Integrated Microfluidic Devices for 18F Labeled PET Probes in Cancer Imaging

描述（由申请人提供）：正电子发射断层扫描（PET）是一种非常敏感的非侵入性成像技术，用于测量全身生化过程。限制这项强大技术在临床前和临床环境中广泛使用的主要障碍之一是PET探针的可用性。生物学家和临床医生需要新的方法来合成各种PET探针。集成微流控技术具有速度快、化学经济、灵活、用户友好、安全、模块化和低成本等固有优势，是生产放射性标记分子探针的主要技术平台。在过去的三年里，我们的研究小组已经证明，集成微流体装置可以用于高效生产PET探针。在本提案中，我们将创建一个自动化、用户友好且经济高效的微流控平台，以促进[18F]标记的PET探针的合成和标记，并利用这些微流控平台生产几种基于小分子和双分子的[18F]标记的PET探针，其尺寸从1到10 nm不等。最初，我们将并行开发三个独立的微流控功能模块，包括：(i)用于[18F]氟化物浓度的片外模块，（ii）核心-一组用于试剂混合，溶剂交换，脱保护和/或官能团转换的数字控制微流控电路。（在这里，聚氟聚醚（PFPE）弹性体将用于制造该核心模块，以实现改进的化学惰性和设备稳健性），以及（iii）在线净化和表征系统。我们将把这三个功能模块组装成一个集成设备，该设备将被托管在一个独立的、轻量级的、自屏蔽的热槽中，并配备一个数字控制接口。基于面包板的概念，我们将构建两种新型的集成设备，设备配置相对复杂，以满足PET探针的两大类合成方案，即小分子和放射性标记生物分子。我们将简化和概括设备设计和模块连接，以允许“插件”设备重新配置。同时，将开发一个用户友好的操作界面，以便更广泛地实施所建议的技术。然后，我们将测试快速构建用于生产新型PET探针的新设备的可行性。最终的[18F]标记化合物将通过我们在研究所的合作进行评估。该提案汇集了八个研究小组的专业知识，涵盖放射化学、微流体、聚合物材料、设备原型、分子成像和抗体工程等领域。我们设想这项研究的成功将提供一种强大的、通用的技术，以方便地供应各种[18F]标记的PET探针，加速新PET探针的发现和开发过程，并促进PET成像的更广泛实施。公共卫生相关：我们的想法是创建一个模块化，自动化和用户友好的微流控平台，能够根据需要合成和标记已知的和新的[18F]标记的正电子发射断层扫描（PET）成像探针。本提案的长期目标是使[18F]标记的PET探针易于获取，以便研究人员和临床医生可以针对癌症中的特定分子病变进行广泛的PET研究。

DESCRIPTION (provided by applicant): Positron emission tomography (PET) is a very sensitive non-invasive imaging technology for measuring biochemical processes at a whole body level. One of the major roadblocks which limits the widespread use of this powerful technology in both preclinical and clinical settings is the availability of PET probes. New approaches are needed to enable biologists and clinicians to synthesize a wide range of PET probes. Integrated microfluidic technology with intrinsic advantages of speed, chemical economy, flexibility, user- friendliness, safety, modularity and low cost is a prime technology platform for producing radiolabeled molecular probes. Over the past three years, our research groups have demonstrated that integrated microfluidic devices can be used for efficient production of PET probes. In this proposal, we will create an automated, user-friendly and cost efficient microfluidic platform to facilitate syntheses and labeling of [18F]- labeled PET probes, and several small molecule- and bimolecule-based [18F]-labeled PET probes with sizes ranging from 1 to 10 nm will be produced using these microfluidic platform. Initially, we will develop three separate microfluidic functional modules in parallel, including: (i) An off-chip module for concentration of [18F]fluoride, (ii) the core-a set of digitally controlled microfluidic circuits for reagent mixing, solvent exchange, deprotection and/or functional group transformations. (Here, polyperfluoropolyether (PFPE)-elastomer will be utilized to fabricate this core module to achieve improved chemical inertness and device robustness), and (iii) an in-line purification and characterization system. We will assemble the three functional modules into an integrated device, which will be hosted in a standalone, light- weight, self-shielded hot cell, equipped with a digitally controlled interface. Based on a breadboard concept, we will build two new types of integrated devices with relatively more complicated device configurations to meet the synthetic protocols of two major categories of PET probes, i.e., small molecules and radiolabeled biomolecules. We will simplify and generalize the device design and the module connections to allow "plug-in" device reconfiguration. In parallel, a user-friendly operation interface will be developed for broader implementation of the proposed technology. We will then test the feasibility to quickly build new devices for producing novel PET probes. The resulting [18F]-labeled compounds will be evaluated through our collaborative efforts in our research Institute. This proposal brings together the expertise of eight research groups covering the fields of radiochemistry, microfluidics, polymer materials, device prototyping, molecular imaging and antibody engineering. We envision the success of proposed of research will provide a powerful, universal technology to allow a convenient supply of a wide range of [18F]-labeled PET probes, accelerate the discovery and development processes o new PET probes, and facilitate a broader implementation of PET imaging. PUBLIC HEALTH RELEVANCE: Our idea is to create a modular, automated and user-friendly microfluidic platform capable of synthesizing and labeling known and novel [18F]-labeled positron emission tomography (PET) imaging probes on demand. The long term objective of this proposal is to make [18F]-labeled PET probes easily accessible so that researchers and clinicians can perform a wide range of PET studies targeting specific molecular lesions in cancer.