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

开发实验室 XANES 系统，用于分析组织中的金属，用于癌症研究和化疗药物开发

• 批准号: 9559611
• 负责人: Wenbing Yun
• 金额: $ 22.5万
• 依托单位: SIGRAY, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-04 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9559611
• 关键词: Acceleration; Address; Anodes; Antineoplastic Agents; Area; Awareness; Biochemistry; Biological; Biological Process; Brain; Cancer Patient; Cell Culture Techniques; Cells; Chemicals; Chemistry; Chemotherapy-Oncologic Procedure; Communities; Complex; Crystallization; Custom; Development; Disadvantaged; Drug Targeting; Drug resistance; Electrons; Elements; Ensure; Formulation; Geometry; Goals; Hair; Inorganic Chemistry; Kidney; Laboratories; Learning; Legal patent; Light; Malignant Neoplasms; Measurement; Medical; Metalloproteins; Metals; Methods; Minor; Neoplasm Metastasis; Neurodegenerative Disorders; Optics; Organ; Pathology; Pathway interactions; Patients; Peer Review; Performance; Pharmaceutical Preparations; Phase; Platinum; Play; Preparation; Process; Prodrugs; Production; Property; Protocols documentation; Research; Research Personnel; Resistance; Resolution; Roentgen Rays; Role; Running; Ruthenium; Sampling; Serum; Solid; Source; Specimen; Spectrum Analysis; Speed; Spottings; Standardization; Structure; Synchrotrons; System; Systems Analysis; Techniques; Technology; Testing; Therapeutic Human Experimentation; Tissues; Toxic effect; Trace Elements; Trace metal; Transportation; Travel; Validation; absorption; anti-cancer; anti-cancer therapeutic; anticancer research; atomic state; base; beamline; biological research; biological systems; chemotherapy; commercialization; cost; design; drug development; drug structure; frontier; in vivo; innovation; interest; novel; oxidation; prevent; prototype; stem; success; temporal measurement; tumor; voltage

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.

项目概要/摘要 由于最近在了解铂类化疗药物方面取得了重大进展， 治疗估计 50-70% 的癌症患者，这是金属抗癌药物的新领域 正在兴起。许多有前途的新型金属基药物（如钌、钴、金、锡等）和一些新的 目前正在研究铂前药的制剂作为传统药物的替代品 铂类疗法。这些替代方案具有克服众所周知的问题的巨大潜力 当前基于 Pt 的化疗的缺点，包括患者的发展 对非肿瘤组织的耐药性和毒性，包括毛发脱落和生命体受损 肾脏和大脑等器官。 X 射线吸收近边光谱 (XANES) 是一种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 金属化疗药物对其性能至关重要，包括： 肿瘤细胞的激活、向肿瘤的运输、药物的活性和寿命。 然而，这些药物在生物组织中的浓度很低，目前，XANES 分析需要研究人员前往同步加速器光源，这些光源会产生强烈的 X 射线束，但数量很少，因为它们的建造成本为 10 亿美元 每年运营费用约为 1 亿美元。同步加速器 XANES 系统通常被极度超额认购， 申请流程长达 6-9 个月，并且某些光束线限制每个组只能运行一次 年，所有这些都极大地限制了访问和研究进展的速度。 我们建议开发一种实验室 XANES 系统，该系统利用突破性的组合 为实验室带来基于同步加速器的 XANES 功能的创新 全世界。该系统预计将极大地促进新型金属抗癌研究 除了关于痕量金属化学在病理学中的作用的新兴研究之外，药物 包括癌症。 拟议的为期 6 个月的第一阶段项目是对优势的原理验证论证 源自面包板原型中的 X 射线光学器件和几何形状。拟议的第二阶段 为期24个月的项目是开发一个完整的原型。