Mapping Anti-Cancer Drugs using Advanced X-ray Microanalysis

使用先进的 X 射线微量分析绘制抗癌药物图谱

• 批准号: 7833289
• 负责人: Eric H Silver
• 金额: $ 49.79万
• 依托单位: SMITHSONIAN ASTROPHYSICAL OBSERVATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7833289
• 关键词: Antineoplastic Agents; Apoptosis; Arts; Astronomy; Back; Behavior; Biological; Biological Markers; Biology; Cell Proliferation; Cells; Cellular Structures; Chemicals; Cisplatin; Collection; Custom; Deposition; Diagnostic; Dimensions; Disease; Drug usage; Electron Beam; Electron Microscope; Electron Microscopy; Electron Probe Microanalysis; Electrons; Elements; Generations; Germanium; Image; Ion Transport; Lead; Location; Malignant Neoplasms; Maps; Measurement; Measures; Mission; Morphologic artifacts; Operative Surgical Procedures; Optics; Performance; Pharmaceutical Preparations; Preparation; Production; Proteins; Relative (related person); Resolution; Sampling; Scanning; Screening for cancer; Sentinel; Signal Transduction; Solid; System; Trace Elements; United States National Aeronautics and Space Administration; base; chemotherapy; cryogenics; density; detector; improved; insight; instrument; novel diagnostics; prototype; tool

DESCRIPTION (provided by applicant): We have developed a prototype x-ray microanalysis system with unprecedented spatial and spectroscopic resolution. It combines two state-of-the art instruments. One is a cryogenic x-ray microcalorimeter that we built several years ago for x-ray astronomy missions under NASA auspices. The second is a high resolution, environmental scanning electron microscope (ESEM) developed by the FEI Company. Although the microcalorimeter's application to biology may seem far afield from astronomy and astrophysics, its unprecedented power to simultaneously resolve x-ray emission lines over a broad range of energies has already provided tantalizing hints of unusually rich chemical information at sub-cellular dimensions when operating in conjunction with the ESEM. To date, we have conducted proof-of-principle measurements on a few representative biological samples. The increased spectral resolution (2.5 - 6 eV) and consequent signal-to back ground ratio of the microcalorimeter over the energy range of 0.2 keV to 10 keV is at least a 60-fold improvement over present generation EDS (Si(Li) or germanium) detectors. Its superior performance at low x-ray energies could enable ESEM operation at low electron energies and lower electron beam current, thereby minimizing the power deposited into very small volumes while enhancing x-ray image resolution and cellular diagnostics. Under these beam conditions, the x-ray production from low density biological samples is relatively small compared to the emission intensity from dense solid targets. By employing a custom-made, x-ray optic to significantly increase x-ray collection, we intend to compensate for lower x-ray production. Our plan is to use this new microanalytical tool to comprehensively study a range of biological samples. In turn, accurate, relative elemental abundance measurements could become routine and their correlation with ion transport, cell proliferation, and apoptosis could lead to powerful diagnostics of cellular behavior. Trace element biomarkers found at specific cellular locations may prove to be reliable sentinels of disease. Spectroscopic x-ray images of heavy element-based chemotherapy drugs such as cisplatin promise better understanding of the actions of anti-cancer drugs. High spectral resolution may make it possible to choose protein markers from a more biologically relevant set of elements, rather than from the heavy-elements needed to date for high contrast electron microscopy. This would greatly simplify sample preparation, maintain cell integrity and minimize artifacts in the image. We expect to have an incredible wealth of new information about cellular behavior and indications of its diagnostic potential for early cancer detection.

描述（由申请人提供）：我们已经开发了一个原型X射线微分析系统，具有前所未有的空间和光谱分辨率。它结合了两种最先进的乐器。一种是我们几年前为NASA主持下的X射线天文学任务而建造的低温X射线微钙化计。第二个是FEI公司开发的高分辨率，环境扫描电子显微镜（ESEM）。尽管微酸酸钙化计在生物学上的应用似乎远非天文学和天体物理学，但其前所未有的能力可以同时解决X射线排放线上在广泛的能量上，已经为在与Esem结合时的亚细胞尺寸时已经提供了诱人的，在亚细胞尺寸上的诱人化学信息。 迄今为止，我们已经对一些代表性的生物样品进行了原理测量。在0.2 keV与10 KEV的能量范围内，光谱分辨率增加（2.5-6 eV），并导致微钙化计的信号对背景比至少比现代生成EDS（SI（LI）或锗）探测器提高了60倍。它在低X射线能量下的出色性能可以使ESEM在低电子能量和较低的电子束电流下运行，从而最大程度地将沉积到很小的体积的功率最小化，同时增强X射线图像分辨率和细胞诊断。在这些光束条件下，与密度固体靶标的发射强度相比，低密度生物样品的X射线产生相对较小。通过采用定制的X射线光学功能来显着增加X射线收集，我们打算补偿较低的X射线产生。 我们的计划是使用这种新的微分析工具来全面研究一系列生物样品。反过来，准确的，相对的元素丰度测量可能成为常规，它们与离子传输，细胞增殖和凋亡的相关性可能导致细胞行为的强大诊断。在特定细胞位置发现的痕量元素生物标志物可能被证明是可靠的疾病前哨。诸如顺铂等重元素化疗药物的光谱X射线图像有望更好地了解抗癌药物的作用。高光谱分辨率可能使得从更具生物学相关的元素集中选择蛋白质标记是可能的，而不是从高对比度电子显微镜所需的重元素中选择蛋白质标记。这将极大地简化样品制备，保持细胞完整性并最大程度地减少图像中的伪影。我们期望有关细胞行为以及其早期癌症检测的诊断潜力的迹象，拥有大量的新信息。