Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model
2022
Аутори
Pavić, AleksandarStojanović, Zoran
Pekmezović, Marina
Veljović, Đorđe
O'Connor, Kevin
Malagurski, Ivana
Nikodinović-Runić, Jasmina
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 formulat...ions 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.
Кључне речи:
zebrafish / polyhydroxyalkanoate / polyene / PHA / microsphere / formulation / Candida albicansИзвор:
Pharmaceutics, 2022, 14, 4Издавач:
- MDPI, Basel
Финансирање / пројекти:
- European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200042 (Универзитет у Београду, Институт за молекуларну генетику и генетичко инжењерство) (RS-MESTD-inst-2020-200042)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200175 (Институт техничких наука САНУ, Београд) (RS-MESTD-inst-2020-200175)
DOI: 10.3390/pharmaceutics14040696
ISSN: 1999-4923
WoS: 000786808300001
Scopus: 2-s2.0-85127808436
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Pavić, Aleksandar AU - Stojanović, Zoran AU - Pekmezović, Marina AU - Veljović, Đorđe AU - O'Connor, Kevin AU - Malagurski, Ivana AU - Nikodinović-Runić, Jasmina PY - 2022 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1554 AB - 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. PB - MDPI, Basel T2 - Pharmaceutics T1 - Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model IS - 4 VL - 14 DO - 10.3390/pharmaceutics14040696 ER -
@article{ author = "Pavić, Aleksandar and Stojanović, Zoran and Pekmezović, Marina and Veljović, Đorđe and O'Connor, Kevin and Malagurski, Ivana and Nikodinović-Runić, Jasmina", year = "2022", abstract = "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.", publisher = "MDPI, Basel", journal = "Pharmaceutics", title = "Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model", number = "4", volume = "14", doi = "10.3390/pharmaceutics14040696" }
Pavić, A., Stojanović, Z., Pekmezović, M., Veljović, Đ., O'Connor, K., Malagurski, I.,& Nikodinović-Runić, J.. (2022). Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model. in Pharmaceutics MDPI, Basel., 14(4). https://doi.org/10.3390/pharmaceutics14040696
Pavić A, Stojanović Z, Pekmezović M, Veljović Đ, O'Connor K, Malagurski I, Nikodinović-Runić J. Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model. in Pharmaceutics. 2022;14(4). doi:10.3390/pharmaceutics14040696 .
Pavić, Aleksandar, Stojanović, Zoran, Pekmezović, Marina, Veljović, Đorđe, O'Connor, Kevin, Malagurski, Ivana, Nikodinović-Runić, Jasmina, "Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model" in Pharmaceutics, 14, no. 4 (2022), https://doi.org/10.3390/pharmaceutics14040696 . .