MRI-based method detects water exchange in tumor cells to measure their malignancy
The cycling of water across membrane transporters is an
hallmark of the cell metabolism and is potentially of high diagnostic
significance for the characterization of tumors and other diseases. In
the journal Angewandte Chemie, an Italian research team has now
introduced a new MRI-based method for assessing this water exchange. By
this method, they were able to estimate the degree of malignancy and the
success of treatments in mice tumor models.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Not all cancers are equal. Depending on the type of tumor,
a given treatment may be spot on or fail completely. For targeted,
effective, treatment that is as gentle as possible, it is important to
precisely locate the tumor and determine its malignancy. Magnetic
resonance imaging (MRI) provides excellent time- and spatially resolved
images for the characterization of tumors. During this procedure, the
patient lies in a “tube” in which there is a very strong magnetic field.
The spins of protons (the nuclei of hydrogen atoms) align themselves in
this magnetic field. Radio waves are beamed in and synchronize the
precessions of the spins, temporarily flipping some of them. Depending
on the composition of the tissue, this “magnetization” is lost at
different times (relaxation). This can be used to compute 3D images.
Gadolinium contrast agents reduce the relaxation times. These agents are
more concentrated in tumors because their blood vessels are particularly
permeable. This increases the contrast and makes it easier to define the
tumor.
Contrast agents only spread through the extracellular
compartments of the tumor; they do not enter tumor cells. A team led by
Giuseppe Ferrauto and Silvio Aime wanted to exploit this feature to
determine the degree of water exchange through the cell membrane. Tumor
cells are more metabolically active than healthy cells and have more
transport proteins and channels in their cell membranes. These proteins
also allow water to enter and exit the cell, and the degree of water
exchange is a measure of the aggressiveness of a tumor. Yet, classic MRI
cannot show this.
The team from the University of Torino and IRCCS SDN SynLab
in Naples decided to work with a new MRI method called CEST (Chemical
Exchange Saturation Transfer). There is constant proton exchange between
free water and hydrogen-containing groups in biomolecules, such as the
amine groups in creatine. The radio frequencies at which a proton can be
“magnetized” depends on the chemical environment of that proton, so
frequencies are different for protons in free water and those bound to
creatine, for example. With a matching pulse, the creatine-bound protons
can be saturated. These protons are exchanged and bind to nearby free
water. They keep their “saturated magnetization state” as they do this.
If radio waves with the right frequency for free water protons are then
pulsed, an increasing number of these protons are already magnetized and
cannot absorb the energy (the CEST signal in MR images). Absorption
decreases until the proton exchange reaches equilibrium. This makes it
possible to draw conclusions about the concentration of creatine and
other proton exchanging molecules in a cell, which can be used for
cancer phenotyping.
If a contrast agent is then administered and enters the
extracellular compartment, the magnetization of the water protons there
decreases significantly faster. Because water is exchanged through the
membrane, the number of magnetized water protons within the cells also
decreases more quickly. This in turn changes the CEST signals. The
changes after addition of contrast agent reflect the permeability of the
tumor cell membrane to water.
The team tested this method in mouse models for breast
cancer with different degrees of malignancy. As expected, the observable
water exchange increase as the tumors grew more aggressive. Within the
tumors, it was also possible to differentiate between areas of differing
malignancy. The cytostatic drug Doxorubicin immediately reduced the
water permeability.
Hence, the developed method sheds light into tumor
phenotype and provides a new tool to assess the outcome of chemotherapy.
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About the Author
Dr Silvio Aime is Em. Professor of Chemistry at the
University of Torino where he was the founder of the Center for
Molecular Imaging at the Department of Molecular Biotechnologies and
Health Sciences. He is the recipient of numerous awards for his research
in the field of Magnetic Resonance Imaging and chemistry of imaging
probes.
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