RUI: The Three Facets of Amphotericin B Activity

目前市场上有三种膜活性抗生素两性霉素B（AmB）的脂质相关超分子制剂：AmBisome、Amphorectin和Abelcet。它们在物理上有着根本的不同：AmBisome是真正的封闭脂质体双层制剂，Amphosome是含有胆固醇硫酸酯的胶束分散体，Abelcet是指叉型脂质分散体。尽管存在这些差异，但与哺乳动物细胞相比，所有三种制剂都损害真菌膜，并且都比由摩尔比为约1：2的AmB：脱氧胆酸盐组成的原始胶束商业制剂（Fungizone，FZ）更有活性。简单的AmB或FZ溶液可以用中等温度处理（70 ℃，20分钟），以产生AmB的新的自缔合状态，一种非超聚集体，称为热处理的Fungizone（HFZ）。本项目的目标是梳理这五种两性霉素B超分子制剂的哪些特异性生化和生物物理性质使它们对真菌和哺乳动物细胞膜具有选择性反应性。将通过光谱和分子生物学方法研究影响AmB制剂的毒性和选择性的三个因素：1）通过离子通道形成的直接膜活性，2）由于在血清脂蛋白/蛋白质存在下AmB复合物的稳定性差异导致的分布和递送至组织的差异，以及3）炎症细胞因子应答的启动。

Three lipid-associated supramolecular preparations of the membrane-active antibiotic Amphotericin B (AmB) are currently on the market: AmBisome, Amphocil, and Abelcet. They are fundamentally different physically: AmBisome is a true closed liposomal bilayer preparation, Amphocil is micellar dispersion with cholesteryl sulfate and Abelcet is interdigitated lipid dispersion. Despite these differences, all three preparations damage fungal membranes compared to mammalian cell and all are more active than the original micellar commercial preparation consisting of AmB: deoxycholate in a mole ratio of ~1:2 (Fungizone, FZ). Simple AmB or FZ solutions may be treated with moderate heat (70 o C for 20 minutes) to produce a new self-associated state of AmB, a imsuperaggregatel., termed heat-treated Fungizone (HFZ). The goal of this project is to tease apart which specificbiochemical and biophysical properties of these five Amphotericin B supramolecular preparations make them selectively reactive toward fungal versus mammalian cell membranes. Three factors which influence the toxicity and selectivity of AmB preparations will be investigated by spectroscopic and molecular biology methods: 1) direct membrane activity via ion channel formation, 2) differences in distribution and delivery to tissues due to differences in stability of AmB complexes in the presence of serum lipoproteins/proteins, and 3) initiation of an inflammatory cytokine response.