Rapid low-cost production of contrast agents for metabolic imaging

快速低成本生产代谢成像造影剂

• 批准号: 10572052
• 负责人: Eduard Chekmenev
• 金额: $ 19.58万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572052
• 关键词: 3-Dimensional; Address; Award; Biochemical Pathway; Buffers; Cell Line; Cell model; Cells; Clinical; Clinical Trials; Collaborations; Complex; Contrast Media; Detection; Devices; Diagnosis; Diagnostic; Disease; Dose; Emission-Computed Tomography; Energy Metabolism; Ethanol; Evaluation; Excision; Fasting; Feasibility Studies; Formulation; Future; Gases; Goals; Hela Cells; Hour; Image; Imaging Techniques; Imaging technology; Injectable; Ionizing radiation; Isotonic Solutions; Legal patent; MCF10A cells; MCF7 cell; MRI Scans; Magnetic Resonance Imaging; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammography; Maps; Metabolic; Metabolism; Metals; Methods; Minor; Modality; Molecular; Monitor; Normal Cell; Nuclear; Output; Patients; Positron-Emission Tomography; Preparation; Process; Production; Protons; Pyruvate; Reaction; Reporting; Research Personnel; Roentgen Rays; Route; Scanning; Signal Transduction; Source; Stress; Technology; Temperature; Time; Tissues; Use of New Techniques; Validation; Water; Work; X-Ray Computed Tomography; alcohol content; aqueous; biomaterial compatibility; catalyst; cellular imaging; clinical application; clinical translation; cohort; commercialization; cost; cost effective; cryogenics; diagnostic tool; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; high risk; imaging modality; improved; in vivo; instrumentation; invention; irradiation; magnetic field; metabolic imaging; metal complex; microwave electromagnetic radiation; molecular imaging; new technology; next generation; non-invasive imaging; operation; pre-clinical; prototype; radio frequency; reconstitution; response; scale up; screening; soft tissue; success; technology development; treatment response; tumorigenic

PROJECT SUMMARY Positron Emission Tomography (PET) with fluorodeoxyglucose (FDG) has revolutionized molecular imaging and substantially improved diagnosis and monitoring response to treatment of many deadly diseases such as cancer. However, FDG-PET technology has a number of limitations including long examination time, long pre-scan fasting time, and the use ionizing radiation. Hyperpolarization of nuclear spins increases their alignment with the field of an MRI scanner by 4-6 orders of magnitude, resulting in corresponding gains in the MRI signal. As a result, it becomes possible to detect low-concentration metabolites in vivo. Furthermore, spectroscopic MRI enables detection of real-time metabolism of an injected exogenous hyperpolarized contrast agent because it can map the injected metabolic probe and its products. The entire hyperpolarized MRI scan is performed in approximately 1 minute. The leading hyperpolarized contrast agent is [1-13C]pyruvate, which probes the biochemical pathways of aberrant energy metabolism at the cellular level. This next-generation technology has the potential to revolutionize molecular imaging in the future. It is now being evaluated in nearly 30 clinical trials. The hyperpolarized state of [1-13C]pyruvate is currently produced at clinical-scale via dissolution Dynamic Nuclear Polarization (d-DNP) technology, which employs cryogenic temperature, high magnetic field, and high- power microwave irradiation. This technology is very slow: it takes approximately 1 hour to produce a clinical dose. Minor concerns are the high cost of over $2M and requirement for expensive cryogens for operation. Faster and more affordable approaches are needed to make hyperpolarized [1-13C]pyruvate accessible for widespread clinical use. In 2015, we have co-invented an alternative technology for low-cost production of metabolic probes called Signal Amplification by Reversible Exchange Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH). In 2019-2022, we and others have demonstrated that hyperpolarized [1- 13C]pyruvate can be produced using this new technique, which relies on the simultaneous exchange of parahydrogen gas (the source of nuclear spin hyperpolarization) and [1-13C]pyruvate on metal complexes. Unlike d-DNP, SABRE-SHEATH is highly scalable, rapid (1 min) potentially allowing to produce over 10 doses per hour. Moreover, our collaboration has demonstrated the feasibility of removing the SABRE catalyst from hyperpolarized solutions to prepare catalyst-free solutions of hyperpolarized compounds. This proposal focuses on addressing the key remaining aspects of SABRE-SHEATH to prepare bio-compatible formulations of hyperpolarized [1-13C]pyruvate contrast agent. Specifically, the investigators will develop and optimize the instrumentation (based on an already commercialized prototype) that will integrate (1) clinical-scale (~1 g dose) production; (2) SABRE-catalyst extraction; and (3) reconstitution in a biocompatible buffer, followed by feasibility studies in cells. We anticipate that our end product of this two-year award, i.e., the developed instrumentation (a.k.a. hyperpolarizer) will enter clinical trials and will be commercialized.

项目概要 使用氟脱氧葡萄糖 (FDG) 的正电子发射断层扫描 (PET) 彻底改变了分子成像和 显着改善癌症等许多致命疾病的诊断和治疗反应监测。 然而，FDG-PET技术存在检查时间长、预扫描时间长等诸多局限性。 禁食时间，以及使用电离辐射。核自旋的超极化增加了它们与 MRI 扫描仪的磁场增强 4-6 个数量级，从而导致 MRI 信号相应的增益。作为一个 结果，可以检测体内低浓度的代谢物。此外，光谱 MRI 能够检测注射的外源性超极化造影剂的实时代谢，因为它 可以绘制注射的代谢探针及其产物的图谱。整个超极化 MRI 扫描在 约1分钟。主要的超极化造影剂是[1-13C]丙酮酸盐，它可以探测 细胞水平异常能量代谢的生化途径。这项下一代技术已经 未来分子成像革命的潜力。目前正在近 30 项临床试验中对其进行评估。 [1-13C]丙酮酸的超极化状态目前通过溶解动态在临床规模上产生 核极化（d-DNP）技术，采用低温、高磁场和高强度 功率微波照射。这项技术非常慢：大约需要 1 小时才能产生临床数据 剂量。次要问题是超过 200 万美元的高成本以及运行所需的昂贵冷冻剂。 需要更快、更实惠的方法来使超极化[1-13C]丙酮酸易于获得 临床广泛使用。 2015年，我们共同发明了一种低成本生产的替代技术 通过可逆交换进行信号放大的代谢探针可实现比对转移 异核（SABRE-SHEATH）。在 2019-2022 年，我们和其他人已经证明，超极化 [1- 13C]丙酮酸可以使用这种新技术来生产，该技术依赖于同时交换 仲氢气（核自旋超极化的来源）和金属配合物上的[1-13C]丙酮酸盐。 与 d-DNP 不同，SABRE-SHEATH 具有高度可扩展性、快速（1 分钟），可能可以生产超过 10 剂剂量 每小时。此外，我们的合作证明了去除 SABRE 催化剂的可行性 超极化溶液制备超极化化合物的无催化剂溶液。该提案重点 解决 SABRE-SHEATH 的关键剩余问题，以制备生物相容性制剂 超极化[1-13C]丙酮酸盐造影剂。具体来说，研究人员将开发和优化 仪器（基于已经商业化的原型）将集成（1）临床规模（约1克剂量） 生产; (2) SABRE-催化剂萃取； (3) 在生物相容性缓冲液中重建，然后进行可行性研究 细胞研究。我们预计这个为期两年的奖项的最终产品，即开发的仪器 （又名超极化器）将进入临床试验并将商业化。