Selenide-based electrocatalytic sensors for sensitive peroxynitrite detection in biological media: a bottom-up approach for functional interface design

用于生物介质中敏感过氧亚硝酸盐检测的硒化物电催化传感器：功能界面设计的自下而上方法

• 批准号: 10203223
• 负责人: MEKKI BAYACHOU
• 金额: $ 44.71万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203223
• 关键词: Address; Adult; Affect; American Heart Association; Antioxidants; Apoptosis; Behavior; Biochemical; Biological; Cardiovascular Diseases; Cell Death Induction; Cell membrane; Cell physiology; Cessation of life; Chemicals; Chronic; Clinical; Complex; Coupled; DNA; Data; Detection; Development; Disease; Electrodes; Electron Spin Resonance Spectroscopy; Evaluation; Film; Fluorescent Probes; Functional disorder; Goals; Illusions; Immune response; Immunohistochemistry; In Situ; Inflammation; Libraries; Light; Link; Lipids; Masks; Measurement; Measures; Mediating; Methods; Molecular; Monitor; Morbidity - disease rate; Natural graphite; Necrosis; Nitric Oxide; Organoselenium Compounds; Oxidation-Reduction; Paper; Pathologic; Pathology; Pathway interactions; Performance; Peroxonitrite; Pharmaceutical Chemistry; Physiological; Physiological Processes; Play; Process; Property; Proteins; PubMed; Publishing; Reaction; Reporting; Role; Selenium; Sepsis; Signal Transduction; Superoxides; Surface; Techniques; Testing; Thinness; Time; United States; Work; analytical method; assault; base; biological systems; carbon fiber; cytotoxic; design; detection method; in vivo; innovation; microsensor; miniaturize; mortality; mortality statistics; nitration; oxidation; sensor; statistics; stress reactivity; tool

Project Summary: Background and Challenge: Peroxynitrite (OONO-) emerged as a potent cytotoxic compound and has been implicated in a host of pathophysiological conditions. Peroxynitrite is the primary product of the in vivo reaction of nitric oxide and superoxide anion-radical. The multifaceted physiologic reactions of this compound are directly implicated in a number of pathologies including cardiovascular disease, immune response, chronic inflammation, and sepsis, to cite a few. According to recent statistics by the American Heart Association, just cardiovascular disease alone claims about 7 deaths every 4 minutes. On the other hand, sepsis affects 1.7 million adults in the United States each year and potentially contributes to more than 250,000 deaths. Just these two statistics are staggering and make the footprint of this deadly biological analyte an important priority. The common thread that links peroxynitrite to all cited pathologies is its potent reactivity toward most cellular components including DNA, proteins, and lipids in cell membranes. Substantial oxidations and other transformations of proteins, DNA, and lipids contribute to the disruption of key cellular functions. Assessing peroxynitrite’s deleterious effects and examining hypotheses of its potential signaling roles cannot be achieved without first accurately measuring and monitoring its concentration. This task is however inherently difficult due to low submicromolar concentrations under physiologic conditions coupled with its high reactivity. Sensitive and accurate measurement of peroxynitrite is crucial in order to shed light on the illusive pathophysiologic roles of this metabolite. Some of the known detection methods for peroxynitrite include oxidation of fluorescent probes, EPR spectroscopy, chemiluminescence, immunohistochemistry, and probe nitration; however, these are more difficult to apply for real-time quantification due to their inherent complexity. The electrochemical detection of peroxynitrite is a simpler and more convenient technique for application in biological settings. However, a systematic development of the right electrode interface that enhances the sensitivity and selectivity for this molecule is lacking. Recently, several synthetic organic selenides have been prepared as antioxidants in medicinal chemistry. Electrochemical data in our hands showed that some organoselenium compounds have specific redox activity with peroxynitrite in solution. For these reasons, we believe that an electrode interface decorated with organoselenides attached to the surface will potentially serve as catalytic entities for mediated PON electrocatalytic determination. Our proposal: In this work, we propose to develop a functional thin film material based on defined organic selenides chemically attached on graphite electrodes and use this interface in sensitive electrochemical determination of peroxynitrite. This bottom-up interface design approach is innovative because it allows us to design an electrocatalytic interface for the detection and determination of peroxynitrite driven by molecular and electronic properties of the organic selenides used. This is driven by the overall hypothesis that the redox-rich organoselenium compounds will allow us to use them as active redox catalytic centers tethered to the electrode surface to electrocatalytically measure PON in solution. The work will pursue three specific aims including: 1) developing a selenide-decorated electrode for PON determination using a reference compound, followed by 2) generating a library of selenides with varying substituents on the selenium catalytic center and test the catalytic properties of the resulting modified interface towards PON determination; and finally 3) miniaturizing the best performing catalytic interfaces by transferring the process to ultramicroelectrodes (carbon fiber) to prepare a single-body PON microsensor for use under biological settings. Significance: The successful development of a reliable PON microsensor will not only enable in-situ measurement of this reactive stress marker under biological setting but will also shed light on obscure mechanisms through which this potent species operates under many disease states.

