抗生素载体植物体是开发创新型多烯大环内酯脂质制剂的一种途径

S. Efimova, O. Ostroumova
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摘要

背景:真菌病原体对抗生素产生抗药性的威胁,以及最有效药物多烯大环内酯类药物的高毒性,迫使我们寻找开发创新型抗真菌制剂的新方法。研究目的本研究旨在确定多烯类抗生素脂质体形式(尤其是两性霉素 B(AmB))的甾醇、磷脂和类黄酮成分如何影响其增加模拟哺乳动物和真菌细胞膜的脂质双分子层渗透性的能力。研究方法为了监测各种基于聚烯烃的脂质制剂诱导的膜渗透性,使用了钙蓝蛋白渗漏测定法和基于平面脂质双分子层的电生理技术。主要结果用胆固醇的生物合成前体--7-脱氢胆固醇替代胆固醇,会降低 AmB 脂质体对模拟哺乳动物细胞膜的脂质双分子层的渗透能力。在 AmB 脂质体中加入植物黄酮类化合物植物黄酮素,可提高制剂从模拟目标真菌膜的脂质囊泡中脱离荧光标记物的能力。经 AmB 植物脂质体处理的类真菌脂质双分子层的 I-V 特性是对称的,这证明了双长 AmB 孔的功能,并假定抗生素阈值浓度会降低。结论与展望:改变多烯脂质制剂的固醇组成可扩大其治疗窗口。多烯载植物体可被视为创新脂质抗生素制剂的原型。
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Antibiotic Loaded Phytosomes as a Way to Develop Innovative Lipid Formulations of Polyene Macrolides
Background: The threat of antibiotic resistance of fungal pathogens and the high toxicity of the most effective drugs, polyene macrolides, force us to look for new ways to develop innovative antifungal formulations. Objective: The aim of this study was to determine how the sterol, phospholipid, and flavonoid composition of liposomal forms of polyene antibiotics, and in particular, amphotericin B (AmB), affects their ability to increase the permeability of lipid bilayers that mimic the membranes of mammalian and fungal cells. Methods: To monitor the membrane permeability induced by various polyene-based lipid formulations, a calcein leakage assay and the electrophysiological technique based on planar lipid bilayers were used. Key results: The replacement of cholesterol with its biosynthetic precursor, 7-dehydrocholesterol, led to a decrease in the ability of AmB-loaded liposomes to permeabilize lipid bilayers mimicking mammalian cell membranes. The inclusion of plant flavonoid phloretin in AmB-loaded liposomes increased the ability of the formulation to disengage a fluorescent marker from lipid vesicles mimicking the membranes of target fungi. I–V characteristics of the fungal-like lipid bilayers treated with the AmB phytosomes were symmetric, demonstrating the functioning of double-length AmB pores and assuming a decrease in the antibiotic threshold concentration. Conclusions and Perspectives: The therapeutic window of polyene lipid formulations might be expanded by varying their sterol composition. Polyene-loaded phytosomes might be considered as the prototypes for innovative lipid antibiotic formulations.
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