MRC Award for Young Scientists

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  • Published: Jul 17, 2015
  • Source: Wiley-Blackwell
  • Channels: NMR Knowledge Base / MRI Spectroscopy
thumbnail image: MRC Award for Young Scientists

The MRC Award for Young Scientists, established in 2006, is open to outstanding researchers under the age of 40 working with NMR spectroscopy in analytical chemistry within industry or academia in any part of the world. The Award will be presented annually at the EUROMAR conference and judged by the respective scientific committee. The Awardees will give a Magnetic Resonance in Chemistry Award Lecture at the appropriate sessions of conference, and receive a certificate and a cheque for 500 Euros.

This year's awardees are shown below.

From left to right: Vladimir Sklenář (2015 Euromar Chair); Thomas Theis; Anne Fages; Krzysztof Kazimierczuk; Paul Trevorrow (MRC Managing Editor, Wiley-Blackwell).

Dr. Anne Fages
Weizmann Institute of Science, Chemical and Physics, Rehovot, Israel

MAGNETIC RESONANCE DETECTION OF LYMPHATIC BREAST CANCER METASTASIS IN A XENOGRAFT MODEL BY HYPERPOLARIZED 13C-PYRUVATE

Breast cancer is the most commonly diagnosed cancer among women. Besides significant progress in therapeutic strategies, the prognosis of metastatic breast cancer (MBC) is poor with a five years survival rate around 25%. An early event of MBC is the dissemination of tumor cells in the lymphatic system to form metastasis in lymph nodes (LN). Thus, a key challenge is the ability to non-invasively detect and characterize the metastatic LN in order to improve patient management.

The emergence of dissolution dynamic nuclear polarization (DNP) technique in combination with magnetic resonance imaging and/or spectroscopy (MRI/MRS) has opened new avenues for real-time imaging of the metabolism. The DNP of a 13C-labelled metabolite enables its hyperpolarization leading to an increase in signal-to-noise ratio around 10^4 allowing then for the fast MRI/MRS detection of not only the substrate but also its metabolic products. Taking advantage of the fast anaerobic glycolytic pathway (Warburg effect) in cancer cells, like positron Emission Tomography, this cutting-edge method has already shown its potential for the detection of human prostate tumors. The interest for its clinical application is even larger for the detection and the monitoring of the metastatic process. While the metabolic reprogramming of cancer cells is well identified, little is known about the metabolic profile of the disseminated tumor cells leading to metastasis.

In this study we have used DNP-enhanced 13C MRS method to probe the metabolism of the primary tumors and metastatic LN in a breast cancer xenograft model using 1-13C hyperpolarized pyruvate. MDA-MB-231 human breast cancer cells were injected into the mammary fat pad of seven immunodeficient nude mice. Three to six weeks after cells implantation, the primary tumor growth and the contralateral inguinal LN were monitored by 1H MRI at 4.7T. Arrays of 13C MRS spectra were recorded on both sites by a 3mm 13C surface coil following the intravenous injection of hyperpolarized 13C-pyruvate. The animals were later sacrificed and the presence of metastasis at the inguinal LN was confirmed or denied by histopathology.

Lactate production from injected pyruvate was observed in both tissues. The highest lactate/pyruvate signal was observed for a metastatic LN (1.14; n=1) while the mean normalized lactate signal from the primary tumors and the non-metastatic LN were 0.50 (± 0.2, n=7) and 0.62 (± 0.2; n=6) respectively. The dynamic data also enabled the extraction of pyruvate-to-lactate rate constant (k-rate). The highest k-rate was observed for the metastatic LN (0.06 s-1), which was twice the mean of the ones calculated from primary tumor spectra (0.03 s-1; ± 0.008). The mean k-rate obtained from the non-metastatic LN was 0.05 s-1 (± 0.01). Further studies of metastatic LN are required in order to define the metabolic changes occurring during the infiltration of cancer cells into the lymphatic system. This work, still under progress, presents an unprecedented effort to characterize the metabolism of both the primary tumor cells and their metastatic spread to regional LN, that once successful might be of valuable interest for clinical application.

Dr. Krzysztof Kazimierczuk
University of Warsaw, Centre of New Technologies, Warsaw, Poland

DYNAMIC NON-UNIFORM SAMPLING

Non-uniform sampling (NUS) has become a widely applied way of accelerating multidimensional NMR experiments. Most of the standard signal acquisition software allows to run experiments in the NUS mode. There are also numerous NUS processing methods, among which sparsity-based reconstructions, known also as compressed sensing (CS), have recently become popular [1].

Interestingly, NUS can be also applied in a way slightly different from the usual undersampling of the full Nyquist grid, i.e. it can be used to implement time-resolved experiments with extraordinary temporal resolution. The original idea of Mayzel et al. [2] assumed, that the random sampling of the indirect dimensions is performed in parallel to some chemical or physical process occurring in the sample. Then, overlapping subsets of the acquired dataset are used for the reconstruction of the series of multidimensional spectra corresponding to various moments of the process.