项目概要： 背景和挑战：过氧亚硝酸盐 (OONO-) 作为一种有效的细胞毒性化合物出现， 过氧亚硝酸盐与许多病理生理状况有关。 一氧化氮和超氧阴离子自由基的体内反应 这种多方面的生理反应。 化合物直接涉及许多病理学，包括心血管疾病、免疫疾病 据美国最近的统计数据显示，反应、慢性炎症和败血症等。 心脏协会称，仅心血管疾病就导致每 4 分钟就有 7 人死亡。 另一方面，脓毒症每年影响美国 170 万成年人，并可能导致更多 仅这两个统计数字就令人震惊，并造成了如此致命的后果。 生物分析物是一个重要的优先事项，将过氧亚硝酸盐与所有引用的病理联系起来。 是它对大多数细胞成分（包括细胞中的 DNA、蛋白质和脂质）具有强大的反应性 蛋白质、DNA 和脂质的大量氧化和其他转化有助于 关键细胞功能的破坏。 评估过氧亚硝酸盐的有害影响并检验其潜在信号作用的假设 如果不首先准确测量和监测其浓度，就无法完成这项任务。 然而，由于生理条件下亚微摩尔浓度较低，因此本质上很困难 过氧亚硝酸盐的高反应性对于阐明这一点至关重要。 关于这种代谢物的一些已知的检测方法的虚幻的病理生理学作用。 过氧亚硝酸盐包括荧光探针的氧化、EPR光谱、化学发光、 免疫组织化学和探针硝化；然而，这些技术更难以实时应用。 由于其固有的复杂性，过氧亚硝酸盐的电化学检测更为简单。 然而，在生物环境中应用更方便的技术仍然是一个系统的发展。 缺乏增强该分子灵敏度和选择性的正确电极界面。 最近，一些合成的有机硒化物已被制备作为药物化学中的抗氧化剂。 我们手中的电化学数据表明，一些有机硒化合物具有特定的氧化还原作用 由于这些原因，我们认为电极界面被修饰。 表面附着有机硒化物将有可能作为介导 PON 的催化实体 电催化测定。 我们的建议：在这项工作中，我们建议开发一种基于定义的功能薄膜材料 有机硒化物化学附着在石墨电极上，并使用该界面敏感 这种自下而上的界面设计方法是创新的。 因为它使我们能够设计一个电催化界面来检测和测定 过氧亚硝酸盐由所使用的有机硒化物的分子和电子特性驱动。 总体假设是富含氧化还原的有机硒化合物将使我们能够将它们用作活性物质 氧化还原催化中心连接到电极表面，以电催化方式测量溶液中的 PON。 这项工作将追求三个具体目标，包括：1）开发用于 PON 的硒化物装饰电极 使用参考化合物进行测定，然后 2) 生成具有不同浓度的硒化物库 硒催化中心上的取代基并测试所得修饰的催化性能 PON 测定接口；最后 3) 小型化性能最佳的催化接口 通过将该过程转移到超微电极（碳纤维）来制备单体PON 意义：成功开发出一种可靠的生物环境下使用的微传感器。 PON 微传感器不仅能够在生物条件下对这种反应性应激标记物进行原位测量 设定，但也将揭示这个强大的物种在其下运作的模糊机制 许多疾病状态。