Magnetic Resonance Spectroscopy and Molecular Imaging of Metabolic Pathways in Cancer

项目摘要 仲氢诱导极化（PHIP）是一种替代性超极化技术，其基于 仲氢气体与不饱和分子前体的分子加成。与更广泛的 溶解动态核极化（d-DNP），它是高度可扩展的和相对便宜的。 然而，它在历史上并没有享受快速的临床前适应和最终的临床翻译作为d- DNP的成功有几个关键原因：（i）不能使代谢造影剂（如丙酮酸盐）过氧化氢， 或乳酸盐），（ii）对配备有双通道无线电的高度专业化超极化器硬件的要求 频率NMR光谱仪，（iii）生产纯（来自氢化催化剂）的挑战 超极化造影剂的超极化溶液。在2014-2016年期间， 在PHIP领域中公开的证明了所有上述限制都可以克服， 物理化学、合成化学和催化的进展。我们的国际合作（建立 在2013年），特别是一直在领导大多数这些发展表明，上述每一个 这些挑战可以单独解决，原则上可以生产廉价的代谢造影剂， 通过新的合成方法，侧臂氢化和磁场循环， 催化或催化剂螯合。在本提案中，我们将探讨这些分离的假设， 这些发展可以协同地结合起来，以实现以下具体目标：（一）发展 通过仲氢诱导极化产生超极化C13-丙酮酸盐的分子前体 技术（PHIP）;（ii）使用磁场循环接近过程优化PHIP超极化， 最大化超极化C13-丙酮酸盐的极化百分比和浓度;（iii）开发有效的 仅使用非均相PHIP催化或均相PHIP催化制备超极化溶液的方法 金属螯合剂辅助PHIP催化制备超极化C13- （iv）提高传感能力（即，在细胞中对升高的乳酸代谢的非侵入性传感）， 癌症）的细胞和小啮齿动物癌症模型中发展的超极化C13-丙酮酸盐。我们 组建了一个由来自美国和俄罗斯的合作科学家组成的高度协同的团队， 合作研究和同行评审出版物的跟踪记录，由11个同行评审 出版物（美国和俄罗斯合作者之间），3篇手稿正在审查中，还有更多 准备.美国团队将由成像科学家，物理化学家，有机化学家，体内 俄罗斯团队包括物理化学家/成像科学家、催化剂科学家和其他科学家。 化学家、细胞学家和其他人。该团队将通过利用专业知识、材料和 俄罗斯和美国子团队独有的设备，以开发廉价和高通量的生产 超极化C13-丙酮酸造影剂，可以彻底改变临床癌症成像。

PROJECT SUMMARY Parahydrogen Induced Polarization (PHIP) is an alternative hyperpolarization technique, which is based on molecular addition of parahydrogen gas to an unsaturated molecular precursor. Unlike the more widespread dissolution-Dynamic Nuclear Polarization (d-DNP), it is highly scalable and relatively inexpensive. Nevertheless, it historically did NOT enjoy rapid preclinical adaptation and ultimate clinical translation as d- DNP did for several critical reasons: (i) inability to hyperpolarize key metabolic contrast agents (e.g. pyruvate or lactate), (ii) requirements for highly specialized hyperpolarizer hardware equipped with dual-channel radio frequency NMR spectrometer, (iii) challenges for production of pure (from hydrogenation catalyst) hyperpolarized solutions of hyperpolarized contrast agents. In 2014-2016, several seminal works have been published in the field of PHIP demonstrating all of the above limitations can be overcome due to fundamental advances in physical chemistry, synthetic chemistry and catalysis. Our international collaboration (established in 2013) in particular has been leading most of these developments demonstrating that each of the above challenges can be solved separately, and cheap metabolic contrast agents can be produced in principle through new synthetic approaches, side-arm hydrogenation and magnetic field cycling, and heterogeneous catalysis or catalyst chelation. In this proposal, we will explore the hypothesis that these separate developments can be synergistically combined to accomplish the following Specific Aims: (i) Develop molecular precursors for production of hyperpolarized C13-pyruvate via parahydrogen induced polarization technique (PHIP); (ii) Optimize PHIP hyperpolarization using magnetic field cycling approach process to maximize the percentage polarization and concentration of hyperpolarized C13-pyruvate; (iii) Develop efficient method for producing hyperpolarized solutions using heterogeneous PHIP catalysis only or homogeneous PHIP catalysis assisted by metal chelating agents to prepare pure aqueous solutions of hyperpolarized C13- pyruvate; (iv) Validate the sensing capability (i.e. non-invasive sensing of elevated lactate metabolism in cancer) of the developed hyperpolarized C13-pyruvate in cellular and small rodent models of cancer. We assembled a highly synergistic team of collaborating scientists from the US and Russia with proven three-year track record of collaborative research and peer-reviewed publications documented by 11 peer-reviewed publications (between US and Russian collaborators), 3 manuscripts under review and many more in preparation. The US team will be comprised on imaging scientist, physical chemist, organic chemist, in vivo molecular imaging scientist and others; and Russian team includes physical chemist/imaging scientist, catalytic chemist, cytologist, and others. This team will focus on the above Aims by leveraging expertise, materials and equipment uniquely available in Russian and US sub-teams to develop cheap and high-throughput production of hyperpolarized C13-pyruvate – contrast agent that can revolutionize clinical cancer imaging.