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 具有氟脱氧葡萄糖（FDG）的正电子发射断层扫描（PET）已革新分子成像和 大大改善了对许多致命疾病（例如癌症）治疗的诊断和监测。 但是，FDG-PET技术有许多限制，包括长时间检查时间，长期前扫描 禁食时间和使用电离辐射。核自旋的超极化增加了与 MRI扫描仪的场通过4-6个数量级，从而导致MRI信号的相应增长。作为 结果，可以在体内检测低浓缩代谢物。此外，光谱MRI 能够检测注射外源性超极化对比剂的实时代谢，因为它 可以绘制注射的代谢探针及其产品。整个超极化MRI扫描均在 大约1分钟。领先的超极化对比剂是[1-13c]丙酮酸，它探测 细胞水平异常代谢的生化途径。这种下一代技术有 未来革新分子成像的潜力。现在正在近30次临床试验中对其进行评估。 [1-13c]丙酮酸的超极化状态目前是通过溶解动态在临床尺度上产生的 核极化（D-DNP）技术，采用低温温度，高磁场和高 电源微波辐照。这项技术非常慢：生产临床大约需要1小时 剂量。较小的担忧是超过200万美元的高成本，并且需要昂贵的冷冻剂进行操作。 需要更快，更实惠的方法来使超极化[1-13c]丙酮酸可访问 广泛的临床用途。在2015年，我们合作了一项替代技术，用于低成本生产 通过可逆交换称为信号扩增的代谢探针可以使对齐转移到 杂核（剑毛）。在2019 - 2022年，我们和其他人证明了超极化[1- 13c]丙酮酸可以使用这种新技术生产，该技术依赖于同时交换 金属络合物上的偏二氢气体（核自旋超极化的来源）和[1-13C]丙酮酸。 与D-DNP不同，Sabre-Sheath具有高度可扩展性，快速（1分钟）可能会产生超过10剂 每小时。此外，我们的合作证明了从 超极化溶液以制备超极化化合物的无催化剂溶液。该提案重点是 解决Sabre-Sheath的剩余关键方面，以准备生物兼容的配方 超极化[1-13C]丙酮酸对比剂。具体而言，调查人员将开发并优化 仪器（基于已经商业化的原型）将整合（1）临床规模（〜1 g剂量） 生产; （2）Sabre-Catalyst提取； （3）在生物相容性缓冲区中重建，然后是可行性 细胞研究。我们预计我们的两年奖励的最终产品，即开发的仪器 （又称超极化器）将进入临床试验，并将进行商业化。