PET and MR-Compatible Bioreactor for Cross-Platform Biomarker Development

描述（由申请人提供）：本研究的目标是优化5mm MR兼容PET 3D细胞/组织培养生物反应器，并使用超极化（HP） 13C MR和PET探针的组合进行测试。三维（3D）细胞和组织培养生物反应器提供了一个新的平台，在一个非常可控和成本有效的环境中，研究细胞和组织的代谢和功能以及对治疗的反应。将HP 13C标记的MR探针与MR兼容的3D组织培养生物反应器相结合，可以在没有培养基背景信号的情况下，以高时间分辨率（秒）监测代谢通量。加上带有一系列标记示踪剂的正电子发射断层扫描（PET）成像，为理解生物反应器系统中的代谢功能、蛋白质相互作用、信号通路和药物药代动力学/药效学（PK/PD）提供了另一个维度。超极化13C MR和PET都有各自的优点和缺点，但人们对研究它们在为评估新疗法提供伴生成像生物标志物方面的互补作用非常感兴趣。为了实现这一目标，我们将优化一个5mm MR兼容的PET生物反应器（目标1），并使用该平台研究PET和HP MR的协同作用（目标2）。测试研究旨在展示这种跨平台生物反应器系统的应用广度，涵盖多核PET和MR。将现有的微工程MR兼容3D培养生物反应器设计用于PET成像研究代表了一个新的方向，将对新的放射性示踪剂和治疗方法的筛选和评估产生重大影响，并在确定HP MR和PET在未来临床应用中的协同作用。提出的研究也将提供新的信息关于MR和PET探针的协同作用。这种优化的5毫米生物反应器可以进一步进行微工程设计，以允许研究更少量的原代人类细胞和组织，包括活检样本，最终影响患者管理。

DESCRIPTION (provided by applicant): The goal of this research is to optimize a 5mm MR-compatible PET 3D cell/tissue culture bioreactor and test it by using a combination of hyperpolarized (HP) 13C MR and PET probes. Three-dimensional (3D) cell and tissue culture bioreactors provide a novel platform to investigate, in a very controlled and cost effective environment, cell and tissue metabolism and function as well as response to therapy. Combining HP 13C labeled MR probes with MR-compatible 3D tissue culture bioreactors has allowed the monitoring of metabolic fluxes with high temporal resolution (seconds) without background signals from the culture media. The addition of positron emission tomography (PET) imaging with an array of labeled tracers provides yet another dimension to understanding metabolic function, protein interaction, signaling pathways and drug pharmacokinetics/pharmacodynamics (PK/PD), in the bioreactor system. Both hyperpolarized 13C MR and PET have advantages and disadvantages, yet there is great interest in investigating their complimentary roles in the setting of providing companion imaging biomarkers for assessing new therapies. To accomplish this we will optimize a 5mm MR-compatible PET Bioreactor (aim 1) and use this platform to investigate the synergistic role of PET and HP MR (aim 2). The test studies aim to demonstrate the breadth of application of this cross- platform bioreactor system, spanning both multinuclear PET and MR. Adapting existing micro-engineered MR compatible 3D culture bioreactor designs for PET imaging studies represents a novel direction that will have a major impact on screening and evaluation of new radiotracers and therapeutics, and in identifying the synergistic role of HP MR and PET for future clinical applications. The proposed studies will also provide new information concerning the synergistic role of MR and PET probes. This optimized 5 mm bioreactor can be further micro-engineered to allow the study of smaller amounts of primary human cells and tissues, including biopsy samples, ultimately influencing patient management. PUBLIC HEALTH RELEVANCE: The bioreactor system described in this project offers a unique environment to evaluate cellular metabolism and function utilizing the complementary features of MR and PET imaging. This in vitro platform technology will (1) enable the discovery of clinically translatable tissue biomarkers related to various diseases; (2) support screening and evaluation of new radiotracers and therapeutics; and (3) improve treatment planning through direct assessment of patient cells and tissue samples. The facile measurement of metabolic and functional changes in cells and tissue may be directly translated into patient-specific therapeutic management.