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An Activatable T1-Weighted MR Contrast Agent: A Noninvasive Tool for Tracking the Vicinal Thiol Motif of Thioredoxin in Live Cells.

ABSTRACT: We have synthesized new magnetic resonance imaging (MRI) T1 contrast agents (CA1 and CA2) that permit the activatable recognition of the cellular vicinal thiol motifs of the protein thioredoxin. The contrast agents showed MR relaxivities typical of gadolinium complexes with a single water molecule coordinated to a Gd3+ center (i.e., ~4.54 mM-1s-1) for both CA1 and CA2 at 60 MHz. The contrast agent CA1 showed a ~140% relaxivity enhancement in the presence of thioredoxin, a finding attributed to a reduction in the flexibility of the molecule after binding to thioredoxin. Support for this rationale, as opposed to one based on preferential binding, came from 1H-15N-HSQC NMR spectral studies; these revealed that the binding affinities toward thioredoxin were almost the same for both CA1 and CA2. In the case of CA1, T1-weighted phantom images of cancer cells (MCF-7, A549) could be generated based on the expression of thioredoxin. We further confirmed thioredoxin expression-dependent changes in the T1-weighted contrast via knockdown of the expression of the thioredoxin using siRNA-transfected MCF-7 cells. The nontoxic nature of CA1, coupled with its relaxivity features, leads us to suggest that it constitutes a first-in-class MRI T1 contrast agent that allows for the facile and noninvasive monitoring of vicinal thiol protein motif expression in live cells.

SUBMITTER: Kang J

PROVIDER: S-EPMC8037249 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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An Activatable T1-Weighted MR Contrast Agent: A Noninvasive Tool for Tracking the Vicinal Thiol Motif of Thioredoxin in Live Cells.

Kang Jongeun J Hwang Eunha E Lee Hyunseung H Cho Mi Young MY Karan Sanu S Kim Hak Nam HN Kim Jong Seung JS Sessler Jonathan L JL Bhuniya Sankarprasad S Hong Kwan Soo KS

Molecules (Basel, Switzerland) 20210401 7

We have synthesized new magnetic resonance imaging (MRI) T1 contrast agents (CA1 and CA2) that permit the activatable recognition of the cellular vicinal thiol motifs of the protein thioredoxin. The contrast agents showed MR relaxivities typical of gadolinium complexes with a single water molecule coordinated to a Gd3+ center (i.e., ~4.54 mM-1s-1) for both CA1 and CA2 at 60 MHz. The contrast agent CA1 showed a ~140% relaxivity enhancement in the presen ...[more]

PMID: 33916181

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Project description:IntroductionTo compare the diagnostic accuracy of contrast-enhanced 3D(dimensional) T1-weighted sampling perfection with application-optimized contrasts by using different flip angle evolutions (T1-SPACE), 2D fluid attenuated inversion recovery (FLAIR) images and 2D contrast-enhanced T1-weighted image in detection of leptomeningeal metastasis except for invasive procedures such as a CSF tapping.Materials and methodsThree groups of patients were included retrospectively for 9 months (from 2013-04-01 to 2013-12-31). Group 1 patients with positive malignant cells in CSF cytology (n = 22); group 2, stroke patients with steno-occlusion in ICA or MCA (n = 16); and group 3, patients with negative results on MRI, whose symptom were dizziness or headache (n = 25). A total of 63 sets of MR images are separately collected and randomly arranged: (1) CE 3D T1-SPACE; (2) 2D FLAIR; and (3) CE T1-GRE using a 3-Tesla MR system. A faculty neuroradiologist with 8-year-experience and another 2nd grade trainee in radiology reviewed each MR image- blinded by the results of CSF cytology and coded their observations as positives or negatives of leptomeningeal metastasis. The CSF cytology result was considered as a gold standard. Sensitivity and specificity of each MR images were calculated. Diagnostic accuracy was compared using a McNemar's test. A Cohen's kappa analysis was performed to assess inter-observer agreements.ResultsDiagnostic accuracy was not different between 3D T1-SPACE and CSF cytology by both raters. However, the accuracy test of 2D FLAIR and 2D contrast-enhanced T1-weighted GRE was inconsistent by the two raters. The Kappa statistic results were 0.657 (3D T1-SPACE), 0.420 (2D FLAIR), and 0.160 (2D contrast-enhanced T1-weighted GRE). The 3D T1-SPACE images showed the highest inter-observer agreements between the raters.ConclusionsCompared to 2D FLAIR and 2D contrast-enhanced T1-weighted GRE, contrast-enhanced 3D T1 SPACE showed a better detection rate of leptomeningeal metastasis.

Dataset Information

An Activatable T1-Weighted MR Contrast Agent: A Noninvasive Tool for Tracking the Vicinal Thiol Motif of Thioredoxin in Live Cells.

Publications

An Activatable T<sub>1</sub>-Weighted MR Contrast Agent: A Noninvasive Tool for Tracking the Vicinal Thiol Motif of Thioredoxin in Live Cells.

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