Isotope Ratios at ppt level by TOF-MS

本项目旨在开发和演示一种新型多级激光解吸飞行时间质谱仪的性能，该质谱仪可在极低水平下精确测量同位素的相对丰度。该仪器最终将提供至少等同于采用加速器质谱仪的既定方法所取得的性能，而成本仅为加速器质谱仪的一小部分。该台式仪器体积小，自动化程度高，适合医院或医学研究实验室中相对未受过培训的操作人员使用。这项工作的主要重点是那些需要在十亿分之一以下的水平上测量特定同位素的应用。这些应用通常涉及半衰期很长的放射性同位素（100 - 1000年）。具体的例子包括用于放射性碳测年和生物示踪研究的14C，以及用于监测人类患者骨长期代谢状态的41Ca示踪剂。这些应用通常需要精确测定10-10以下和10-15以下水平的同位素相对丰度。目前，这些测量需要使用位于中心设施的非常大且昂贵的“加速器质谱仪”（AMS）。加速器质谱法已经证明了长寿命放射性同位素作为生物示踪剂的效用，但由于成本相对较高和中心设施中复杂仪器的难以获得，其应用受到限制。尽管如此，在美国国立卫生研究院、制药行业和几家基于AMS的企业的支持下，2006年FDA发布了一份指导声明，其中包括基于AMS的14C微剂量（即药物药代动力学和药理学的首次人体“0期”研究），以及用于癌症诊断的41Ca的AMS研究也得到了美国国立卫生研究院的早期支持。该技术仅限于固体样品沉积在合适的目标上，并且似乎为AMS开发的样品制备程序可以在建议的仪器中进行很少或不进行修改。公共卫生相关性：在使用加速器质谱法（AMS）进行的基础科学工作的基础上，该项目将通过提供适合临床和医学研究实验室常规使用的具有竞争性性能的廉价仪器，使这些最先进的研究和诊断方法得到更广泛的应用。例如，测量尿液和血清中41Ca/Ca的比值来评估患者的钙代谢状态，可能有助于早期发现和改善骨质疏松症、多发性骨髓瘤和骨转移癌的临床管理。据估计，多达30%的人口可能会从这项测试中受益，这可能会提高生活质量，降低医疗费用。与基于ams的41Ca所需的数百万美元的设施相比，通过开发价格合理且易于使用的分析平台可以实现多个小型业务机会。

DESCRIPTION (provided by applicant): Quantitative Measurement of Isotope Ratios at the part-per-trillion Level by TOF MS Summary This project is aimed at developing and demonstrating the performance of a new multi-stage laser desorption time-of-flight mass spectrometer that provides accurate measurement of the relative abundance of isotopes at very low levels. This instrument will ultimately provide performance at least equal to that achieved by established methods employing accelerator mass spectrometers at a very small fraction of the cost. The proposed benchtop instrument is small, highly automated and suitable for use by relatively untrained operators in a hospital or medical research laboratory. The major focus in this work is on those applications that require measurements of specific isotopes at levels below the part-per-billion level. These applications generally involve radioactive isotopes with very long half-lives (>1000 years). Specific examples include 14C for radiocarbon dating and biological tracer studies, and 41Ca used as a tracer for monitoring bone long term metabolic status in human patients. These applications often require precise determination of the relative abundance of isotopes at levels below 10-10 and extending down to 10-15. At present these measurements require use of a very large and expensive "accelerator mass spectrometer" (AMS) located in a central facility. Accelerator mass spectrometry has demonstrated the utility of long- lived radioisotopes as biological tracers, but applications have been limited by the relatively high cost and inaccessibility of complex instruments housed in central facilities. Nevertheless, support from the NIH, the pharmaceutical industry, and several AMS-based businesses led to a 2006 FDA guidance statement including AMS-based 14C microdosing (i.e., first-in-human "Phase 0" studies) of drug pharmacokinetics and pharmacodynamics, and AMS studies of 41Ca for cancer diagnostics have also seen early support from the NIH. The technique is limited to solid samples deposited on a suitable target, and it appears that the sample preparation procedures that have been developed for AMS can be employed with little or no modification in the proposed instrument. PUBLIC HEALTH RELEVANCE: Building on the basic scientific work conducted using accelerator mass spectrometry (AMS), this project will enable broader application of these state-of-the-art research and diagnostic methods by providing inexpensive instruments with competitive performance that are suitable for routine use in clinical and medical research laboratories. For example, measurement of the ratio of 41Ca/Ca in urine and serum to evaluate the calcium metabolic status of patients may enable early detection and improved clinical management of osteoporosis, multiple myeloma, and cancer metastatic to the bone. It has been estimated that as much as 30% of the population may benefit from this test and this could lead to better quality of life and lower medical care costs. Multiple small business opportunities may be enabled by development of an affordable and easy to use analytical platform, versus the multi-million dollar facilities needed for AMS-based 41Ca.