Ultrasensitive 129Xe Magnetic Resonance Imaging: From Clinical Monitoring to Molecular Sensing

Abstract

Magnetic resonance imaging (MRI) is a cornerstone technology in clinical diagnostics and in vivo research, offering unparalleled visualization capabilities. Despite significant advancements in the past century, traditional ¹H MRI still faces sensitivity limitations that hinder its further development. To overcome this challenge, hyperpolarization methods have been introduced, disrupting the thermal equilibrium of nuclear spins and leading to an increased proportion of hyperpolarized spins, thereby enhancing sensitivity by hundreds to tens of thousands of times. Among these methods, hyperpolarized (HP) ¹²⁹Xe MRI, also known as ultrasensitive ¹²⁹Xe MRI, stands out for achieving the highest polarization enhancement and has recently received clinical approval. It effectively tackles the challenge of weak MRI signals from low proton density in the lungs. HP ¹²⁹Xe MRI is valuable for assessing structural and functional changes in lung physiology during pulmonary disease progression, tracking cells, and detecting target molecules at pico-molar concentrations. This review summarizes recent developments in HP ¹²⁹Xe MRI, including its physical principles, manufacturing methods, in vivo characteristics, and diverse applications in biomedical, chemical, and material sciences. In addition, it carefully discusses potential technical improvements and future prospects for enhancing its utility in these fields, further establishing HP ¹²⁹Xe MRI's importance in advancing medical imaging and research.

Keywords: biosensors; hyperpolarization; magnetic resonance imaging; nanomaterials; the lungs.

Figure 1

Hyperpolarized (HP) ¹²⁹Xe is introduced to visualize the lungs and monitor target molecules in MRI. a) The process of generating HP ¹²⁹Xe involves the transfer of angular momentum from photons to ¹²⁹Xe atoms via an alkali metal intermediary, leading to an enhancement of the HP ¹²⁹Xe magnetic resonance signal by over 10 000 times compared to that at thermal equilibrium. b) The produced HP ¹²⁹Xe gas is inhaled, generating distinct magnetic resonance signals in pulmonary alveoli (0 ppm), lung tissues and plasma (197 ppm) and red blood cells (217 ppm), respectively. c) Using the diverse signals, ultrasensitive ¹²⁹Xe MRI enables the quantitative assessment of gas–gas and gas–blood exchanges, as well as the visualization of lung structure and function. d) Typical procedures for identifying target molecules within living cells by introducing ¹²⁹Xe‐based biosensors.

Figure 2

Quantification of lung microstructure and function by using noninvasive HP ¹²⁹Xe MRI. a) The acinar lung airway model that describes the pulmonary microstructure parameters, and b) the diagram of the gas–blood exchange region of the alveoli. Reproduced with permission.^{[ 26 ]} Copyright 2021, The American Association for the Advancement of Science.

Figure 3

Diffusion sensitive pulse gradient waveform introduced in simulations.

Figure 4

Images of human chest. a) The ¹H MRI reveals a “black hole” in the lungs due to the lack of signal sources from protons. The HP ¹²⁹Xe magnetic resonance spectrum and images show that ¹²⁹Xe in the lung airspace registers a signal at 0 ppm, while dissolved ¹²⁹Xe in TP and RBC shows signals around 197 and 217 ppm, respectively. b) A comparison of ventilation images between a healthy volunteer and a discharged COVID‐19 patient. Reproduced with permission.^{[ 44 ]} Copyright 2024, Wiley. c) ¹²⁹Xe MRI provides functional information of the lungs to guide radiotherapy planning. Reproduced with permission.^{[ 45 ]} Copyright 2022, Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.

Figure 5

Endowing targeting ability to inert ¹²⁹Xe. a) In a typical ¹²⁹Xe probe, the host‐cage identifies targets by the guidance of the modified targeting molecule, and then captures ¹²⁹Xe atoms to produce a specific MR signal. b) The exchange process between ¹²⁹Xe atoms and host‐cages.

Figure 6

Different types of host cages for xenon atoms. There are three main categories, one for molecular‐hosts, another for nano‐hosts, and a combination of the two, which embeds the molecular hosts in a nanocarrier. Reproduced with permission.^{[ 116 ]} Copyright 2006, American Chemical Society. Reproduced with permission.^{[ 117 ]} Copyright 2015, Royal Society of Chemistry. Reproduced with permission.^{[ 118 ]} Copyright 2008, Wiley. Reproduced with permission.^{[ 119 ]} Copyright 2020, Springer Nature. Reproduced with permission.^{[ 120 ]} Copyright 2020, American Chemical Society. Reproduced with permission.^{[ 121 ]} Copyright 2013, American Chemical Society. Reproduced with permission.^{[ 122 ]} Copyright 2014, Springer Nature. Reproduced with permission.^{[ 123 ]} Copyright 2020, PNAS. Reproduced with permission.^{[ 124 ]} Copyright 2024, American Chemical Society. Reproduced with permission.^{[ 125 ]} Copyright 2020, Wiley‐VCH, Weinheim.

Figure 7

Hyperpolarized ¹²⁹Xe chemical exchange saturation transfer (Hyper‐CSET): Amplifying the target ¹²⁹Xe within “host‐cages” by indirectly detecting the reduction in signal of free HP ¹²⁹Xe. a) An RF pulse is applied to target the HP ¹²⁹Xe in host‐cages, resulting in depolarization of these ¹²⁹Xe atoms and saturation of the corresponding MR signal. b) Subsequently, the ¹²⁹Xe atoms within the host‐cages exchange with the free HP ¹²⁹Xe atoms, c) leading to a reduction in MR signal of the free HP ¹²⁹Xe due to the accompanying saturation transfe. d) A Hyper‐CSET spectrum is obtained by comparing the reduction in MR signal from free HP ¹²⁹Xe atoms before and after the application of a saturation pulse, which reflects the specific MR signal generated by HP ¹²⁹Xe within host‐cages.

Figure 8

Functionalization and applications of ¹²⁹Xe hosts. a) CrypA was functionalized with a solubilizing group (purple) and a targeting group (yellow) via a rink amide resin linker. Adapted with permission.^{[ 149 ]} Copyright 2001, PNAS. b) A “turn‐on” strategy for target analysis using a CB[6]‐based probe. Initially, the cavity of the CB[6] host was occupied by rotaxane molecules. Upon encountering the target molecule H₂O₂, the rotaxane was cleaved, freeing the host cavity for HP ¹²⁹Xe exchange. As a result, the specific ¹²⁹Xe MR signal for CB[6] was recovered with the introduction of the target molecules. Reproduced with permission.^{[ 158 ]} Copyright 2019, Wiley. c) The ultrasensitive property of HP ¹²⁹Xe allows for the differentiation of diastereoisomers of Fe‐MOP. Reproduced with permission.^{[ 137 ]} Copyright 2022, Springer Nature. d) PFOB nano‐emulsions were functionalized with RGD peptides to target tumor cells, and resulting systems were imaged using ultrasensitive ¹²⁹Xe MRI. Reproduced with permission.^{[ 159 ]} Copyright 2019, American Chemical Society. e) GVs displayed a characteristic signal peak only when their structure remains intact; this peak vanished when the structure collapses. Reproduced with permission.^{[ 122 ]} Copyright 2014, Springer Nature. f) Establishment of a 3D map to illustrate the relationships among the ¹²⁹Xe CEST MRI contrast, MOL concentration, and saturation pulse, with its application in quantifying MOL‐hosts and the content of drug molecules within living cells. Reproduced with permission.^{[ 124 ]} Copyright 2024, American Chemical Society.