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）：我们开发了一种原型 X 射线微量分析系统，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仪器。其中之一是低温 X 射线微热量计，是我们几年前在 NASA 赞助下为 X 射线天文学任务建造的。第二种是FEI公司开发的高分辨率环境扫描电子显微镜（ESEM）。尽管微量热计在生物学中的应用似乎与天文学和天体物理学相距甚远，但其在广泛能量范围内同时解析 X 射线发射线的前所未有的能力，已经在亚细胞维度上运行时提供了诱人的线索，提供了异常丰富的化学信息。与 ESEM 结合。 迄今为止，我们已经对一些有代表性的生物样本进行了原理验证测量。微量热计在 0.2 keV 至 10 keV 的能量范围内提高了光谱分辨率 (2.5 - 6 eV) 和随之而来的信号背景比，比当前一代 EDS（Si(Li) 或锗）至少提高了 60 倍）探测器。其在低 X 射线能量下的卓越性能可以使 ESEM 在低电子能量和较低电子束电流下运行，从而最大限度地减少沉积在非常小的体积中的功率，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，与致密固体目标的发射强度相比，低密度生物样品产生的 X 射线相对较小。通过采用定制的 X 射线光学器件来显着增加 X 射线收集，我们打算弥补 X 射线产量的下降。 我们的计划是使用这种新的微量分析工具来全面研究一系列生物样品。反过来，准确的相对元素丰度测量可能会成为常规，它们与离子传输、细胞增殖和凋亡的相关性可能会导致对细胞行为的强有力的诊断。在特定细胞位置发现的微量元素生物标志物可能被证明是可靠的疾病哨兵。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一组更具生物学相关性的元素中选择蛋白质标记物成为可能，而不是从高对比度电子显微镜迄今为止所需的重元素中选择蛋白质标记物。这将大大简化样品制备、保持细胞完整性并最大限度地减少图像中的伪影。我们期望获得大量有关细胞行为的新信息及其对早期癌症检测的诊断潜力的迹象。