Dataset Information

The Development of a Smart Magnetic Resonance Imaging and Chemical Exchange Saturation Transfer Contrast Agent for the Imaging of Sulfatase Activity.

ABSTRACT: The molecular imaging of biomarkers plays an increasing role in medical diagnostics. In particular, the imaging of enzyme activity is a promising approach, as it enables the use of its inherent catalytic activity for the amplification of an imaging signal. The increased activity of a sulfatase enzyme has been observed in several types of cancers. We describe the development and in vitro evaluation of molecular imaging agents that allow for the detection of sulfatase activity using the whole-body, non-invasive MRI and CEST imaging methods. This approach relies on a responsive ligand that features a sulfate ester moiety, which upon sulfatase-catalyzed hydrolysis undergoes an elimination process that changes the functional group, coordinating with the metal ion. When Gd³⁺ is used as the metal, the complex can be used for MRI, showing a 25% decrease at 0.23T and a 42% decrease at 4.7T in magnetic relaxivity after enzymatic conversion, thus providing a "switch-off" contrast agent. Conversely, the use of Yb³⁺ as the metal leads to a "switch-on" effect in the CEST imaging of sulfatase activity. Altogether, the results presented here provide a molecular basis and a proof-of-principle for the magnetic imaging of the activity of a key cancer biomarker.

SUBMITTER: Welleman IM

PROVIDER: S-EPMC10610007 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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The Development of a Smart Magnetic Resonance Imaging and Chemical Exchange Saturation Transfer Contrast Agent for the Imaging of Sulfatase Activity.

Welleman Ilse M IM Reeβing Friederike F Boersma Hendrikus H HH Dierckx Rudi A J O RAJO Feringa Ben L BL Szymanski Wiktor W

Pharmaceuticals (Basel, Switzerland) 20231011 10

The molecular imaging of biomarkers plays an increasing role in medical diagnostics. In particular, the imaging of enzyme activity is a promising approach, as it enables the use of its inherent catalytic activity for the amplification of an imaging signal. The increased activity of a sulfatase enzyme has been observed in several types of cancers. We describe the development and in vitro evaluation of molecular imaging agents that allow for the detection of sulfatase activity using the whole-body ...[more]

PMID: 37895910

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Project description:Hepatic encephalopathy (HE) is a common complication in liver cirrhosis and associated with an invasion of ammonia into the brain through the blood-brain barrier. Resulting higher ammonia concentrations in the brain are suggested to lead to a dose-dependent gradual increase of HE severity and an associated impairment of brain function. Amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) imaging has been found to be sensitive to ammonia concentration. The aim of this work was to study APTw CEST imaging in patients with HE and to investigate the relationship between disease severity, critical flicker frequency (CFF), psychometric test scores, blood ammonia, and APTw signals in different brain regions. Whole-brain APTw CEST images were acquired in 34 participants (14 controls, 20 patients (10 minimal HE, 10 manifest HE)) on a 3 T clinical MRI system accompanied by T1 mapping and structural images. T1 normalized magnetization transfer ratio asymmetry analysis was performed around 3 ppm after B0 and B1 correction to create APTw images. All APTw images were spatially normalized into a cohort space to allow direct comparison. APTw images in 6 brain regions (cerebellum, occipital cortex, putamen, thalamus, caudate, white matter) were tested for group differences as well as the link to CFF, psychometric test scores, and blood ammonia. A decrease in APTw intensities was found in the cerebellum and the occipital cortex of manifest HE patients. In addition, APTw intensities in the cerebellum correlated positively with several psychometric scores, such as the fine motor performance scores MLS1 for hand steadiness / tremor (r = 0.466; p = .044) and WRT2 for motor reaction time (r = 0.523; p = .022). Moreover, a negative correlation between APTw intensities and blood ammonia was found for the cerebellum (r = -0.615; p = .007) and the occipital cortex (r = -0.478; p = .045). An increase of APTw intensities was observed in the putamen of patients with minimal HE and correlated negatively with the CFF (r = -0.423; p = .013). Our findings demonstrate that HE is associated with regional differential alterations in APTw signals. These variations are most likely a consequence of hyperammonemia or hepatocerebral degeneration processes, and develop in parallel with disease severity.

Dataset Information

The Development of a Smart Magnetic Resonance Imaging and Chemical Exchange Saturation Transfer Contrast Agent for the Imaging of Sulfatase Activity.

Publications

The Development of a Smart Magnetic Resonance Imaging and Chemical Exchange Saturation Transfer Contrast Agent for the Imaging of Sulfatase Activity.

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