Photochemical Delivery and Metal Mediated Reactions of Bioactive Small Molecules

生物活性小分子的光化学传递和金属介导的反应

• 批准号: 1405062
• 负责人: Peter Ford
• 金额: $ 15.3万
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1405062&HistoricalAwards=false
• 关键词: Photochemical; Delivery; Metal; Mediated; Reactions

It is now well established that the gaseous molecules nitric oxide, carbon monoxide and carbon disulfide are important regulators of many biological functions in mammals and, more specifically, in humans. For examples, nitric oxide is a regulator of blood pressure, while nitric oxide, carbon monoxide, and sulfur compounds such as carbon disulfide have key, but still poorly understood, roles in wound healing and inflammation. The continuing research represented by this project encompasses two related topics. The first is concerned with elucidating the fundamental chemistry that defines the physiology of these species, while the second is concerned with designing new technology to deliver such bioactive small molecules (BSMs) to specific biological targets on demand. The former topic involves the application of modern instrumentation to examine rates of the chemical reactions of these BSMs with biologically relevant metal centers, while the latter is focused on utilizing light as a trigger for controlling the timing, location and dosage of BSM release at specific sites. Graduate and undergraduate student researchers in these projects acquire interdisciplinary training in micro- and nano-materials science, chemical biology, photochemistry and chemical synthesis and kinetics. They also are active in K-12 outreach activities, where they share the excitement of their research activities with teachers and students in local schools. With this award, the Chemistry of Life Processes Program in the NSF Chemistry Division is funding Dr. Peter C. Ford from the University of California, Santa Barbara for interdisciplinary investigations into new strategies and precursors for photochemical delivery of the BSMs NO and CO to physiological targets and for exploratory studies into delivery of the potentially bioactive molecule CS2. Experimental methods will include syntheses of conjugates between BSM precursors and chromophores including organic dyes and nano-materials for one- and 2-photon excitation. Modern optical methods (ultra-fast laser studies, confocal microscopy, etc.) will evaluate quantitative photosensitization mechanisms and provide guidelines for design optimization, while in vitro (cell culture) studies provide initial tests of biological viability. In collaborative studies, the investigators will explore polymer-based nano- and micro-carriers for delivery of BSM precursor-chromophore conjugates to specific biological sites. The principles thus defined should be broadly applicable to delivery of other bioactive molecules. In addition, stopped-flow and flash photolysis kinetics spectroscopy, computations and collaborative low temperature matrix studies will be used to elucidate fundamental mechanisms of BSM reactions with biologically relevant metal-centered substrates. Evaluating such pathways is crucial to defining the chemistry/physiology relationships of these complex systems.

现在已经确定，气态分子一氧化氮、一氧化碳和二硫化碳是哺乳动物，更具体地说，是人类许多生物功能的重要调节器。例如，一氧化氮是血压调节剂，而一氧化氮、一氧化碳和硫化合物（如二硫化碳）在伤口愈合和炎症中发挥着关键作用，但人们对这些作用知之甚少。该项目所代表的持续研究包括两个相关主题。第一个是阐明定义这些物种生理的基本化学，而第二个是设计新技术，根据需要将这些生物活性小分子（bsm）输送到特定的生物目标。前者涉及应用现代仪器来检查这些BSM与生物相关金属中心的化学反应速率，而后者侧重于利用光作为触发器来控制BSM在特定部位释放的时间、位置和剂量。这些项目的研究生和本科生研究人员在微纳米材料科学、化学生物学、光化学、化学合成和动力学方面获得跨学科的培训。他们还积极参加K-12的外展活动，在那里他们与当地学校的老师和学生分享他们研究活动的兴奋。美国国家科学基金会化学部的生命过程化学项目资助了加州大学圣巴巴拉分校的Peter C. Ford博士，对bsm NO和CO光化学传递到生理目标的新策略和前体进行跨学科研究，并对潜在生物活性分子CS2的传递进行探索性研究。实验方法将包括合成BSM前体和发色团之间的共轭物，包括有机染料和单光子和双光子激发的纳米材料。现代光学方法（超快激光研究，共聚焦显微镜等）将评估定量光敏机制并为设计优化提供指导，而体外（细胞培养）研究提供了生物活力的初步测试。在合作研究中，研究人员将探索基于聚合物的纳米和微载体，用于将BSM前体-发色团偶联物递送到特定的生物位点。这样定义的原则应该广泛适用于其他生物活性分子的递送。此外，停止流动和闪光光解动力学光谱，计算和协同低温基质研究将用于阐明BSM与生物相关金属中心底物反应的基本机制。评估这些途径对于定义这些复杂系统的化学/生理关系至关重要。