Magnetic Resonance Spectroscopy and Molecular Imaging of Metabolic Pathways in Cancer

癌症代谢途径的磁共振波谱和分子成像

基本信息

批准号：
9755386
负责人：
Eduard Chekmenev
金额：
$ 11.82万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-12 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9755386
关键词：
Bilateral Cancer Model Catalysis Cell model Chelating Agents Clinical Clinical Trials Collaborations Communities Contrast Media Coupled Detection Development Doctor of Philosophy Equipment Face Gases Glucose Hydrogenation Image Imaging Techniques Injectable Injections International Label Life Lipids MRI Scans Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant Neoplasms Malignant neoplasm of prostate Manuscripts Metabolic Metabolic Pathway Metabolism Methods Modeling Molecular Molecular Probes Monitor NMR Spectroscopy Nuclear Peer Review Physical Chemistry Play Positron-Emission Tomography Preparation Process Production Protons Publications Publishing Pyruvate Research Research Peer Review Resolution Resources Rodent Model Russia Scanning Scientist Screening for cancer Seminal Side Signal Transduction Site Surrogate Markers Synthesis Chemistry Techniques Time Tracer Work aqueous arm base cancer care cancer imaging catalyst chelation clinical translation cost fluorodeoxyglucose fluorodeoxyglucose positron emission tomography glucose uptake high risk population imaging detection imaging probe imaging scientist in vivo magnetic field magnetic resonance spectroscopic imaging metal chelator milligram molecular imaging pre-clinical radio frequency tool treatment response tumor tumor metabolism uptake volunteer

项目摘要

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.

项目摘要寄生诱导的极化（PHIP）是一种替代性超极化技术，它基于分子在不饱和的分子前体中添加甲状腺素气体。与更宽度不同溶解动态核极化（D-DNP），它是高度可扩展的且相对便宜的。然而，从历史上看，它并不享有快速的临床前适应和最终的临床翻译 DNP出于几个关键原因而进行：（i）无法超极化密钥代谢对比剂（例如丙酮酸（ii）配备双通道无线电的高度专业超极化器硬件的要求频率NMR光谱仪，（iii）纯生产挑战（来自氢化催化剂）超极化对比剂的超极化溶液。在2014 - 2016年，已经进行了几幅第二件作品在PHIP领域发表，证明了上述所有局限物理化学，合成化学和催化的进展。我们的国际合作（成立特别是在2013年）领导着大多数这些事态发展，表明上述每个发展可以单独解决挑战，并且可以原则上产生廉价的代谢对比剂代理通过新的合成方法，侧臂氢化和磁场循环以及异质催化或催化剂螯合。在此提议中，我们将探讨这些分开的假设发展可以协同结合以实现以下特定目标：（i）发展分子前体，用于生产超极化的C13-丙酮酸通过偏二酸酯诱导的极化技术（PHIP）; （ii）使用磁场循环进近的过程优化PHIP超极化最大化超极化C13-丙酮酸的极化百分比和浓度；（iii）提高效率仅使用异质PHIP催化或均质产生超极化溶液的方法金属螯合剂辅助的PHIP催化剂准备了超极化C13-的纯水溶液丙酮酸；（iv）验证灵敏度能力（即，升高鞋底代谢的非侵入性敏感性在癌症细胞模型中，发达的超极化C13-丙酮的癌症。我们组装了一个高度来自美国和俄罗斯的科学家合作的协同团队，具有三年的良好记录 > 20个经过同行评审的出版物记录的合作研究和同行评审的出版物（在美国和俄罗斯合作者之间），以及正在审查和准备的更多手稿。这美国团队将完成成像科学家，物理化学家，体内分子成像科学家和其他的;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。该团队将通过利用专业知识，材料和设备独特的目的来关注上述目标俄罗斯和美国的子团队，开发出廉价且高通量的超极化C13-丙酮酸 - 可以彻底改变临床癌成像的对比剂。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pulse-Programmable Magnetic Field Sweeping of Parahydrogen-Induced Polarization by Side Arm Hydrogenation

DOI：
10.1021/acs.analchem.9b04501
发表时间：
2020-01-07
期刊：
ANALYTICAL CHEMISTRY
影响因子：
7.4
作者：
Joalland, Baptiste;Schmidt, Andreas B.;Chekmenev, Eduard Y.
通讯作者：
Chekmenev, Eduard Y.

Toward Cleavable Metabolic/pH Sensing "Double Agents" Hyperpolarized by NMR Signal Amplification by Reversible Exchange.

DOI：
10.1002/chem.201802622
发表时间：
2018-07-25
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
0
作者：
Kidd BE;Mashni JA;Limbach MN;Shi F;Chekmenev EY;Hou Y;Goodson BM
通讯作者：
Goodson BM

15 N MRI of SLIC-SABRE Hyperpolarized 15 N-Labelled Pyridine and Nicotinamide.

SLIC-SABRE 超极化 15 N 标记吡啶和烟酰胺的 15 N MRI。

DOI：
10.1002/chem.201900430
发表时间：
2019
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
0
作者：
Svyatova,Alexandra;Skovpin,IvanV;Chukanov,NikitaV;Kovtunov,KirillV;Chekmenev,EduardY;Pravdivtsev,AndreyN;Hövener,Jan-Bernd;Koptyug,IgorV
通讯作者：
Koptyug,IgorV

Heterogeneous Parahydrogen Pairwise Addition to Cyclopropane.

DOI：
10.1002/cphc.201800690
发表时间：
2018-10-19
期刊：
Chemphyschem : a European journal of chemical physics and physical chemistry
影响因子：
0
作者：
Salnikov OG;Kovtunov KV;Nikolaou P;Kovtunova LM;Bukhtiyarov VI;Koptyug IV;Chekmenev EY
通讯作者：
Chekmenev EY

Chemical Exchange Reaction Effect on Polarization Transfer Efficiency in SLIC-SABRE.

化学交换反应对 SLIC-SABRE 偏振传输效率的影响。

DOI：
10.1021/acs.jpca.8b07163
发表时间：
2018
期刊：
The journal of physical chemistry. A
影响因子：
0
作者：
Pravdivtsev,AndreyN;Skovpin,IvanV;Svyatova,AlexandraI;Chukanov,NikitaV;Kovtunova,LarisaM;Bukhtiyarov,ValeriiI;Chekmenev,EduardY;Kovtunov,KirillV;Koptyug,IgorV;Hövener,Jan-Bernd
通讯作者：
Hövener,Jan-Bernd