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.

项目摘要 使用氟脱氧葡萄糖（FDG）的正电子发射断层扫描（PET）已经彻底改变了分子成像， 大大改善了对许多致命疾病（如癌症）的诊断和监测反应。 然而，FDG-PET技术具有许多局限性，包括检查时间长，预扫描时间长， 禁食时间和使用电离辐射。核自旋的超极化增加了它们与 MRI扫描仪的场的4-6个数量级，导致MRI信号中的相应增益。作为 结果，可以在体内检测低浓度代谢物。此外，光谱MRI 能够实时检测注射的外源性超极化造影剂的代谢， 可以映射注入的代谢探针及其产物。整个超极化MRI扫描在 大约1分钟。主要的超极化造影剂是[1- 13 C]丙酮酸盐，其探测 在细胞水平上异常能量代谢的生化途径。这种新一代技术 在未来彻底改变分子成像的潜力。目前正在近30项临床试验中进行评估。 [1- 13 C]丙酮酸盐的超极化状态目前通过溶解动力学在临床规模上产生 核极化（d-DNP）技术，它采用低温，高磁场和高- 功率微波辐射这项技术非常缓慢：大约需要1小时才能生产出临床 次给药结束次要的问题是超过200万美元的高成本和操作所需的昂贵冷冻剂。 需要更快和更实惠的方法来使超极化[1- 13 C]丙酮酸可用于 广泛的临床应用。2015年，我们共同发明了一种替代技术，用于低成本生产 通过可逆交换实现信号放大的代谢探针 异核（鞘管）。在2019-2022年，我们和其他人已经证明，超极化[1- 13 C]丙酮酸可以使用这种新技术生产，该技术依赖于同时交换 仲氢气体（核自旋超极化的来源）和[1- 13 C]丙酮酸盐的金属络合物。 与d-DNP不同，SABRE-SHEATH具有高度可扩展性，快速（1分钟），可能允许生产超过10个剂量 每小时此外，我们的合作已经证明了将SABRE催化剂从 超极化溶液以制备超极化化合物的无催化剂溶液。该提案重点 解决SABRE-SHEATH的关键剩余方面，以制备生物相容性制剂， 超极化[1- 13 C]丙酮酸盐造影剂。具体而言，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 g剂量） 生产;（2）SABRE-catalystextraction;和（3）在生物相容性缓冲液中重构，然后进行可行性研究 研究细胞。我们预计这个两年期奖项的最终产品，即所开发的仪器 （又称超极化剂）将进入临床试验并将商业化。