Transition metals have been employed in medical applications throughout history. Metallic compounds have been developed as targeted therapeutics, from iron to treat anemia to cisplatin as an effective chemotherapeutic. Additionally, diagnostic imaging, such as radioisotope imaging or contrast agents in magnetic resonance imaging (MRI), exploits characteristics uniquely featured by organometallic agents.
An important application of MRI is to provide real-time visual feedback during therapeutic thermal ablation therapy of malignant tissues. This real-time data is crucial for ensuring that all cancerous tissue is destroyed and minimal healthy tissue is damaged during procedures. MRI scans are acquired by placing a patient in a strong magnetic field and applying pulses of radiofrequency energy to excite the hydrogen nuclei in the water molecules that are ubiquitous throughout the body. The nuclei then relax to the ground state emitting radiofrequency signals that are measured and converted computationally into an image. These images are largely based on signal intensity associated with relative amounts of water in different tissues, much like an NMR spectrometer. Coordination complexes containing a paramagnetic metal center (“contrast agents”), which undergo rapid ligand exchange with neighboring water molecules and subsequently alter the timescale with which excited protons emit radiation, have been developed to aid in revealing structural differences within the body.
The crux of our work is to develop dynamic activatable, or ‘intelligent’, MRI contrast agents based on Fe(II) complexes that undergo thermally induced spin-state crossover. These novel contrast agents will allow for the monitoring of tissue environments with spatial and temporal data feedback, and the complexes will enhance signal resolution at therapeutically relevant temperatures. The Fe(II) crossover complexes can exist in an ‘on’ or ‘off’ state depending on the local temperature of their physiological environment, providing an added layer of detail in real-time MRI scans. There are few known recent examples of such complexes for this application, and their results are not yet being used clinically. Designing coordination complexes as contrast agents that provide signal only when the medical professional has reached the desired MR thermometry treatment temperature would allow them to monitor both temperature and tissue composition. The PARACEST effect would likely be observed, in addition to switching from MRI silent diamagnetic compounds to MRI active paramagnetic compounds at various temperatures based on design and ligand tuning. Furthermore, it is likely that these iron complexes would be far less toxic in patients than the lanthanide-based contrast agents, given the natural abundance of iron in the body.