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）：新型基于原子的 EPR 自旋探针的开发 摘要/摘要 电子顺磁共振（EPR）方法在医学中的使用是一个快速发展的领域。在过去十年中已经取得了重大进展，EPR 可能很快就会用于指导癌症、中风以及对氧合和缺氧进行无创测量至关重要的疾病的治疗。然而，进一步改进以提高其检测活性氧（ROS）产生的自由基的灵敏度将使其适用于更广泛的疾病。生物医学 EPR 系统的一个关键组成部分是自旋探针，它是检测顺磁性自由基所必需的基本化学试剂。然而，当前的自旋探针有局限性。例如，当前一代的自旋探针不够灵敏，无法直接检测或成像年龄相关病症或ROS介导的疾病（例如帕金森病和阿尔茨海默病）中活性氧的体内生成。为了克服这些限制，我们建议研究基于封装在富勒烯笼中的顺磁性原子的新自旋探针。含有不成对电子的原子，例如固定在对称 C60 笼中心的原子氮，完全受到保护，不会与外部物质发生反应，并产生前所未有的窄线宽。例如，N@C60 是已知 EPR 线宽最窄的化合物之一，其检测效率比现有化合物高 100 至 1000 倍。除了保护封装的原子之外，富勒烯笼还可以与自由基物质相互作用，并且 N@C60 表面发生的反应会在其 EPR 光谱中产生可测量的变化。这些特性以及经过验证的生物相容性使富勒烯封装的原子成为理想的自旋探针。 N@C60 是理想自旋探针的缩影，但目前对其研究因批量生产和纯化困难而受到阻碍。然而，原子N并不是富勒烯封装的唯一可能选择。我们已经研究了替代原子，它们具有类似的 EPR 特性，但更容易商业化生产。该项目的具体目标是合成和表征这些候选化合物中最有前途的，并证明它可以构成新型 EPR 自旋探针的基础，与现有化合物相比具有许多优点。 公共健康相关性：电子顺磁共振 (EPR) 是一种类似于磁共振成像 (MRI) 的新兴技术，有可能帮助诊断和指导治疗癌症、中风和其他涉及活性氧破坏的疾病（ROS）稳态。 EPR 依靠称为自旋探针的分子试剂与附近的氧或活性氧自由基相互作用，产生可检测的信号。然而，需要具有更高灵敏度的新化合物来改进EPR技术并使其用于更多疾病。为了消除当前自旋探针固有的局限性，我们建议研究基于封装在 C60 富勒烯中的顺磁性原子的新型自旋探针，这些探针在检测活性氧的能力方面将具有更高的灵敏度。开发新的自旋探针可以体内检测帕金森病和其他 ROS 疾病产生的 ROS，这将代表生物医学 EPR 技术的重大进步。