Our group developed CS methods dedicated for the acquisition and processing of the time-resolved data. The examples of both artificially induced processes [3] and uncontrolled reactions [4] have been given. Currently, the idea is being extended to the experiments where the observed change in the spectrum is induced not by the changes in the molecular structure, but by varying the coherence transfer. The examples of applications, as well as the main principles of the method, referred to as dynamic NUS, will be mentioned during the talk.

References:
1. a) K. Kazimierczuk, V. Y. Orekhov, Angew. Chem. Int. Ed. 2011, 50 (24), 5556–5559 b) D. J., Holland, M. J., Bostock, L. F., Gladden, & D. Nietlispach, 2011, Angew. Chem. Int. Ed. Engl., 50(29), 6548–6551. c) S. Hyberts, A. Milbradt, A. Wagner, H. Arthanari, H., & G. Wagner, 2012, J. Biomol. NMR, 1–13.
2. M. Mayzel, J. Rosenlöw, L. Isaksson, & V.Y. Orekhov (2014). J. Biomol. NMR, 58(2), 129–39.
3. W. Bermel, R. Dass, K.-P. Neidig, K. Kazimierczuk, ChemPhysChem 2014, 15, 2217-2220.
4. R. Dass, W. Koźmiński, K. Kazimierczuk, Analytical Chemistry 2015, 87 (2), 1337–1343.

Dr. Thomas Theis
Duke University, Chemistry, Durham, USA

ENHANCING SABRE WITH MICROTESLA FIELDS: BROADLY APPLICABLE, >10,000 FOLD DIRECT HETERONUCLEAR SIGNAL ENHANCEMENT WITH >20 MINUTE SIGNAL LIFETIMES

Hyperpolarization, particularly with dissolution dynamic nuclear polarization (d-DNP) (Ardenkjaer-Larsen, PNAS 2003) is opening new applications in NMR and MRI. However, d-DNP has high costs ($3M for the commercial, GE SpinLabTM), lengthy hyperpolarization times (~20 min – 1h), and serious scalability challenges (because the mm wave irradiation barely penetrates large samples). An alternative, cost-effective and fast (or even continuous) source of hyperpolarization is “Signal Amplification By Reversible Exchange” (SABRE; Duckett Science 2009). SABRE uses an organometallic Ir-catalyst, which transiently binds both parahydrogen and targeted molecules, permitting transfer of spin order from parahydrogen to the target. Until now, the main limitations of SABRE have been that it only hyperpolarized protons efficiently (associated with few-second T1 lifetimes), and that it was limited to a relatively small class of molecules. Here we show that both of these limitations are overcome by conducting SABRE in a magnetic shield directly targeting heteronuclei.

We introduced this method as SABRE-SHEATH (SABRE in Shield Enables Alignment Transfer To Heteronuclei). (Theis, JACS 2015; Truong, JPCC 2015). With this method we can directly target spin systems with long signal lifetimes and hyperpolarize much wider classes of molecules. In our first SABRE-SHEATH paper (Theis, JACS 2015) we hyperpolarized 15N-pyridine and 15N-nicotineamide (Vitamin B3 amide) with enhancements of 30,000 fold and 20,000 fold respectively over thermal signals at 9.4 T, and with 15N T1 of above 1 min.

In our more recent work, the true advance from SABRE-SHEATH is becoming even clearer. Traditional 1H SABRE requires strong J-coupling between the parahydrogen derived hydrides on the catalyst and the protons on the substrate, which has limited effective 1H-SABRE to pyridine like substrates. However, by directly targeting heteronuclei this restriction is removed and many more classes of molecules become amenable. For example, we demonstrate >15,000 fold enhancements on15N-acetonitrile (with T1 > 1 min), which is a very poor substrate for traditional 1H SABRE. More importantly, we have discovered that heteronuclear SABRE can directly hyperpolarize long-lived singlet states with very long lifetimes (TS > 20 min) on 15N spin pairs in diazirine (N=N bound to one C, forming a three membered ring). We report >10,000 fold signal enhancements on the 15N sites even though the molecule displays no proton signal enhancement via conventional 1H-SABRE. Diazirines have not even been reported as Ir-ligands before, yet they hyperpolarize via reversible exchange on the SABRE catalyst. In addition, diazirines can be incorporated as small tags into a large range of biomolecules. The >20 min lifetimes, paired with the significant signal enhancements, set the stage for hour long molecular imaging.

It is our prediction, based on accompanying theoretical models, that these groundbreaking results will enable heteronuclear hyperpolarization of many other substrates that exhibit weak interactions with the reversibly exchanging Iridium complex, be it in a solution or even as ‘neat’ liquids. (Shchepin, 2015, submitted). Over the last decade d-DNP has changed magnetic resonance research; we believe that SABRE-SHEATH will do so once again, because it puts a generalized hyperpolarization technique into the hands of any interested researcher at a modest budget.

For more information about this Award, please visit Magnetic Resonance in Chemistry.

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