Molecular Umbrella-Amphotericin B Conjugates

描述(申请人提供)：分子伞是一种新型的两亲性化合物，当暴露在疏水或亲水的微环境中时，可以分别产生疏水或亲水的外表。它们的独特之处在于，它们可以促进亲脂分子和亲水分子在脂双层之间的被动运输。此外，分子伞不遵循经典的大小/亲脂性规则，在该规则中，较小的亲脂性试剂预计会比相对较大和亲水性的试剂更快地穿过脂类双层。基于这些独特的性质，分子伞提供了一种机会，以以前不可能的方式促进生物活性物质在BBB中的被动运输。实质上，这项研究将在(I)模型膜研究、(Ii)细胞毒性、溶血和抗真菌测量以及(Iii)体内血脑屏障转运实验中，使用由分子伞和两性霉素B(Amb)制成的各种结合物来严格检验这一假说。与未结合的Amb相比，几种将被合成的分子伞-两性霉素B结合物也有望表现出更广泛的治疗指数。出于这个原因，它们可能也是系统性使用的有吸引力的替代方案。在更广泛的背景下，在促进Amb跨血脑屏障转运方面的成功将为探索用于治疗其他疾病的其他分子伞状药物结合物提供强大的动力。在更根本的层面上，这个计划挑战了目前的教条，即药物的传输受到分子大小和亲脂性的限制。本研究的近期目标有四个方面：(1)合成一系列不同的分子伞-AMB结合物，所述分子伞-AMB结合物具有不同的聚硫化或多羟基化壁的数量、伞状骨架的大小和柔性、所使用的聚乙二醇间隔物的长度以及可切割的二硫键的存在，(2)确定分子伞-AMB结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)表征每个新的分子伞-AMB结合物的膜结合和双层转运特性，以及(4)确定所选择的分子伞-AMB偶联物在跨越血脑屏障时的有效性。

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.