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MR Hyperpolarization for diagnostics

Francesca Reineri - PI

Francesca Reineri
Biographical sketch

Associate Professor of General and Inorganic Chemistry, Dept. Molecular Biotechnology and Health Sciences, Univ. of Torino 

Main group members
Main group members

  • Ginevra Di Matteo PhD Student

  • Sumit Mishra Postdoctoral fellow

  • Bhahreh Saadat Deghan Master Student

RESEARCH ACTIVITY

MRI is a powerful diagnostic tool to obtain information about the health state of tissues and to detect the onset of pathologies non-invasively. Due to its intrinsic low sensitivity, the wealth of chemical information that can be obtained from MR remains widely unexploited. Hyperpolarization increases the intensity of the MR signals of specific molecules by orders of magnitude, making them clearly detectable by MRS/MRI and allowing the investigation of metabolic processes in-vivo, in real time. A hyperpolarization procedure, named PHIP-SAH (ParaHydrogen Induced Polarization -Side Arm Hydrogenation) (figure 1) has been invented in our laboratory, to generate hyperpolarized metabolites in an easy to handle and affordable way. 

Figure 1
Figure 2

Among them, pyruvate (usually obtained by the expensive and technically demanding d-DNP technique) is the most widely used for the study of metabolism and its alterations in different pathologies. A pilot study has been carried out in-vivo using this hyperpolarized probe, that demonstrated its applicability of PHIP polarized pyruvate for metabolic investigations (figure 2). 

Figure 3

The up-regulated conversion of pyruvate into lactate, even in the presence of oxygen (i.e. the Warburg effect), is a common feature of cancer tissues. HP-pyruvate, obtained using parahydrogen, has also been used to investigate these metabolic changes in cancer cell lines characterized by different aggressiveness (figure 3).

For the future we plan to: 

  1. optimize the hyperpolarization procedure, using different precursors of the target molecules and different methods for spin order transfer, in order to increase the hyperpolarization level on the final product; 

  2. use the hyperpolarized substrates (in particular HP-pyruvate) for the investigation of metabolic changes in different pathologies and following to treatment; 

  3. explore different biological substrates suitable for hyperpolarization using parahydrogen.

  • Since October 2019 to September 2023. Partner in the H2020 FETOpen Project Alternatives to Gd (www.alternativestogd.eu). Project n. 848149 

  • Since February 2018 to December 2021 . Partner in the Marie-Curie ITN H2020-MSCA-ITN-2017, n. 766402, Zero and Ultra-Low Field Nuclear Magnetic Resonance (ZULF) 

  • Since 01 May 2017 to 30 April 2020. Athenaeum call 2016 (Compagnia San Paolo), Research for the territory, projet n. CSTO164550, Hyperpolarized metabolites for MRI of cancer 

  • Since January 2016 to December 2018. AIRC- Cariplo foundation TRIDEO 2015, “Metabolic Imaging with ParaHydrogen Polarized tracers for cancer detection and treatment monitoring”. 

ParaHydrogen Induced Polarization of 13C carboxylate resonance in Acetate and pyruvate” Reineri F., Boi T., Aime S., Nat. Commun. 2015, 6:5858. doi: 10.1038/ ncomms6858 

13C-MR Hyperpolarization of Lactate using ParaHydrogen and metabolic transformation in vitro. CAVALLARI, ELEONORA, CARRERA, CARLA, AIME, Silvio, REINERI, Francesca (2016). CHEMISTRY-A EUROPEAN JOURNAL, p. 1-5, ISSN: 0947-6539, doi: 10.1002/ chem.201605329. 

The 13C hyperpolarized pyruvate generated by ParaHydrogen detects the response of the heart to altered metabolism in real time, Eleonora Cavallari, Carla Carrera, Matteo Sorge, Gisèle Bonne, Antoine Muchir, Silvio Aime, Francesca Reineri Scientifc Reports, 2018, 8:8366 DOI:10.1038/s41598-018-26583-2. 

“Metabolic Studies of Tumor Cells Using [1-13C] Pyruvate Hyperpolarized by Means of PHIP-Side Arm Hydrogenation” Eleonora Cavallari, Carla Carrera, Silvio Aime, Francesca Reineri ChemPhysChem 2019, 20, 318–325. Doi: 10.1002/cphc.201800652 

Real-Time Nuclear Magnetic Resonance Detection of Fumarase Activity Using Parahydrogen-Hyperpolarized [1-13C]Fumarate. James Eills,, Eleonora Cavallari, Carla Carrera, Dmitry Budker, Silvio Aime and Francesca Reineri J. Am. Chem. Soc. 2019, 141, 20209−20214. Doi 10.1021/jacs.9b10094 

In-vitro NMR Studies of Prostate Tumor Cell Metabolism by Means of Hyperpolarized [1-13C]Pyruvate Obtained Using the PHIP-SAH. Eleonora Cavallari , Carla Carrera, Ginevra Di Matteo, Oksana Bondar , Silvio Aime and Francesca Reineri Method Front. Oncol. April 2020 | Volume 10 | Article 497. doi: 10.3389/ fonc.2020.00497 

Singlet-contrast Magnetic Resonance Imaging: Unlocking Hyperpolarization with Metabolism” Eills J., Cavallari E., Kircher R., Di Matteo G., Carrera C., Dagys L., Levitt M.H., Ivanov K.L., Aime S., Reineri F., Münnemann K., Budker D., Buntkowsky G., Knecht S. (2021) Angewandte Chemie - International Edition, 60 (12), pp. 6791 - 6798, Cited 16 times. DOI: 10.1002/ anie.202014933 

ParaHydrogen polarized ethyl-[1-13C]pyruvate in water, a key substrate for fostering the PHIP-SAH approach to metabolic imaging. C. Carrera, E. Cavallari, G. Digilio, S. Aime F. Reineri; Chem Phys Chem 2021, 22(11), pp.1042-1048. Doi: 10.1002/cphc.202100062 

Rapid hyperpolarization and purification of the metabolite fumarate in aqueous solution” Knecht S., Blanchard J.W., Barskiy D., Cavallari E., Dagys L., van Dyke E., Tsukanov M., Bliemel B., Münnemann K., Aime S., Reineri F., Levitt M.H., Buntkowsky G., Pines A., Blümler P., Budker D., Eills J. (2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (13), art. no. e2025383118, DOI: 10.1073/pnas.2025383118 

Effect of the hydrogenation solvent in the PHIP-SAH hyperpolarization of [1-13C]pyruvate” Bondar O., Cavallari E., Carrera C., Aime S., Reineri F. (2022) Catalysis Today, 397-399, pp. 94 - 102, DOI: 10.1016/j.cattod.2021.11.03

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