CE19 - Technologies pour la santé

pH Observation of Extracellular Fluid by NMR Involving Xenon – PHOENIX

NMR cartography of extracellular fluid pH

The goal of the PHOENIX project is to develop a sensitive, specific and non-invasive method to assess and monitor extracellular pH in vivo. This concept is based on the design of pH sensors that can bind 129Xe at physiological pH. Thanks to the high sensitivity of the hyperpolarized 129Xe NMR/MRI technique, this approach will represent a fast and easy way to detect pH variation in tissues and has many advantages over the existing techniques aimed at measuring extra-cellular pH.

pH Observation of Extracellular Fluid by NMR Involving Xenon

Extracellular pH is determined by the net flux of acid and base into and out of the extracellular fluid; it provides crucial clues on the metabolism of living organisms. On the other hand, the control of pH is critical for the maintenance and regulation of organ and cell function, as is evident from the severe consequences of inborn or acquired forms of acidosis. Noteworthy, recent data support the participation of local acidosis in cancer progression via stimulation of autophagy and immunosuppression. A means to measure, non-invasively, tissular pH changes would be therefore extremely valuable for assessing the aggressiveness of tumors at an early stage of their development and to monitor the effect of treatments. <br /> Magnetic Resonance Imaging is a powerful diagnostic tool commonly used by clinicians as it can map deep tissues with a spatial resolution of few mm. Different approaches for in vivo NMR-based pH measurement have been developed, based on either endogenous or exogenous species but the crucial point is to overpass the sensitivity limitations of this modality. Thus, non-toxic tracers that can map and monitor extracellular pH in vivo are still highly needed.

Here we present an innovative approach, which is simple, easy to implement, sensitive and devoid of most of the biases that can be encountered in vivo. The principle is to perform a differential measurement by using a pair of pH-sensitive hyperpolarized 129Xe NMR-based sensors. Xenon is an element of high interest for MRI applications as it can be used as an exogenous tracer readily delivered and released from the body and it shows a low toxicity. The method will be rendered very pH-sensitive by the choice of two xenon hosts in which the frequencies of the noble gas signals vary in opposite manner with the free H+ concentration. The validation of this concept has already been demonstrated in vitro and recently published.

In progress

The most important asset, that makes a large difference with the other NMR/MRI techniques using hyperpolarized species, lies in its implementation if our pH-sensors fulfill all the biological conditions: low quantities of them will be injected in a first step only once. Then xenon will be introduced at will, possibly several times. Thus, with PHOENIX we will no more be limited to a one-shot experiment and longitudinal follow-up of in vivo pH will be possible. This also represents an asset for extension of this application towards human experimentation.

Martin Doll, Patrick Berthault, Estelle Léonce, Céline Boutin, Thierry Buffeteau, et al. Are the physical properties of Xe@cryptophane complexes easily predictable? the case of syn and anti tris-aza-cryptophanes. J Org. Chem. 2021, 86 (11), .7648-7658

Martin Doll, Patrick Berthault, Estelle Léonce, Céline Boutin, Erwann Jeanneau, Thierry Brotin, Nicolas De Rycke. . Study of syn and anti Xenon-Cryptophanes Complexes Decorated with Aromatic Amine Groups: Chemical Platforms for Accessing New Cryptophanes J. Org. Chem. 2022, 87 (5), 2912-2920.

The main purpose of the PHOENIX project is to develop a sensitive, specific and non-invasive method to assess and monitor extracellular pH in living organisms. We shall conceive, produce and use new smart pH-sensors based on hyperpolarized 129Xe NMR/MRI detection. This project combines fundamental researches (synthesis of biosensors and relativistic quantum chemistry calculation for prediction of the caged xenon chemical shift for instance) and cutting-edge applications in the biomedical field. Three complementary teams will be involved in this three years project in order to achieve the various tasks described in PHOENIX. This consortium is composed of organic chemists who will conceive the pH-sensors, physical-chemists who will produce the hyperpolarized 129-xenon, and who will study, together with biologists, these pH-sensors in vitro and in vivo by NMR and MRI. Density functional theory calculations that take into account relativistic effects will be a precious tool to predict the behavior of these molecules, thus allowing optimization of these 129Xe NMR-based pH sensors. The participation in the project of biologists and physicians with extensive experience in animal models and acid-base homeostasis is a major asset for the development and the success of PHOENIX.
Extracellular pH is determined by the net flux of acid and base into and out of the extracellular fluid; it provides crucial clues on the metabolism of living organisms. On the other hand, the control of pH is critical for the maintenance and regulation of organ and cell function, as is evident from the severe consequences of inborn or acquired forms of acidosis. Noteworthy, recent data support the participation of local acidosis in cancer progression via stimulation of autophagy and immunosuppression. A means to measure, non-invasively, tissular pH changes would be therefore extremely valuable for assessing the aggressiveness of tumors at an early stage of their development and to monitor the effect of treatments.
Magnetic Resonance Imaging is a powerful diagnostic tool commonly used by clinicians as it can map deep tissues with a spatial resolution of few mm. Different approaches for in vivo NMR-based pH measurement have been developed, based on either endogenous or exogenous species but the crucial point is to overpass the sensitivity limitations of this modality. Thus, non-toxic tracers that can map and monitor extracellular pH in vivo are still highly needed.
Here we present an innovative approach, which is simple, easy to implement, sensitive and devoid of most of the biases that can be encountered in vivo. The principle is to perform a differential measurement by using a pair of pH-sensitive hyperpolarized 129Xe NMR-based sensors. Xenon is an element of high interest for MRI applications as it can be used as an exogenous tracer readily delivered and released from the body and it shows a low toxicity. The method will be rendered very pH-sensitive by the choice of two xenon hosts in which the frequencies of the noble gas signals vary in opposite manner with the free H+ concentration. The validation of this concept has already been demonstrated in vitro and recently published.
PHOENIX is thus an original, innovative and ambitious project, with a potentially large impact. This project presents several assets. Maybe the most important one, that makes a large difference with the other NMR/MRI techniques using hyperpolarized species, lies in its implementation if our pH-sensors fulfill all the biological conditions: low quantities of them will be injected in a first step only once. Then xenon will be introduced at will, possibly several times. Thus, with PHOENIX we will no more be limited to a one-shot experiment and longitudinal follow-up of in vivo pH will be possible. This also represents an asset for extension of this application towards human experimentation.

Project coordinator

Monsieur Pascal HOUILLIER (CENTRE DE RECHERCHE DES CORDELIERS)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CRC CENTRE DE RECHERCHE DES CORDELIERS
NIMBE Nanosciences et innovation pour les matériaux, la biomédecine et l'énergie
LCH LABORATOIRE Pinton

Help of the ANR 486,953 euros
Beginning and duration of the scientific project: December 2019 - 36 Months

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