Photochemical Delivery and Metal Mediated Reactions of Bioactive Small Molecules

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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.