Molecular Umbrella-Amphotericin B Conjugates

描述（由申请人提供）：分子伞是一类新的两亲分子，当暴露于疏水或亲水微环境时，分别可以产生疏水或亲水的外部。它们的独特之处在于，它们可以促进亲脂和亲水分子在脂质双分子层上的被动运输。此外，分子伞不遵循经典的大小/亲脂性规则，即小而亲脂的试剂比相对大而亲水的试剂更快地穿过脂质双层。基于这些独特的特性，分子伞提供了一个促进生物活性药物通过血脑屏障的被动运输的机会，这在以前是不可能的。从本质上讲，本研究将严格地验证这一假设，使用由分子伞和两性霉素B （AmB）制成的各种缀合物进行(i)模型膜研究，（ii）细胞毒性，溶血和抗真菌测量，以及（iii）体内血脑屏障运输实验。将合成的一些分子伞-两性霉素B偶联物也有望表现出相对于未偶联的AmB的广泛治疗指数。由于这个原因，它们也可能是系统使用的有吸引力的替代方案。在更广泛的背景下，成功促进AmB在血脑屏障上的运输将为探索其他分子伞状药物偶联物以治疗其他疾病提供强大的动力。在更基本的层面上，这个项目挑战了目前药物运输受分子大小和亲脂性限制的教条。本研究的直接目标有四个方面：(1)合成一系列广泛的分子伞- amb偶联物，这些分子伞- amb偶联物在多硫酸盐或多羟基化壁的数量、伞形框架的大小和柔韧性、所使用的聚乙二醇间隔物的长度以及可切割二硫键的存在方面各不相同；(2)确定分子伞- amb偶联物识别含麦角甾醇脂质体和真菌细胞的能力，并评估其细胞毒性；(3)表征每一种新的分子伞- amb偶联物的膜结合和双层运输特性；(4)确定所选分子伞- amb偶联物穿过血脑屏障的功效。

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. PUBLIC HEALTH RELEVANCE: Promoting the transport of hydrophilic drugs across cell membranes, and the blood-brain barrier in particular, represent major challenges for modern medicinal chemistry. Molecular umbrellas (molecules that can create an oil-loving or a water-loving exterior on demand) offer a fundamentally new approach for this long-standing problem. This program will test the feasibility of creating molecular umbrella-amphotericin B conjugates, which can be used as therapeutic agents for the treatment of fungal infections in the brain.