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

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不可或缺的工具， 由于其非常高的灵敏度和定量性质。PET示踪剂生产的复杂性和高成本 限制了它们在研究中的使用以及它们在定量体内生物测定中的开发和验证。为 例如，已经报道了数千种不同的PET示踪剂，但很少有被验证用于 动物或人类，只有一小部分被批准用于患者的常规使用。 正在开发的PET示踪剂制造新方法-特别是微流体-已经证明 通过（i）减少昂贵的试剂， (ii)临床前和临床规模的高效生产，以及（iii）可操作的紧凑型仪器 基础设施最少。作为确保放射性药物安全性所必需的质量控制（QC）测试， 必须在每次合成后进行，已经有一些努力将微流体应用于该领域， 好. DropletPharm，Inc.旨在利用微流体的发展，创造一个桌面放射性药物 平台，以消除典型的昂贵的放射性制药基础设施（即热室，放射性合成器，堆栈 监测系统，QC设备），并将其替换为自屏蔽台式设备， 综合与分析。在目前的项目中，我们寻求开发一个基于微流体的QC平台， 自动执行所有必要的放射性药物QC测试，降低成本并提高产量。 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）来实现， 与指示剂预混），（放射性）化学特性和纯度测试更具挑战性， 化学分离最近，许多研究小组已经使用毛细管电泳进行快速分析。 用各种同位素标记的放射性药物的分离和分析（包括Tc-99 m和F-18）。的 货车Dam实验室使用[18 F]FLT样品来证明使用 微芯片电泳（MCE），具有体积小、成本低、分析时间短等优点， 使得该技术作为放射性HPLC的金标准技术的替代品具有高度吸引力，或者 用于评估放射化学鉴别和纯度以及化学纯度和摩尔活性的放射性TLC。到 评估在DropletPharm的QC测试平台的核心使用该技术的技术可行性， 该提案旨在解决迄今为止公布的方法的两个局限性，并比较分析 与放射性HPLC或放射性TLC的头对头性能。目标1将探索改善辐射的策略 检测灵敏度，以便能够分析更广泛的临床批次（即稀释程度更高的批次）。 目标2将探索示例性放射性示踪剂的放射性MCE分离，包括[18F]FLT和[68 Ga]Ga-PSMA-11， 并与金标准（放射性HPLC和放射性TLC）进行性能比较。成功完成 里程碑将表明第二阶段商业开发为完整的QC测试模块是有保证的。

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.