Development of New Atomic-Based EPR Spin Probes

新型原子 EPR 自旋探针的开发

• 批准号: 8253407
• 负责人: JOHN M ALFORD
• 金额: $ 14.91万
• 依托单位: TDA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253407
• 关键词: Aging; Alzheimer' s Disease; Animal Model; Antioxidants; Biological; Chemical Agents; Chemistry; Chicago; Coupled; Detection; Development; Diagnosis; Disease; Electron Spin Resonance Spectroscopy; Electrons; Encapsulated; Environment; Exhibits; Feedback; Free Radicals; Fullerenes; Generations; Goals; Homeostasis; Hybrids; Hypoxia; Image; Implant; Ions; Letters; Magnetic Resonance Imaging; Malignant Neoplasms; Mass Spectrum Analysis; Measurable; Measurement; Measures; Mediating; Medicine; Methods; Molecular; Molecular Probes; Nature; Nitrogen; Oxidation-Reduction; Oxygen; Parkinson Disease; Phase; Physiology; Play; Positioning Attribute; Process; Production; Property; Reaction; Reactive Oxygen Species; Research; Research Methodology; Research Personnel; Signal Transduction; Stroke; Superoxides; Surface; System; Techniques; Technology; Time; United States National Institutes of Health; Universities; Water; Width; abstracting; age related; base; cancer therapy; detector; experience; fullerene C60; functional group; fundamental research; improved; in vivo; interest; nitroxyl; novel; pi bond; professor

DESCRIPTION (provided by applicant): Development of New Atomic-Based EPR Spin Probes Summary/Abstract The use of electron paramagnetic resonance (EPR) methods in medicine is a rapidly advancing field. There has been significant progress in the past decade, and EPR may soon be used to guide the treatment of cancer, strokes, and conditions where it is crucial to make non-invasive measurements of oxygenation and hypoxia. However, further improvements to increase its sensitivity to detect radicals generated by reactive oxygen species (ROS) would make it applicable to a wider range of diseases. A key component of the biomedical EPR system is the spin probe, the fundamental chemical agent necessary to detect paramagnetic radicals. However, current spin probes have limitations. For example, the current generation of spin probes are not sensitive enough to directly detect or image the in vivo generation of reactive oxygen species in age related disorders or diseases mediated by ROS such as Parkinson's and Alzheimer's disease. To overcome these limitations, we propose to investigate new spin probes based upon paramagnetic atoms encapsulated in fullerene cages. Atoms containing unpaired electrons, such as atomic nitrogen pinned at the center of the symmetric C60 cage, are completely protected from reaction with external species and produce unprecedented narrow line widths. For example, N@C60 has one of the narrowest known EPR line widths, giving it a detection efficiency 100 to 1000 times better than the current compounds. In addition to protecting the encapsulated atom, the fullerene cage can interact with radical species, and reactions occurring on the surface of N@C60 produce measurable shifts in its EPR spectrum. Such features, along with proven biological compatibility, make fullerene-encapsulated atoms ideal spin probes. N@C60 epitomizes the ideal spin probe, but research on it is currently hindered by difficulties in producing and purifying it in bulk. However, atomic N is not the only possible choice for fullerene encapsulation. We have examined alternative atoms that will have similar EPR properties, but will be far easier to produce commercially. The specific aim of this project is to synthesize and characterize the most promising of these candidates and demonstrate that it can form the basis for a new type of EPR spin probe with many advantages over the current compounds. PUBLIC HEALTH RELEVANCE: Electron paramagnetic resonance (EPR) is an emerging technique similar to magnetic resonance imaging (MRI) that has the potential to help diagnose and guide the treatment of diseases such as cancer, stroke, and other conditions involving disruption of reactive oxygen species (ROS) homeostasis. EPR relies upon molecular agents called spin probes to interact with nearby oxygen or reactive oxygen radicals to generate a detectable signal. However, new compounds with higher sensitivity are needed to improve EPR technology and allow it to be used for more diseases. To remove the limitations inherent to current spin probes, we propose to investigate new types of spin probes based upon paramagnetic atoms encapsulated in C60 fullerenes that will have higher sensitivity in their ability to detect reactive oxygen species. The development of new spin probes that allow in vivo detection of ROS produced, for example, by Parkinson's and other ROS diseases would represent a significant advance in biomedical EPR technology.

描述（由申请人提供）：新的基于原子的EPR旋转探针摘要/摘要在医学中使用电子顺磁共振（EPR）方法是一个快速前进的领域。在过去的十年中，进展取得了重大进展，EPR可能很快被用来指导癌症，中风和条件的治疗，在这种情况下，对于非侵入性测量的氧合和缺氧至关重要。但是，进一步的改进，以提高其对检测活性氧（ROS）产生的自由基的敏感性，将使其适用于更广泛的疾病。生物医学EPR系统的关键组成部分是自旋探针，这是检测顺磁性自由基所需的基本化学剂。但是，当前的自旋探针有局限性。例如，当前的自旋探针的敏感性不足以直接检测或成像由年龄相关疾病或由ROS介导的疾病（例如帕金森氏症和阿尔茨海默氏病）介导的反应性氧。为了克服这些局限性，我们建议根据富勒烯笼中封装的顺磁原子研究新的自旋探针。含有未配对电子的原子，例如固定在对称C60笼的中心的原子氮，受到完全保护与外部物种反应的保护，并产生前所未有的窄线宽度。例如，N@C60具有最狭窄的EPR线宽度之一，它的检测效率比当前化合物高100至1000倍。除了保护封装原子外，富勒烯笼还可以与自由基物种相互作用，并且在N@C60的表面上发生反应，在其EPR光谱中产生可测量的变化。这种特征以及经过验证的生物学兼容性使富勒烯封装的原子理想旋转探针。 n@c60体现了理想的自旋探针，但目前对其进行研究的困难使其批量产生和净化。但是，原子N并不是富勒烯封装的唯一选择。我们已经检查了具有类似EPR属性的替代原子，但在商业上生产会更容易。该项目的具体目的是综合和表征这些候选人最有前途的，并证明它可以为新型EPR旋转探针的基础构成比当前化合物具有许多优势的基础。 公共卫生相关性：电子顺磁共振（EPR）是一种类似于磁共振成像（MRI）的新兴技术，它具有帮助诊断和指导癌症，中风和其他疾病（涉及破坏活性氧的稳态（ROS）稳态的疾病）的潜力。 EPR依靠称为自旋探针的分子剂与附近的氧气或活性氧自由基相互作用，以产生可检测的信号。但是，需要具有更高敏感性的新化合物来改善EPR技术，并允许将其用于更多疾病。为了消除当前自旋探针固有的局限性，我们建议根据封装在C60 Fullerenes中的顺磁性原子的新型自旋探针，这些探针的能力将具有更高的灵敏度，以检测活性氧。允许在帕金森氏症和其他ROS疾病中对ROS产生的体内检测的新旋转探针的开发将代表生物医学EPR技术的重大进展。