Mapping Anti-Cancer Drugs using Advanced X-ray Microanalysis

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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.