Cluster-Based Redox-Responsive Super-Atomic MRI Contrast Agents

Physical Chemistry Chemistry Medicinal Chemistry Medical Imaging Bioengineering Life Sciences Medicine
redox-responsive super-atomic clusters MRI contrast agents tumor microenvironment molecular imaging

Academic Background

Magnetic Resonance Imaging (MRI) is a crucial tool in modern medical diagnostics, and its effectiveness relies heavily on the use of contrast agents (CAs). Traditional MRI contrast agents are mainly based on gadolinium (Gd) complexes. Although these agents are widely used in clinical practice, their long-term safety is controversial, especially for patients with impaired renal function, as they may induce nephrogenic systemic fibrosis (NSF). Thus, developing new MRI contrast agents based on transition metals has become a research hotspot. Transition metals (such as iron and manganese) are not only earth-abundant, but also possess multiple oxidation states, which enables them to respond to redox changes in biological environments, offering the possibility to design “smart” contrast agents.

Additionally, redox imbalance within the tumor microenvironment is a key driver of cancer progression and the development of drug resistance. Therefore, developing MRI contrast agents that can monitor tissue redox status in real-time will not only enhance diagnostic sensitivity and accuracy, but will also provide important information for personalized medicine. The aim of this research is to design a super-atomic cluster MRI contrast agent based on iron and manganese, enabling non-invasive imaging of the tumor microenvironment via redox-responsive mechanisms.

Source of the Paper

This paper was completed by Alexandros A. Kitos, Raúl Castañeda, Zachary J. Comeau, and others, with the research team based at the Department of Chemistry and Biomolecular Sciences, University of Ottawa, Canada, as well as the Robarts Research Institute at Western University, Canada. The paper was published on March 13, 2025, in the journal Chem with the title “Cluster-Based Redox-Responsive Super-Atomic MRI Contrast Agents”.

Research Process and Results

1. Design and Synthesis

The research team designed a multinuclear metal cluster contrast agent based on the N-2-pyrimidylimidoyl-2-pyrimidylamidine (pm2imam) ligand. The pm2imam ligand can selectively bind with 3d transition metal ions (such as iron and manganese) to form highly stable mixed-metal clusters. Through spectroscopic, electrochemical, and magnetic analyses, the team synthesized a variety of homonuclear and heteronuclear metal clusters, including [MnIII MnII3(pm2imam)3Cl6]·5H2O (MnMn3), [FeIII MnII3(pm2imam)3Cl6]·8H2O (FeMn3), and others.

2. Stability and Redox Responsiveness

The team verified the stability of these metal clusters in biological media using thermogravimetric analysis (TGA), infrared spectroscopy (IR), and dynamic light scattering (DLS). Results showed that these clusters exhibit excellent stability in aqueous solution and phosphate-buffered saline (PBS), and can maintain stability for at least 8 hours at 37°C.

Additionally, through cyclic voltammetry (CV) and spectroelectrochemical experiments, the researchers demonstrated the redox-responsive properties of these clusters. FeMn3 and MnMn3 displayed different redox responses when exposed to reducing agents (such as glutathione) or oxidizing agents (such as hydrogen peroxide), indicating that these clusters can respond to redox changes in biological environments.

3. MRI Contrast Enhancement

The research team further studied the MRI contrast enhancement effects of these clusters both in vitro and in vivo. In vitro experiments revealed that FeMn3 and MnMn3 exhibited different T1 and T2 weighted contrast enhancement effects under reducing and oxidizing environments. Specifically, FeMn3 displayed stronger T1-weighted enhancement in reducing environments, whereas MnMn3 showed stronger T2-weighted enhancement in oxidizing environments.

In vivo experiments used a mouse xenograft model (H460 human lung cancer) to verify these clusters’ ability to image redox features within the tumor microenvironment. The results showed that FeMn3 could effectively map reducing regions within tumors, whereas MnMn3 could map oxidative microenvironments. By using the ratio of T1-weighted to T2-weighted images (T1w/T2w), the team achieved semi-quantitative imaging of tumor redox status.

4. Magnetic Studies

Through direct-current (DC) susceptibility measurements, the research team validated the magnetic properties of these metal clusters. The results indicate that there are strong antiferromagnetic couplings between the central and peripheral metal ions in FeMn3 and MnMn3 clusters. This coupling effect, mediated by proton relaxation via the peripheral metal ions, endows these clusters with super-atomic characteristics.

Research Conclusions

This research successfully designed and synthesized a series of iron- and manganese-based super-atomic cluster MRI contrast agents, which exhibit excellent stability and redox-responsive characteristics in biological media. Through both in vitro and in vivo experiments, the research team validated these clusters’ ability to perform redox imaging within the tumor microenvironment. In particular, FeMn3 and MnMn3 display different sensitivities to reducing and oxidizing environments, respectively, providing novel tools for non-invasive imaging of tumor redox status.

Research Highlights

  1. Novel Contrast Agent Design: This work is the first to introduce the super-atomic cluster concept to the design of MRI contrast agents, achieving redox-responsive imaging of the tumor microenvironment via multinuclear metal clusters.
  2. Excellent Stability: These metal clusters show exceptional stability in biological media, overcoming the problem of facile dissociation of traditional polynuclear clusters in aqueous solution.
  3. Redox-Responsive Mechanism: FeMn3 and MnMn3 display different sensitivities to reducing and oxidizing environments, respectively, offering a new approach for semi-quantitative imaging of tumor redox status.
  4. Clinical Application Potential: The ability of these clusters to image redox in the tumor microenvironment provides a new tool for early cancer diagnosis and personalized therapy.

Significance of the Research

This study not only offers a new conception for the design of MRI contrast agents, but also provides a novel tool for non-invasive imaging of the tumor microenvironment. Through the redox-responsive mechanism, these super-atomic clusters can monitor the redox status of the tumor microenvironment in real-time, providing crucial information for early cancer diagnosis and personalized therapy. Furthermore, the outstanding stability and redox-responsive characteristics of these clusters open up new possibilities for other biomedical imaging applications.