Extended Lithium Release from Metal-Organic Frameworks for Therapeutic Applications

项目摘要/摘要 几十年来，锂盐一直被用来治疗严重的双相情感障碍和严重的抑郁症，特别是在 在自杀风险很高的情况下，锂仍然是他们今天最有效的治疗方法。尽管它很有效， 锂的治疗窗口很窄，因为它很难在体内保持有效浓度 而不会招致严重的不良副作用。这项提议旨在使用金属-有机框架，一个 结晶型和多孔型有机-无机混合材料，用于缓慢和延长锂的释放 作为一种治疗情绪障碍的方法。金属-有机框架，坚固耐用，可调，结构合理 定义良好的材料，提供了易于修改和表征的优点。通过明智的选择 金属节点、有机连接物和客体物种，将有可能调整热力学和动力学 对Li+的吸收和释放的影响。锂相互作用的策略将包括将小有机分子添加到 开放的金属配位，将锂结合官能团结合到有机骨架上 连接物，以及在保持结晶度的同时，合成后将锂交换为骨架阳离子。潜力 感兴趣的骨架将使用标准的有机和无机合成方法合成，然后 受到各种表征技术的影响，包括：粉末和单晶X射线 衍射、气体吸附测量、溶液和固态核磁共振光谱，以及多种形式的 元素分析。锂的吸收和释放将通过溶液状态等温线和动力学进行监测 对它们(脱)锂的骨架进行了测量以及结晶学和光谱分析 各州。有希望的材料将被反复改进，并受到模拟生物条件的影响 锂的释放。如果成功，该项目将把金属-有机框架定位为一个通用的平台 解决用锂治疗严重神经疾病的重要健康挑战。这项研究 将在以实验室小组为中心的支持性环境中进行，该小组拥有丰富的 多孔材料的合成与表征。这项研究将得到许多长期的 工业、学术和国家实验室合作。除了在实验技术方面的重要培训外， 该项目将包括对学术教师职业生涯的指导，负责任的研究行为培训， 通过与科学同事的互动和其他人的指导机会来实现专业发展 学生和研究人员。

Project Summary/Abstract Lithium salts have been used to treat severe bipolar disorder and major depression for decades, especially in instances with high suicide risk, and lithium remains their most effective treatment today. Despite its efficacy, lithium's therapeutic window is narrow, since it is difficult to maintain an effective concentration in the body without incurring severely detrimental side effects. This proposal aims to use metal-organic frameworks, a crystalline and porous class of hybrid organic-inorganic materials, for the slow and extended release of lithium as a therapeutic treatment for mood disorders. Metal-organic frameworks, as robust, tunable, and structurally well-defined materials, offer the advantages of facile modification and characterization. Through judicious choice of metals nodes, organic linkers, and guest species it will be possible to tune the thermodynamics and kinetics of Li+ uptake and release. Strategies for lithium interaction will include appending small organic molecules to open metal coordination sites, incorporating lithium-binding functional groups onto the backbones of organic linkers, and post-synthetically exchanging lithium for framework cations while maintaining crystallinity. Potential frameworks of interest will be synthesized using standard organic and inorganic synthesis methods and then subjected to a diverse toolbox of characterization techniques including: powder and single-crystal X-ray diffraction, gas sorption measurements, solution and solid-state NMR spectroscopy, and multiple forms of elemental analysis. Lithium uptake and release will be monitored via solution-state isotherms and kinetic measurements as well as by crystallographic and spectroscopy analysis of the frameworks in their (de)lithiated states. Promising materials will be iteratively improved and subjected to simulated biological conditions for the release of lithium. If successful, this project will position metal-organic frameworks as a versatile platform for addressing the important health challenge of treating severe neurological disorders with lithium. This research will take place in a supportive environment centered within a lab group that has a wealth of expertise in the synthesis and characterization of porous materials. The research will be assisted by a host of long-standing industrial, academic, and national lab collaborations. In addition to significant training in experimental techniques, this project will include guidance toward an academic faculty career, training in responsible conduct of research, professional development through interaction with scientific colleagues, and opportunities for mentorship of other students and researchers.