Selective Small Molecule Membrane Transport Using Cavitand Receptors

描述（由申请人提供）：小分子穿过生物膜的递送一直是药物化学的长期挑战。几种在体外非常有效的药物与人体组织的转运机制不相容，因为细胞膜被证明是不可穿透的。这种药物的输送可以通过精心设计的合成受体来促进，天然受体可以作为设计的灵感。最近的研究表明，间苯二酚芳烃空穴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胶束作为一个有用的工具，直接观察主客体相互作用，但他们没有接近生物膜。另一方面，脂质囊泡作为一个更现实的模型。本项目的目的是制备一系列单功能化的间苯二酚芳烃空穴，可以被荧光标记，以研究荧光标记的受体互补小分子在有序脂质组装体中的转运。空穴和小分子客人将被引入单层囊泡和共聚焦显微镜将被用来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，我们将能够评估各种空腔的细胞膜定位。这些结果将导致新的见解和假设，可以部署到基于细胞的测定，以探索以前的膜耐药候选药物。此外，新的“纳米药物”方法支持探索聚阳离子空腔可以作为直接遗传转染载体的作用。这些选择性分子转运的新方法将为推进当前的药物递送方法和设计纳米级医疗设备提供令人兴奋的机会。 公共卫生相关性：每年，使用体外技术发现几种有前途的临床相关化合物，只是后来由于不能穿透细胞膜而被排除。我们的目标是克服这个问题，通过开发合成受体，适合选择性穿梭荧光团和小药物样分子在简化的脂质双层。最终，我们希望利用这些信息来开发与细胞系统相容的受体，并有一天提供一种克服药物化学和有效治疗人类疾病的主要障碍的方法。

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.