Pavic Aleksandar, Stojanovic Zoran, Pekmezovic Marina, Veljović Đorđe, O'Connor Kevin, Malagurski Ivana, Nikodinovic-Runic Jasmina
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11042 Belgrade, Serbia.
Institute of Technical Sciences of the Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia.
Pharmaceutics. 2022 Mar 24;14(4):696. doi: 10.3390/pharmaceutics14040696.
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 , , and 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 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.
与游离药物给药相比，将制霉菌素（Nys）和两性霉素B（AmB）等固定化抗真菌多烯类药物制成可生物降解制剂具有优势，可实现持续释放，通过局部靶向减少给药剂量，并总体降低全身药物毒性。在本研究中，我们将Nys和AmB封装在中链长度聚羟基脂肪酸酯（mcl-PHA）微球（直径7-8 µm）中。所获得的制剂已在体外针对一组致病真菌（包括 属、 属、 属和 属的菌种）进行了抗真菌活性验证，并在体内使用播散性念珠菌病斑马鱼模型验证了其毒性和疗效。虽然游离多烯类药物，尤其是AmB，在有效（MIC）剂量下对斑马鱼胚胎具有高毒性，但将它们负载到mcl-PHA微球中后，即使在100×MIC剂量下，也未观察到与这两种药物相关的内脏毒性和致畸性。所获得的mcl-PHA/多烯类制剂已成功根除 感染，并通过提高受感染胚胎的存活率在斑马鱼中显示出改善的治疗效果。这种方法为抗真菌药物库做出了贡献，因为多烯类药物虽然是市场上最早的广谱抗真菌药物，但仍是治疗真菌感染的金标准。
