Isotope Ratios at ppt level by TOF-MS

描述(由申请人提供)：用飞行时间质谱仪定量测量百万分之万亿的同位素比率本项目旨在开发和展示一种新的多级激光解吸飞行时间质谱仪的性能，该仪器可准确测量极低水平的同位素相对丰度。该仪器最终将以极小的成本提供至少与使用加速器质谱仪的现有方法相同的性能。拟议的台式仪器体积小，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员使用。这项工作的主要重点是那些需要测量低于十亿分之一水平的特定同位素的应用。这些应用通常涉及半衰期非常长(&gt；1000年)的放射性同位素。具体的例子包括用于放射性碳测年和生物示踪剂研究的14C，以及用作监测人类患者骨长期代谢状态的示踪剂的41Ca。这些应用往往需要精确测定低于10-10并向下延伸到10-15的同位素的相对丰度。目前，这些测量需要使用位于中央设施中的非常大且昂贵的“加速器质谱仪”(AMS)。加速器质谱仪已经证明了长寿命放射性同位素作为生物示踪剂的用途，但由于中央设施中的复杂仪器相对较高且无法获得，应用受到了限制。然而，在NIH、制药业和几家基于AMS的企业的支持下，FDA在2006年发布了一份指导声明，其中包括基于AMS的药物药代动力学和药效学的14C微剂量(即，首个人类“0期”研究)，以及用于癌症诊断的AMS研究也得到了NIH的早期支持。这项技术仅限于沉积在合适靶材上的固体样品，而且似乎可以使用为AMS开发的样品制备程序，而只需对拟议的仪器进行很少的修改或不做任何修改。公共卫生相关性：该项目以使用加速器质谱仪(AMS)进行的基础科学工作为基础，通过提供适合临床和医学研究实验室常规使用的价格低廉、性能具有竞争力的仪器，使这些最先进的研究和诊断方法得到更广泛的应用。例如，通过测量尿和血清中41Ca/Ca的比值来评估患者的钙代谢状态，可以早期发现骨质疏松症、多发性骨髓瘤和骨转移癌，并改善临床治疗。据估计，多达30%的人口可能会从这项测试中受益，这可能会导致更好的生活质量和更低的医疗费用。与基于AMS的41Ca所需的数百万美元的设施相比，开发一个负担得起且易于使用的分析平台可能会带来多个小企业机会。

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.