Selective Small Molecule Membrane Transport Using Cavitand Receptors

描述（由申请人提供）：小分子在生物膜上的传递一直是药物化学的一个长期挑战。一些在体外非常有效的药物与人体组织的运输机制不相容，因为细胞膜被证明是不可穿透的。这些药物的输送可以通过精心设计的合成受体来促进，自然受体可以作为设计的灵感来源。最近的研究表明，间苯二甲酸甲酯空腔体能够作为小分子客体的选择性受体，同时定位于磷酸胆碱（PC）胶束中。PC胶束是直接观察宿主和客体相互作用的有用工具，但它们不能近似于生物膜。另一方面，脂质囊泡是一个更现实的模型。本项目旨在制备一系列可荧光标记的单功能化间苯二甲酸甲酯空腔体，以研究荧光标记的受体互补小分子在有序脂质组装中的运输。空腔体和小分子客体将被引入到单层囊泡中，共聚焦显微镜将用于评估成功的膜定位和运输。从这些初步研究中获得的知识将应用于哺乳动物细胞膜。使用荧光标记的空腔体，我们将能够评估各种空腔体的细胞膜定位。这些结果将导致新的见解和假设，可以部署到基于细胞的分析，以探索以前的膜耐药候选药物。此外，新的“纳米医学”方法支持探索多阳离子空腔体作为直接遗传转染载体的作用。这些选择性分子运输的新方法将为推进当前的药物输送方法和设计纳米级医疗设备提供令人兴奋的机会。

DESCRIPTION (provided by applicant): The delivery of small molecules across biological membranes has been a long-standing challenge to medicinal chemistry. Several drugs that are highly effective in vitro are incompatible with the transport mechanisms of the human organism as the cell membrane proves to be impenetrable. The delivery of such drugs could be facilitated by carefully designed synthetic receptors, with natural receptors serving as an inspiration for design. It was recently demonstrated that resorcinarene cavitands are capable of behaving as selective receptors for small-molecule guests while localized in aqueous phosphocholine (PC) micelles. PC micelles serve as a useful tool for the direct observation of host and guest interaction, but they fall short of approximating biological membranes. Lipid vesicles on the other hand, serve as a more realistic model. This project aims to prepare a series of mono-functionalized resorcinarene cavitands that can be fluorescently tagged to study the transport of fluorescently tagged receptor-complementary small molecules across ordered lipid assemblies. Cavitands and small molecule guests will be introduced into unilamellar vesicles and confocal microscopy will be utilized to evaluate successful membrane localization and transport. The knowledge acquired from these initial studies will be applied to mammalian cell membranes. Using fluorescently tagged cavitands we will be able to evaluate a variety of cavitands for cell membrane localization. These results will lead to new insights and hypotheses that can be deployed towards cell based assays to explore previously membrane resistant drug candidates. Additionally, new "nano-medicinal" approaches support exploring roles in which polycationic cavitands can serve as direct genetic transfection vectors. These new approaches to selective molecular transport will provide exciting opportunities towards advancing current drug delivery methods and designing nanoscale medical devices. PUBLIC HEALTH RELEVANCE: Annually, several promising clinically relevant compounds are discovered using in vitro techniques, only later to be dismissed due to an inability to penetrate the cell membrane. We aim to overcome this problem through the development of synthetic receptors that are suitable to selectively shuttle fluorophores and small drug like molecules across simplified lipid bilayers. Ultimately, we hope to use this information to develop receptors that are compatible with cellular systems and one day provide a means to overcoming what remains a major hurdle for medicinal chemistry and the effective treatment of human disease.