Development of a laboratory XANES system for the analysis of metals in tissue for cancer research and chemotherapy drug development

项目总结/摘要 由于最近在了解铂化疗药物方面取得了重大进展， 用于治疗估计50-70%的癌症患者，这是基于金属的抗癌药物的新前沿 正在浮现许多有前途的新型金属基药物（如Ru、Co、Au、Sn等）和几个新 现在正在研究铂前药的制剂作为常规药物的替代品。 铂治疗这些替代品具有克服众所周知的 目前基于铂的化疗的缺点，包括患者的发展， 对非肿瘤组织的抗性和毒性，包括毛发脱落和重要组织的损伤 肾脏和大脑等器官。 X射线吸收近边光谱（XANES）是一种功能强大的化学分析技术 用于研究这些药物的局部原子结构。这些新的电子结构 基于金属的化疗药物对其性能至关重要，包括： 肿瘤细胞中的活化、向肿瘤的运输、活性和药物的寿命。 然而，这些药物在生物组织中以低浓度存在， 分析需要研究人员前往同步加速器光源， X射线束，但其中只有少数，因为它们的成本为10亿美元， 1亿美元/年的运营成本。同步加速器XANES系统往往是非常超额认购， 长达6-9个月的应用程序和一些光束线限制组到一个单一的运行， 所有这些都大大限制了获取和研究进展的速度。 我们建议开发一种实验室XANES系统，该系统利用突破性的 创新，将同步加速器XANES的功能带到实验室 国际吧该系统有望在新型金属抗癌药物的研究中发挥关键作用 药物，以及关于微量金属化学在病理学中的作用的新兴研究 包括癌症 拟议的第一阶段6个月的项目是一个证明的原则示范的优势 源于实验板原型中的X射线光学器件和几何结构。拟议的第二阶段 24-一个月的项目是开发一个完整的原型。

Project Summary/Abstract Due to recent major advances in understanding platinum chemotherapy drugs, which are used to treat an estimated 50-70% of cancer patients, a new frontier of metal-based anti-cancer drugs is emerging. Many promising novel metal-based drugs (e.g. Ru, Co, Au, Sn, etc.) and several new formulations of platinum prodrugs are now being investigated as replacements for conventional platinum therapies. These alternatives hold significant potential for overcoming the well-known disadvantages of current Pt-based chemotherapy, including the development of patient resistance and toxicity to non-tumorous tissue, including hair fall-out and damage to vital organs such as the kidney and brain. X-ray absorption near edge spectroscopy (XANES) is a powerful chemical analysis technique used to investigate the local atomic structure of these drugs. The electron structure of these new metal-based chemotherapy drugs is critical to their performance, including: intracellular activation in tumorous cells, transportation to the tumor, activity, and lifetime of the drug. However, these drugs exist in low concentrations in biological tissue and currently, XANES analysis requires researchers to travel to synchrotron light sources, which generate intense beams of x-rays but of which there are just a handful, as they cost $1B to build and ~$100M/year to operate. Synchrotron XANES systems are often extremely oversubscribed, with up to a 6-9-month application process and some beamlines limiting groups to a single run per year, all of which significantly limit access and the rate of research progress. We propose to develop a laboratory XANES system that utilizes a combination of breakthrough innovations to bring access to the capabilities of synchrotron-based XANES to laboratories worldwide. The system is expected to critically enable research in novel metal-based anti-cancer drugs, in addition to emerging research on the role of trace metal chemistry in pathologies including cancer. The proposed Phase I 6-month project is a proof-of-principle demonstration of the advantages stemming from the x-ray optic and geometry in a breadboard prototype. The proposed Phase II 24-month project is to develop a complete prototype.