic of Serbia [451-03-68/2022-14/200042, 451-03-68/2022-14/200175]
- European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
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Immobilizing antifungal polyenes into biodegradable formulations provides sustained release and reduced systemic drug toxicity. In this study, Nystatin and Amphotericin B were successfully encapsulated in mcl-PHA microspheres, showing great antifungal activity against various pathogenic fungi in zebrafish models.
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 mu m 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 x 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.
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