Microchip electrophoresis as basis for fully integrated, fully automated, low-cost radiopharmaceutical QC platform

微芯片电泳作为完全集成、全自动、低成本放射性药物 QC 平台的基础

• 批准号: 10697506
• 负责人: Jason Jones
• 金额: $ 27.58万
• 依托单位: DROPLETPHARM INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697506
• 关键词: Address; Aliquot; Amines; Animals; Area; Automation; Biological Assay; Blood capillaries; Calibration; Capillary Electrophoresis; Cells; Charge; Chemicals; Clinical; Complex; Consumption; Detection; Development; Devices; Diagnostic Imaging; Dose; Ensure; Equipment; FOLH1 gene; Formulation; Geometry; Gold; Head; High Pressure Liquid Chromatography; Human; Human Resources; Infrastructure; Isotopes; Label; Laboratories; Measurement; Measures; Medicine; Methods; Microchip Electrophoresis; Microfluidics; Miniaturization; Molecular; Monitor; Nature; Optics; Outcome; Patients; Performance; Phase; Play; Positron-Emission Tomography; Process; Production; Publishing; Quality Control; Radiation; Radio; Radiochemistry; Radioisotopes; Radiopharmaceuticals; Reagent; Reporting; Research; Resolution; Role; Safety; Sampling; Silicon Dioxide; Source; Specificity; System; Technetium 99m; Techniques; Technology; Testing; Therapeutic; Time; Tracer; Validation; Work; clinical care; commercial prototype; cost; detection sensitivity; detector; drug development; imaging agent; improved; in vivo; instrument; instrumentation; manufacture; operation; patient safety; pre-clinical; radiochemical; radiotracer; skills; tool

PROJECT SUMMARY Positron emission tomography (PET) is an indispensable tool in research, drug development and clinical care, due to its very high sensitivity and quantitative nature. The complexity and high cost of producing PET tracers limits their use in research and their development and validation into quantitative in vivo biological assays. For example, thousands of different PET tracers have been reported, but very few have been validated for use in animals or humans, and only a tiny fraction are approved for routine use in patients. New methods being developed for PET tracer manufacturing – especially microfluidics – have demonstrated potential for vastly reduced tracer production cost and complexity through (i) reduction of expensive reagents, (ii) efficient production at preclinical and clinical scales, and (iii) compact instrumentation that can be operated with minimal infrastructure. As the quality control (QC) tests necessary to ensure radiopharmaceutical safety must be performed after every synthesis, there have been some efforts to apply microfluidics in this area as well. DropletPharm, Inc. seeks to leverage microfluidic developments to create a tabletop radiopharmacy platform to eliminate the typical costly radiopharmacy infrastructure (i.e. hot cell, radiosynthesizer, stack monitoring system, QC equipment), and replace it with a self-shielded benchtop device that performs both synthesis and analysis. In the current project, we seek to develop a microfluidics-based QC platform to automatically perform all necessary radiopharmaceutical QC tests, reducing costs and increasing throughput. While many QC tests can be implemented as simple optical and radiation measurements (of aliquots pre-mixed with indicators), the (radio)chemical identity and purity tests are more challenging and require chemical separations. Recently, numerous research groups have used capillary electrophoresis for rapid separation and analysis of radiopharmaceuticals labeled with various isotopes (incl. Tc-99m and F-18). The van Dam lab used [18F]FLT samples to demonstrate high-resolution and sensitivity can be achieved using microchip electrophoresis (MCE), where advantages of vastly reduced size, lower cost, and short analysis time makes this technique highly attractive as a replacement for the gold standard techniques of radio-HPLC or radio-TLC for assessing radiochemical identity and purity as well as chemical purity and molar activity. To assess the technical feasibility to use this technology at the core of DropletPharm’s QC testing platform, this proposal aims to address two limitations of the method published to date, and compare the analysis performance head-to-head with radio-HPLC or radio-TLC. Aim 1 will explore strategies to improve radiation detection sensitivity to enable the analysis of a wider range of clinical batches (i.e. those that are more dilute). Aim 2 will explore radio-MCE separation of example radiotracers, including [18F]FLT and [68Ga]Ga-PSMA-11, and compare performance with the gold standard (radio-HPLC and radio-TLC). Successful completion of the milestones will indicate that Phase II commercial development into a full QC-testing module is warranted.

项目摘要 正电子发射断层扫描（PET）是研究，药物开发和临床护理中必不可少的工具， 由于其非常高的灵敏度和定量性质。生产宠物示踪剂的复杂性和高成本 将它们在研究中的使用及其在体内生物学测定中的定量限制。为了 例如，已经报道了成千上万的不同宠物示踪剂，但很少有人被验证 动物或人类，只有很小的部分被批准用于常规患者。 为宠物示踪剂制造（尤其是微流体学）开发的新方法已证明 通过（i）降低昂贵的试剂，可大大降低示踪剂生产成本和复杂性的潜力 （ii）在临床前和临床尺度上的有效产生，以及（iii）可以操作的紧凑型仪器 具有最小的基础设施。由于质量控制（QC）的测试需要确保放射线安全性 每次合成后都必须执行任何努力，以在该区域应用微流体作为 出色地。 DropletPharm，Inc。试图利用微流体开发来创建桌面放射性药物 消除典型昂贵的放射药物基础设施的平台 监视系统，QC设备），并用执行同时执行的自屏蔽台式设备替换 合成和分析。在当前项目中，我们试图开发一个基于微流体的QC平台 自动执行所有必要的放射药QC测试，降低成本并增加吞吐量。 虽然许多QC测试可以作为简单的光学和辐射测量（等分试样）实现 预先混合指标），（无线电）化学身份和纯度测试更具挑战性，需要 化学分离。最近，许多研究小组都使用毛细管电泳快速 用各种同位素标记的放射性药物的分离和分析（包括TC-99M和F-18）。 使用[18F] flt样品的van dam实验室来证明可以使用高分辨率和灵敏度来实现 微芯片电泳（MCE），其中尺寸大大降低，成本较低和短暂分析时间的优势 作为替代Radio-HPLC的黄金标准技术或 Radio-TLC用于评估放射化学身份和纯度以及化学纯度和摩尔活性。到 评估在液滴QC测试平台的核心使用此技术的技术可行性， 提案旨在解决迄今为止发布的方法的两个局限性，并比较分析 与Radio-HPLC或Radio-TLC正对决性能。 AIM 1将探索改善无线电的策略 检测敏感性可以对更广泛的临床批次进行分析（即那些更稀释的批次）。 AIM 2将探索示例放射性示例的无线电分离，包括[18F] FLT和[68GA] GA-PSMA-11， 并将性能与黄金标准（无线电-HPLC和Radio-TLC）进行比较。成功完成 里程碑将表明有必要将II期商业开发成整个QC测试模块。