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

描述(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，用于测量全身水平的生化过程。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探头的可用性。需要新的方法来使生物学家和临床医生能够合成范围广泛的PET探针。集成微流控技术具有快速、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，集成的微流控设备可以用于高效地生产PET探针。在这项提案中，我们将创建一个自动化、用户友好和成本效益高的微流控平台，以促进[18F]标记的PET探针的合成和标记，并将使用这些微流控平台生产几个尺寸从1到10 nm的基于小分子和双分子的[18F]标记的PET探针。首先，我们将并行开发三个独立的微流控功能模块，包括：(I)用于浓缩[18F]氟化物的芯片外模块，(Ii)核心-一套用于试剂混合、溶剂交换、去保护和/或官能团转换的数字控制微流控电路。这里，将使用聚全氟聚醚(PFPE)弹性体来制造该核心模块，以实现更好的化学惰性和设备稳定性)，以及(Iii)在线净化和表征系统。我们将把三个功能模块组装成一个集成设备，该设备将托管在一个独立的、轻型的、自我屏蔽的热室中，配备一个数字控制接口。基于面包板的概念，我们将构建两种具有相对复杂的器件配置的新型集成器件，以满足两大类PET探针的合成协议，即小分子和放射性标记生物分子。我们将简化和推广设备设计和模块连接，以允许“插件式”设备重新配置。同时，将开发一个用户友好的操作界面，以便更广泛地实施拟议的技术。然后，我们将测试快速制造新设备生产新型PET探头的可行性。我们将通过我们研究所的合作努力对得到的[18F]标记化合物进行评估。这项建议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。我们预计，拟议研究的成功将提供一种强大的、通用的技术，允许方便地供应各种[18F]标记的PET探针，加快新的PET探针的发现和开发进程，并促进PET成像的更广泛实施。公共卫生相关性：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和新型的正电子发射断层扫描(PET)成像探针。这项建议的长期目标是使[18F]标记的PET探针易于获得，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.