An activatable T1-weighted MR contrast agent: A noninvasive tool for tracking the vicinal thiol motif of thioredoxin in live cells

Jongeun Kang, Eunha Hwang, Hyunseung Lee, Mi Young Cho, Sanu Karan, Hak Nam Kim, Jong Seung Kim, Jonathan L. Sessler, Sankarprasad Bhuniya, Kwan Soo Hong

Research output: Contribution to journalArticlepeer-review

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 from1H-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.

Original languageEnglish
Article number2018
JournalMolecules
Volume26
Issue number7
DOIs
Publication statusPublished - 2021 Apr 1

Bibliographical note

Funding Information:
Funding: This work was supported by the National Research Council of Science and Technology (NST) grant from the Korea government (MSIT) (KSH, CAP-18-02-KRIBB), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (KSH, 2020R1A2C2012011). Support from the Robert A. Welch Foundation (F-0018 to JLS) is also acknowledged.

Funding Information:
This work was supported by the National Research Council of Science and Technology (NST) grant from the Korea government (MSIT) (KSH, CAP-18-02-KRIBB), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (KSH, 2020R1A2C2012011). Support from the Robert A. Welch Foundation (F-0018 to JLS) is also acknowledged.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Activatable contrast
  • MR relaxivity
  • Thioredoxin
  • Vicinal thiols

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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