¹²⁹Xe NMR-based sensors: biological applications and recent methods

Abstract

aXenon is a first-rate sensor of biological events, due to its large polarizable electron cloud inducing significant modification of NMR parameters through slight changes in its local environment. The use of xenon as a sensor is of increasing interest for sensitive magnetic resonance imaging, since its signal can be enhanced by several orders of magnitude, mainly by spinexchange optical pumping. Furthermore xenon can be vectorized toward targets of interest by using functionalized host systems, enabling their detection at subnanomolar concentrations. Associated with a new generation of detection methods this gives rise to a powerful molecular imaging approach, where xenon can be delivered on purpose several times after introduction of the functionalized host system. IntroductionFrom simple photograph of the inside of the human body providing information on bone structure or form and abnormalities of various organs, molecular imaging now offers a dynamic view of biological processes occurring locally, witnessing for instance the presence of infectious cells or metabolic deregulations. The development of powerful imaging techniques is the key to early diagnosis of disease, best follow-up treatments and also biomedical research tools. These techniques developed particularly in the 21th century form part of the molecular imaging concept. Magnetic resonance imaging (MRI) is a good compromise to achieve molecular imaging in vivo in real time without any perturbative radiation. The major advantages of MRI are its potential high spatial resolution (25-100 µm), its low invasiveness, its harmlessness and the excellent tissue contrast it can provide. In this context, MRI complements and sometimes overruns other molecular imaging approaches by enabling monitoring of events at the cellular or even subcellular level. However, classical implementation of this technique suffers from low sensitivity due to the very low population differences between nuclear spin energy levels at Boltzmann equilibrium. Hyperpolarization techniques 1 that transiently increase the nuclear spin polarization of a very dilute agent by several orders of magnitude circumvent the MRI sensitivity problem. Among the species that can be spinhyperpolarized, xenon is of high interest, due to its exogenous nature (leading to the absence of background signal) and the fact that it can act as a spy of biological events without interfering with them. Moreover, it can be endlessly reloaded and simply removed from the sample since it is a gas at ambient temperature and pressure. Finally, owing to the high deformability of its large electron cloud xenon is deeply sensitive to its local environment and constitutes a perfect probe for various biological interactions. Soluble in most biological fluids, xenon can cross the plasma membrane in a few tens of milliseconds without losing its hyperpolarization. 2The initial applications of hyperpolarized xenon in biology were the anatomical imaging of the lung 3 and the investigation of hydrophobic binding pockets in proteins ...

High Exchange Rate Complexes of 129Xe with Water‐Soluble Pillar[5]arenes for Adjustable Magnetization Transfer MRI

“…Critically, the signal amplification through chemical exchange saturation transfer with hyperpolarised nuclei (Hyper‐CEST) requires the noble gas to be reversibly bound to a host structure that confers a specific chemical shift to the bound noble gas. Different molecular hosts have been used in this context, cryptophane‐A (CrA) being the most prominent one . The major limitations of this host are its hydrophobicity and a required elaborate synthesis for further functionalization of the cyclotriveratrylene (CTV) caps, to allow for binding of the complex to a specific target or for improving solubility.…”

“…Different molecular hosts have been used in this context, cryptophane-A (CrA) being the most prominent one. [5][6][7][8] The major limitations of this host are its hydrophobicity and a required elaborate synthesis for further functionalization of the cyclotriveratrylene (CTV) caps [9,10] to allow for binding of the complex to a specific target or for improving solubility. Cucurbit [6]-uril (CB6), a commercially available macrocyclic host, was recently proposed as an alternative.…”

Functionalized Lipopeptide Micelles as Highly Efficient NMR Depolarization Seed Points for Targeted Cell Labelling in Xenon MRI

“…This is more stable than binding of Xe between aliphatic chains as found in phospholipid membranes and thus efficiently confers a distinct chemical shift to transiently bound spins. Second, CrA is available with various handles for conjugation to other units 34…”

“…Second, CrA is available with various handles for conjugation to other units. [34] Essential aspects of this study include the investigation whether a) the CrA-lipopeptide compound assembles into micelles, b) such nanocarriers retain their preferential interaction and uptake into BBB cells, and c) Xe has sufficient and immediate access to the hosts for reversible binding and experiences a transient change in chemical shift. The latter aspect is crucial to enable Hyper-CEST signal amplification in which CrA binds xenon atoms for a few milliseconds.…”

Chiroptical study of cryptophanes subjected to self‐encapsulation

“…1,2 For instance, these molecular scaffolds are excellent candidates for biosensing applications in combination with hyperpolarized xenon. [3][4][5][6][7][8] Interestingly, the overwhelming majority of the cryptophane derivatives shows an inherently chiral structure, and this property has been exploited to extract valuable information about these derivatives and their [This article is part of the Special issue title: Journées André Collet de la Chiralité (JACC 2018).] complexes in solution.…”