Magnetic Resonance Spectroscopy and Molecular Imaging of Metabolic Pathways in Cancer

Vanderbilt University Medical Center, Nashville TN

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Abstract

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.