Quantitative Measurement of Isotope Ratios by TOF-SIMS MS

通过 TOF-SIMS MS 定量测量同位素比

• 批准号: 8396848
• 负责人: MARVIN L VESTAL
• 金额: $ 10.5万
• 依托单位: VIRGIN INSTRUMENTS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8396848
• 关键词: Biological; Businesses; Calcium; Cancer Diagnostics; Carbon; Clinical; Clinical Management; Clinical Research; Complex; Coupled; Deposition; Development; Diagnostic Procedure; Disease; Dose; Drug Industry; Drug Kinetics; Early Diagnosis; Environment; Future; Hospitals; Housing; Human; Isotopes; Label; Laboratories; Lasers; Life; Mass Spectrum Analysis; Measurement; Measures; Medical; Medical Research; Metabolic; Metabolic Pathway; Metals; Metastatic Neoplasm to the Bone; Methods; Modification; Monitor; Multiple Myeloma; Osteoporosis; Patients; Peptides; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Physiologic pulse; Play; Preparation; Procedures; Radioisotopes; Relative (related person); Research Methodology; Research Personnel; Resources; Role; Safety; Sampling; Serum; Solid; Source; Spectrometry, Mass, Secondary Ion; Speed; Staging; System; Techniques; Technology; Time; Tissues; Tracer; United States National Institutes of Health; Urine; Validation; Work; accelerator mass spectrometry; base; bone loss; cost; drug development; efficacy trial; improved; innovation; instrument; instrumentation; ion source; ionization; long bone; mass spectrometer; microorganism; operation; rapid growth; stable isotope

DESCRIPTION (provided by applicant): This project is aimed at developing and demonstrating the performance of a new multi-stage 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 bench top 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) generally 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 hig 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 micro dosing (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. In addition to developing an economical alternative to AMS for measuring radioactive isotopes at ppt levels, this project will provide a very powerful method for accurate measurement of more abundant isotopes such as 2H, 13C, 15N, 17O, 18O, 33S, and 34S, as well as a wide variety of metals even when present in very complex matrices. SIMS has already been demonstrated for applications to biological tissues, microorganisms, and other complex organic and inorganic samples using conventional SIMS instrumentation. The high mass resolving power, high speed, and high sensitivity available with the new multi-stage TOF analyzer should provide superior results for these applications, and will allow simultaneous accurate measurements of stable isotope levels at sub-picomole levels for components separated by LC. An approach to identification of components in LC fractions by tandem TOF MS in parallel with simultaneous measurements of isotope ratios is presented. Two major innovations in time of flight mass spectrometry make this project feasible. One is the development of a multi-stage TOF mass spectrometer that dramatically improves the abundance sensitivity compared to earlier instruments. The other is invention and implementation of a new principle in time of flight mass spectrometry that provides simultaneous space and velocity focusing with either pulsed or continuous sources of ionization. The latter enables the use of a Cs+ SIMS ion source that provides several orders of magnitude greater ionization rates that are possible with the pulsed lasers used in earlier work. PUBLIC HEALTH RELEVANCE: The introduction of biomedical applications of AMS in the early 1990's brought the possibility of significant changes in strategies employed for drug development. The ability of AMS to distinguish 14C-labeled compounds from their unlabeled counterparts and to quantify exceedingly small amounts of these compounds in any biological matrix enabled "micro dosing" studies to obtain detailed information on metabolic pathways long before safety and efficacy trials in humans. Measurement of 41Ca/Ca in urine and serum enables early detection and improved clinical management of osteoporosis, multiple myeloma, and cancer metastatic to the bone. 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.

说明（由申请人提供）：本项目旨在开发和演示一种新的多级飞行时间质谱仪的性能，该质谱仪可在极低水平下准确测量同位素的相对丰度。该仪器最终将提供至少等于采用加速器质谱仪的已建立方法所实现的性能，而成本仅为非常小的一部分。所提出的台式仪器体积小，自动化程度高，适合医院或医学研究实验室中相对未经培训的操作员使用。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很长（>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14 C，以及用作监测人类患者骨长期代谢状态的示踪剂的41 Ca。这些应用通常需要精确测定同位素的相对丰度，其水平低于10-10，并向下延伸至10-15。目前，这些测量需要使用一个非常大的和昂贵的“加速器质谱仪”（AMS）通常位于一个中央设施。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实用性，但由于相对较高的成本和中心设施中复杂仪器的不可访问性，应用受到限制。然而，来自NIH、制药行业和几家基于AMS的企业的支持导致了2006年FDA指导声明，其中包括基于AMS的14 C微量给药（即，药物药代动力学和药效学的首次人体“0期”研究），以及41 Ca用于癌症诊断的AMS研究也得到了NIH的早期支持。该技术是有限的固体样品沉积在一个合适的目标，它似乎已经开发的AMS样品制备程序可以采用很少或没有修改，在拟议的仪器。 除了开发一种经济的替代AMS测量ppt水平的放射性同位素外，该项目还将提供一种非常强大的方法，用于精确测量更丰富的同位素，如2 H，13 C，15 N，17 O，18 O，33 S和34 S，以及各种金属，即使存在于非常复杂的基质中。西姆斯已经被证明可以应用于生物组织，微生物和其他复杂的有机和无机样品，使用传统的西姆斯仪器。新的多级TOF分析仪具有高质量分辨能力、高速度和高灵敏度，可为这些应用提供上级结果，并将允许对通过LC分离的组分进行亚皮摩尔水平的稳定同位素水平的同时精确测量。提出了一种通过串联TOF MS同时测量同位素比值来鉴定LC馏分中组分的方法。 飞行时间质谱的两个主要创新使该项目可行。一个是多级TOF质谱仪的开发，与早期仪器相比，大大提高了丰度灵敏度。另一个是飞行时间质谱的新原理的发明和实现，该原理提供了同时的空间和速度聚焦，具有脉冲或连续的电离源。后者使得能够使用Cs+西姆斯离子源，该离子源提供了几个数量级的更大的电离率，这是可能的与早期工作中使用的脉冲激光器。 公共卫生关系：20世纪90年代初AMS的生物医学应用的引入带来了药物开发策略发生重大变化的可能性。AMS区分14 C标记化合物与未标记化合物的能力，以及在任何生物基质中定量极少量这些化合物的能力，使“微量给药”研究能够在人体安全性和有效性试验之前很久就获得代谢途径的详细信息。测量尿液和血清中的41 Ca/Ca能够早期检测和改善骨质疏松症、多发性骨髓瘤和骨转移癌的临床管理。该项目将通过提供具有竞争力性能的廉价仪器，使这些最先进的研究和诊断方法得到更广泛的应用，这些仪器适用于临床和医学研究实验室的常规使用。