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

描述(申请人提供)：这项研究的目标是优化5 mm MR兼容的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，可以在非常可控和经济高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，可以在没有来自培养介质的背景信号的情况下，以高时间分辨率(秒)监测代谢通量。正电子发射断层扫描(PET)和一系列标记示踪剂的加入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~(13)C磁共振和正电子发射计算机断层扫描各有优缺点，但在为评估新疗法提供伴随的成像生物标志物方面，人们对研究它们的互补作用很感兴趣。为了实现这一点，我们将优化一个5 mm MR兼容的PET生物反应器(AIM 1)，并利用这个平台来研究PET和HP MR(AIM 2)的协同作用。测试研究旨在展示这种跨平台生物反应器系统的应用范围，该系统跨越多核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，将对筛选和评估新的放射性示踪剂和疗法产生重大影响，并确定HP MR和PET在未来临床应用中的协同作用。拟议的研究还将提供有关MR和PET探针协同作用的新信息。这种优化的5 mm生物反应器可以进一步进行微工程，以允许研究数量较少的原代人类细胞和组织，包括活检样本，最终影响患者的治疗。 公共卫生相关性：本项目中描述的生物反应器系统利用MR和PET成像的互补功能，提供了一个独特的环境来评估细胞新陈代谢和功能。这一体外平台技术将(1)能够发现与各种疾病相关的临床可翻译的组织生物标记物；(2)支持筛选和 评估新的放射示踪剂和治疗方法；以及(3)通过直接评估患者细胞和组织样本来改进治疗计划。对细胞和组织中代谢和功能变化的简便测量可以直接转化为针对患者的治疗方法 管理层。

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.