Magnetic Resonance Spectroscopy and Molecular Imaging of Metabolic Pathways in Cancer

项目总结 对氢激发极化(PhIP)是一种替代超极化技术，它基于 对氢气与不饱和分子前体的分子加成。不同于更广泛的 溶解-动态核极化(d-DNP)，它是高度可扩展的，并且相对便宜。 然而，从历史上看，它并不像d-d那样享受快速的临床前适应和最终的临床翻译。 DNP这样做有几个关键原因：(I)不能超极化关键的代谢造影剂(例如丙酮酸 或乳酸)，(Ii)对配备双通道无线电的高度专业化超极化器硬件的要求 频率核磁共振谱仪(III)(加氢催化剂生产纯品的挑战) 超极化造影剂的超极化溶液。在2014-2016年间，几部开创性的作品 在PhIP领域发表，展示了由于根本原因，上述所有限制都可以克服 物理化学、合成化学和催化方面的进展。我们的国际合作(已建立 在2013年)一直在领导这些发展中的大多数，表明上述每一项 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，以及多相 催化或催化剂络合。在这个提案中，我们将探索这样的假设，即这些独立的 发展可以协同结合，以实现以下具体目标：(1)发展 仲氢诱导极化合成超极化C13-丙酮酸的分子前驱体 技术(PhIP)；(2)使用磁场循环方法优化PhIP超极化过程，以 最大限度地提高超极化C13-丙酮酸的极化百分比和浓度；(Iii)开发高效 仅使用非均相PhIP催化或均相催化产生超极化溶液的方法 金属络合剂辅助PhIP催化制备超极化C13-的纯水溶液 丙酮酸；(4)验证传感能力(即，非侵入性传感乳酸代谢升高 癌症)是在癌症细胞模型中形成的超极化的C13-丙酮酸。我们集结了一个高度 由来自美国和俄罗斯的合作科学家组成的协同团队，已证明有三年的跟踪记录 &gt；20种同行评审出版物记录的协作研究和同行评审出版物 (美国和俄罗斯的合作者之间)，以及更多的手稿正在审查和准备中。这个 美国团队将由成像科学家、物理化学家、活体分子成像科学家和 其他人；俄罗斯团队包括物理化学家/成像科学家、催化化学家、细胞学家等。 该团队将专注于上述目标，利用在 俄罗斯和美国小组将开发廉价和高通量的超极化C13-丙酮酸生产 -可以彻底改变临床癌症成像的造影剂。

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 model 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 >20 peer-reviewed publications (between US and Russian collaborators), and many more manuscripts under review and in preparation. The US team will be comprised on imaging scientist, physical 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.