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Preclinical Investigations Toward Gd-free Molecularly Targeted Dual-Modal, MRI Dynamic (DCE-MRI)/Optical Imaging

CuhaWijay Sathiyajith1, Mikael Jensen2, Alexandre Bénéchet3

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PubMed
Summary

This study developed a novel manganese (Mn)-based contrast agent (MnL1) for MRI, offering a gadolinium-free alternative. MnL1 demonstrated effective cardiac imaging and anticancer properties, paving the way for improved diagnostics and therapeutics.

Keywords:
DCE-MRIMn complexfluorescence imagingmultitargetedpyridinesmall molecule

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Area of Science:

  • Biomedical Imaging
  • Materials Science
  • Oncology

Background:

  • Cardiac tumors are aggressive, often diagnosed late due to early asymptomatic stages, leading to metastasis.
  • Current MRI contrast agents use gadolinium (Gd), posing risks like hypersensitivity and deposition disease.
  • Surgical intervention for cardiac tumors is challenging due to their proximity to vital structures.

Purpose of the Study:

  • To develop a scalable, gadolinium-free, multimodal contrast agent (L1) with manganese (Mn).
  • The agent aims for high relaxivity MRI, sensitive PET/optical imaging, and multikinase anticancer activity.
  • To achieve strong affinity for human serum albumin for enhanced diagnostic capabilities.

Main Methods:

  • Synthesized and characterized Mn complex of EDTA bisamide with pyridine-based fluorophore (MnL1).
  • Evaluated solubility and stability; performed T1 mapping and dynamic contrast-enhanced MRI (DCE-MRI) in mice, using gadobutrol as control.
  • Assessed optical properties and conducted molecular docking and dynamics simulations for kinase inhibition.

Main Results:

  • MnL1 showed high yield and purity, with strong chelation of Mn(II).
  • MRI performance of MnL1 was comparable to gadobutrol; DCE-MRI indicated significant uptake in kidneys, liver, and heart.
  • Docking studies revealed MnL1 inhibits FAP and EGFR kinases, validated by simulations.

Conclusions:

  • Preclinical MRI confirmed the efficacy of Mn(II)L1 as a Gd-free contrast agent.
  • L1 functions as a visible and NIR1 dye, binds to and inhibits FAP and EGFR kinases.
  • Future applications include quantitative DCE-MRI, PET/MRI, and therapy response monitoring via T1 mapping.