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Background and Freiburg Research Activities

Magnetic Resonance (MR) spectroscopy allows for non-invasive measurement of metabolic changes at – however – limited spatial, chemical, or temporal resolution. These limitations can be addressed by improving the sensitivity of MR by strongly aligning nuclei of metabolically active molecules in the magnetic field (i.e. spin hyperpolarization, HP).[1] These novel HP contrast agents (CA) have been used to monitor cancer metabolism in vivo in real-time. They have allowed grading of tumors and to observe metabolic response to chemotherapy within a day, non-invasively and without ionizing radiation.[2,3] Recently, HP has been used to image glioma, prostate and pancreatic cancer in human, with promising results [e.g., 4,5]; more studies are undergoing, e.g. in patients suffering from breast and prostate cancer (our group is contributing imaging methods to these studies).

A problem of currently used HP techniques is that they are time-consuming (>30 min per sample) and expensive (e.g. purchase cost: >1 Mio. €; cost per application: ~100€ for rodents or ~10k€ for human). Another challenge is the short lifetime of HP, which typically decays within 2-3 minutes. CAs are so far produced in a dedicated device (a “polarizer”) and have to be transported to the MRI system for application. During this transfer, typically a significant fraction of HP is irrevocably lost. Another issue is that imaging of hyperpolarized CAs requires dedicated MRI sequences to detect the spins and metabolic conversion; the "perfect" sampling strategy, which effectively exploits the valuable information provided by these novel agents, hasn't been found yet.

The work of our group is dedicated to the research, development and translation to preclinics and clinics of new techniques for HP to overcome current shortcomings. Methologically, we use a phenomenon referred to as parahydrogen induced polarization (PHIP),[6,7] which is cost- and time-efficient and - as we have recently demonstrated - can create hyperpolarization inside the MRI system (see SAMBADENA below).[8] In a line related to this work, we develop new imaging strategies specialized to the detection of hyperpolarized CAs (see me-bSSFP below).[9]

[1] J. G. Skinner et. al., Molecular Imaging and Biology, 2018, 20, 902-918. DOI: 10.1007/s11307-018-1265-0.
[2] S. E. Day et al., Nat. Med. 2007, 13, 1382–1387.
[3] M. J. Albers et al., Cancer Res. 2008, 68, 8607–8615.
[4] A. W. Autry et al., NeuroImage Clin. 2020, 27, 102323.
[5] J. Kurhanewicz et al., Neoplasia N. Y. N 2018, 21, 1–16.
[6] C. R. Bowers, D. P. Weitekamp, J. Am. Chem. Soc. 1987, 109, 5541–5542.
[7] T. C. Eisenschmid et al., J. Am. Chem. Soc. 1987, 109, 8089–8091.
[8] A. B. Schmidt et al., Nat. Commun. 2017, 8, 14535.
[9] C. A. Müller et al., NMR Biomed. 2020, 33, e4291. DOI: 10.1002/nbm.4291



Interdisciplinary Hyperpolarization: Chemistry and Physics provide the means to gain new, previously unavailable insights to Biology and Medicine.

Hyperpolarization - An Overview

The magnetic resonance signal depends on the alignment of nuclear spins with respect to an outer magnetic field, much like compass needles in the earth's magnetic field. While all compasses point north in the earth's field, only a few parts per million of the spins are aligned. As a result, the corresponding signal that can be detected by MRI is very small. As a spin-1/2 particle, 1H has two energy eigenstates with respect to an outer magnetic field, spin up and spin down. Refering to the analogy of the compass: the magnetic moment of the spin acts like a small compass needle in the nucleus of hydrogen atoms pointing north or south, and how many spins point in one or the other direction in the equilibrium is governed by the well-known Boltzmann statistics.

In MR, only the population difference of both states - of spins pointing north and south -  contributes to the signal (referred to as polarization, P). P = 1 means maximal population difference - all spins point in one direction - and maximum signal (north or south, depending on the spin); P=0 means no population difference - half of the spins point North and half point South -  or no MR signal (Fig. 1).

Unfortunately, the nuclear compass needles are so small, that in the earth magnetic field of ~ 50 microTesla, both levels are almost equally populated. The difference is only P ≈ 10-10. This means that merely 0.00000001 % of all of the spins are polarized (and thus available to contribute to the signal). This is acceptable in the case of 1H MRI where the lack of polarization is offset by the high endogenous concentration, but for MR applications where one is interested in the relative concentrations of a relatively sparse nucleus (such as a 13C labelled biomarker of cancer), this is too little.

Schematic Representation of thermal (left) and hyper-polarization (right). Placed in an external magnetic field, nuclei with spin-1/2 have two energy eigenstates. The population of these states is Boltzmann distributed. In thermal equilibrium, in the earth magnetic field (≈50 microT), the population difference for 1H is P ≈ 10-10, at 1 Tesla P ≈  3·10-6. Hyperpolariaztion circumvents the thermal distribution using various tricks i.e. sources of spin order, including polarized laser light or parahydrogen.

Modern superconducting magnets provide magnetic fields of several Tesla, which is ≈105 times as strong as the earth's field, and ≈10 - 100 times as strong as magnets lifting cars on scarp yards. This has enabled MRI to become one of the most versatile tools in modern science and medicine. Still, even with these humongous, strong magnetic fields of several Tesla, only a miniscule fraction (≈3·10-6/T) of all nuclear hydrogen spins are polarized. Thus, MR is an inherently insensitive method.

We are the 99.9997 %

On the other hand, there is a great potential. All exciting and ground-breaking results of magnetic resonance are achieved using only a few millionths of all spins. What can magnetic resonance do when 100 % of all spins are available instead of merely 0.0003 %?

The goal of nuclear hyperpolarization is to access this vast majority of nuclear spins, 99.9997 % of 1H per Tesla, which do not contribute to the signal of conventional magnetic resonance imaging.

Dr. Andreas B. Schmidt
Head of Hyperpolarization

Killianstr. 5a
D-79106 Freiburg

phone:  +49 (0) 761 270-93911
email: andreas.schmidt@uniklinik-freiburg.de