Molecular Umbrella-Amphotericin B Conjugates

描述（由申请人提供）：分子伞是一类新型的两亲物，当分别暴露于疏水或亲水微环境时，可以产生疏水或亲水的外部。它们的独特之处在于它们可以促进亲脂性以及亲水性分子跨脂质双层的被动转运。此外，分子伞不遵循经典的大小/亲脂性规则，其中小的亲脂性试剂预期比相对大的亲水性试剂更快地穿过脂质双层。基于这些独特的性质，分子伞提供了一个机会，促进被动运输的生物活性剂通过血脑屏障的方式，以前是不可能的。从本质上讲，本研究将严格测试这一假设，使用各种共轭分子伞和阿朴霉素B（AmB）在（i）模型膜研究，（ii）细胞毒性，溶血和抗真菌的测量，和（iii）在体内血脑屏障运输实验。 还预期将合成的几种分子伞-阿替霉素B缀合物相对于未缀合的AmB表现出宽的治疗指数。出于这个原因，它们也可能是全身使用的有吸引力的替代品。在更广泛的背景下，促进AmB穿过BBB的运输的成功将为探索用于治疗其他疾病的其他分子伞-药物缀合物提供强烈的激励。在更基本的层面上，该计划挑战了目前的教条，即药物转运受到分子大小和亲脂性的限制。 这项研究的直接目标有四个方面：（1）合成广泛系列的分子伞形-AmB缀合物，其在多硫酸化或多羟基化壁的数量、伞形框架的大小和柔性、聚硫酸化或多羟基化壁的长度、聚硫酸化（乙二醇）间隔基，以及可裂解二硫键的存在，（2）确定分子伞形-AmB缀合物识别含麦角甾醇的脂质体和真菌细胞的能力，并评估它们的细胞毒性，（3）表征每种新的分子伞-AmB缀合物的膜结合和双层转运性质，和（4）确定所选分子伞-AmB缀合物在穿过BBB中的功效。

DESCRIPTION (provided by applicant): Molecular umbrellas are a novel class of amphiphiles that can create hydrophobic or hydrophilic exteriors when exposed to hydrophobic or hydrophilic microenvironments, respectively. They are unique in that they can promote the passive transport of lipophilic as well as hydrophilic molecules across lipid bilayers. In addition, molecular umbrellas do not follow the classic size/lipophilicity rule, where small and lipophilic agents are expected to cross lipid bilayers faster than ones that are relatively large and hydrophilic. Based on these unique properties, molecular umbrellas provide an opportunity for promoting the passive transport of biologically-active agents across the BBB in ways that have not previously been possible. In essence, this research will test this hypothesis, rigorously, using a variety of conjugates made from molecular umbrellas and amphotericin B (AmB) in (i) model membrane studies, (ii) cytotoxicity, hemolytic and antifungal measurements, and (iii) in vivo BBB-transport experiments. Several of the molecular umbrella-amphotericin B conjugates that will be synthesized are also expected to exhibit a wide therapeutic index relative to unconjugated AmB. For this reason, they may represent attractive alternatives for systemic use as well. In a broader context, success in promoting the transport of AmB across the BBB would provide a strong incentive for exploring other molecular umbrella-drug conjugates for treating other diseases. At a more fundamental level, this program challenges the current dogma that drug transport is limited by molecular size and lipophilicity. The immediate objectives of this research are four-fold: (1) to synthesize a broad series of molecular umbrella-AmB conjugates that vary in the number of polysulfated or polyhydroxylated walls, the size and flexibility of the umbrella framework, the length of the poly(ethylene glycol) spacer used, and the presence of a cleavable disulfide bond, (2) to determine the ability of the molecular umbrella-AmB conjugates to recognize ergosterol-containing liposomes and fungal cells, and to assess their cytotoxicity, (3) to characterize the membrane-binding and bilayer transport properties of each new molecular umbrella-AmB conjugate, and (4) to determine the efficacy of selected molecular umbrella-AmB conjugates in crossing the BBB.