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Into the Future with Metrology - The Challenges of Medical Technology

Searching for biomarkers with the aid of xenon

Quantities of substances determined for the first time without reference material

PTB-News 1.2023
12.01.2023
Especially interesting for

medical engineering

biomedical research

A xenon atom of aligned magnetic moment (red) is bound to the cryptophane A molecule, surrounded by several free, but similarly aligned, i.e., identically hyperpolarized, xenon atoms (blue). If only the bound xenon atom is irradiated with RF waves, its magnetic moment changes its orientation, which then differs from that of the free xenon. This loss of alignment (hyperpolarization) is progressively transferred to the free xenon atoms (blue) via xenon exchange, so that their signal decreases over time during the irradiation. The initial intensity and the rate of this decrease change depending on the experimental parameters selected for xenon density and irradiation amplitude, and this change can be used to perform quantitative analysis.

Detecting biomarkers (i.e., certain proteins or cells) as indicators for diseases is playing an ever more important role both in biomedical research and in clinical care. Such detection requires measurement procedures that are very sensitive and accurate. Using magnetic resonance (MR) with hyperpolarized xenon allows biomarkers to be detected in vitro at nanomolar concentrations. It is thus possible to investigate mechanisms such as the immune response to pathogens.

Xenon, a noble gas, is hyperpolarized to make it easier to detect using MR. Hyperpolarization induces a high degree of alignment of the magnetic moments of the xenon atoms, similar to small magnetic needles in a magnetic field. As a result, the measured MR signals of xenon are amplified and can be detected even at very low concentrations. Moreover, xenon is well suited to searching for molecules, since xenon atoms can alternate between a free state and a state in which they are bound to the target molecule (xenon exchange). Using what are known as saturation transfer MR techniques, the bonding partner of xenon (i.e., the target molecule) can be detected with very high sensitivity. However, it was previously not possible to quantitatively analyze the amount of bonding partner because hyperpolarization is not exactly repeatable and saturation transfer is determined by the details of the exchange dynamics. Comparing signals directly by means of reference materials is therefore no longer a robust method.

This is why PTB has developed a novel approach that exploits xenon exchange selectively. Saturation transfer is repeated several times applying slightly different experimental parameters for each repeat. The bonding partner quantity can then be calculated from the measurement data. This does not require any reference material, and the measurement sequence performs equally well on each device. The new approach therefore requires no reference materials and is platform-independent. It has been established at PTB on the xenon-binding molecule cryptophane A, which may, in addition, also bind the target molecule of interest. Such biosensors are to be used to quantitatively determine biomarkers for the purposes of diagnostic and therapeutic process development.

The activities are funded by the Federal Ministry of Education and Research (BMBF) through its program entitled “Validation of the technological and societal innovation potential of scientific research – VIP+”. A patent application has also been filed.

Contact

Lorenz Mitschang
Department 8.3
Biomedical Optics
Phone: +49 30 3481-7632
Opens local program for sending emaillorenz.mitschang(at)ptb.de

Scientific publication

L. Mitschang, S. Korchak, W. Kilian, T. Riemer: Comprehensive quantitative and calibration-free evaluation of hyperpolarized Xenon-host interaction by multiparametric NMR. Analytical Chemistry, 94, 2561–2568 (2022)