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The invisible becomes visible – a new MR-scanning technology
Ground-breaking hyperpolarization magnetic resonance imaging at Aarhus University Hospital in Denmark
reveals new metabolic details in cancer cells, in atherosclerotic heart muscles, in cerebral stroke and in
organs of the diabetic patient.
Today, doctors use different imaging technologies – CT, PET, SPECT/PT, and MR – to obtain the best
knowledge of the patient’s disease. But, in the future the so-called hyperpolarization MR spectroscopy will
become a new effective way of increasing knowledge of what goes on in the cells of the body –in both
healthy persons as well as in patients.
Very shortly described hyperpolarisation or Dynamic Nuclear Polarization (DNP) is a new MR-scanning
technology for in-vivo quantification of metabolic processes with an extremely high sensitivity. The DNP
technology allows rapid and high-sensitivity in vivo detection of pre-polarized 13C compounds (bio-probes)
with a signal enhancement of more than 10.000 (Figure 1). This substantially increases the detection limit
for quantitative measurements of specific metabolic fluxes involved in processing important intermediates
in lipid, sugar and amino acid metabolism.
Figure 1
A solution (few ml) of a bio-active
molecule (bio-probe), where one of
the 12C atoms is exchanged with a 13C
atom, is hyperpolarized in the
polarisator. The solution is injected
into the patient a few seconds after
finishing the polarization process. The
MR-spectroscopic scanning process
runs through the next few minutes
with a time resolution of about 1 sec.
The injected bio-probes are designed to trace specific metabolic fluxes in living tissue by exchanging
selected 12C atoms with 13C atoms that can be hyperpolarized. Injection of a bio-probe results in a very
strong MR-signal from the main molecule and its breakdown products, thus being quantitated with
extremely high sensitivity.
.
Even though [1-13C]pyruvate is the only bio-probe employed in humans until now, there is already an
availability of a number of bio-probe molecules for tracing various metabolic processes in animals.
[1,4-13C]fumerate might be the next one introduced for human use due to its potential for monitoring
metabolic effects of therapy in for example tumours. Other bio-probes tested right now are lactate,
acetate, leucine and glutamine, but the range of theoretically available bio-probe designs is long. Figure 2
illustrates how the various steps in glycolysis can be quantified dependent on which atoms in the bio-probe
(e.g. glucose) are exchanged with 13C. In contrast to the static quantification in standard spectroscopy a
highly dynamic measure of metabolic fluxes are provided by the DNP technique. This is due to the highly
enhanced signal to noise ratio implying a very high time resolution in the recordings.
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Figure 2
Different 12C atoms in e.g. glucose or in pyruvate can be exchanged with 13C for hyperpolarization and traced through the various steps of the
glycolysis. The colouring of individual carbon atoms allows tracing them through the individual glycolytic steps in the figure. 13C exchange on specific
carbon positions allows for quantification of both intermediary and end product when injected into a living organism. Other steps in the TCA flux
can be traced as well.
Examples of research fields and clinical applications of the DNP technology
Metabolic changes detected by DNP have, in experimental tumours, been shown to correlate with
response to chemotherapy. Therefore, the DNP technology is expected to provide an enhanced prediction
of therapy effects in pancreatic cancer in its potential for detecting possible metabolic markers of response
or resistance in patients.
Another oncological application area of the DNP technology is the combination with hadron therapy.
Commercially available proton accelerators allow deposit of particle (hadron) radiation energy very locally
in a solid tumour thus minimizing radiation damage to nearby healthy tissue and additionally minimizing
the risks of secondary cancers following years later. The DNP technology can identify areas in e.g. the
prostate gland that present the most abnormal metabolism and thus the highest malignity. Thus DNP might
be used for guidance of the hadron radiation.
The DNP methodology can also be used for in vivo quantification of fluxes of lipid, sugar and amino acid
metabolism in lifestyle related diseases. It allows possible acquisition changes in metabolic fluxes in liver
and muscles following a dietary shift to proteins with varying amino acid composition and load (e.g. low
glycine) in nutrients. Other examples are dietary programs with focus on branched-chain amino acids
(Leucine, Isoleusine and Valine). The study of enzymatic controlled metabolic fluxes is a final example of
DNP application in the studies of the metabolic inflexibility in diabetic or obese persons switch (metabolic
flexibility) between utilization of carbohydrates and lipid derivatives. This includes ketone bodies as fuel
substrates and preventive interventions like exercise, high glucose diet, high fat diet or anti-inflammatory
treatment affecting the dys-metabolic state of obese subjects, with or without diabetes or metabolic
syndrome.
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A metabolic and pharmacological study in cells cultured in MR-compatible bio-reactors is a future
application of DNP due to the high sensitivity of this technology. Regarding surface adherent cells a
substantial concentration of cells can be achieved in a reactor. An example is endothelial progenitor cells
that are believed to be influential on tissue regeneration by enhancing the formation of new blood vessels
in ischemic tissue. Other relevant cell types are various cancer cell lines. A design example of an MRcompatible bio-reactor is shown in figure 3. The bio-reactor is located deeply in the system circumvented
by the MR-electronics (RF-coils) and connected to various fluid lines.
Figure 3
Upper: a vertical MR-compatible bioreactor prepared for 13C DNP metabolic
measurements in cells grown on a
scaffold located inside the reactor.
Lower: microscopy of progenitor cells.
They adhere to hydrophilic surfaces of
3D printed scaffold with predefined
spaces between fibres. Adherent
cells on the fibres (stained for
nuclei) are shown to the right.
With the cells in position inside the
bio-reactor this is submerged into
the RF circuitry and pushed forward
to the iso-centre of a high field
horizontal magnet.
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