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Science Highlight: October 6, 2017

NIH-funded researchers develop metal-free MRI contrast agent

Nanotechnology spurs innovative system for effective and safe contrast delivery

A team led by National Institutes of Health-funded researchers at the Massachusetts Institute of Technology (MIT) and the University of Nebraska has developed a method to enhance a magnetic resonance imaging (MRI) contrast agent with safe-to-use, metal-free compounds. The researchers used organic molecules carried by synthetic nanoparticles. The nanoparticles illuminated tumor tissue in mice just as well as metal-based contrast agents.

figure representing insertion of organic radical nitroxide into brush arm star polymer

Metal-free magnetic resonance imaging (MRI) agents could overcome the toxicity associated with metal-based agents in some patient populations and enable new modes of functional MRI. The unique nanoparticle architecture of a metal-free contrast agent produces enhanced MRI contrast while remaining stable in the blood of mice and not causing toxicity. Left in the image is the chemical structure of nitroxide, an organic radical compound carried by the brush-arm star polymer, middle, to produce contrast in mouse tumor, right. Source: Johnson lab, MIT.

“The ability to diagnose and monitor many diseases using MRI can be greatly enhanced with the use of contrast agents,” said Shumin Wang, Ph.D., program director of the National Institute of Biomedical Imaging and Bioengineering program in Magnetic Resonance Imaging. “The new metal-free contrast agents on the horizon are an exciting prospect that may be helpful for people who cannot tolerate metal-based MRI contrast agents, which are currently the only clinically available option for patients.”

As with x-ray imaging, MRI is a non-invasive way to scan internal anatomy. While x-rays make bone visible, MRI scans mainly depict the soft tissues of the body. The MRI machine creates a magnetic field, pulling and then releasing spinning protons in the water molecules in the body. This releases energy that MRI sensors can detect and translate into an image of the tissue.

MRI contrast agents change the magnetic properties of water molecules and cause spinning protons to respond differently to the magnetic field created by an MRI magnet. These differences affect how different tissues appear on the MRI scans and can make certain tissues, like tumors, more visible. Tumor tissue tends to draw in certain contrast agents so that it accumulates there temporarily making it possible for physicians to see the tumor clearly and monitor the disease progression.

All current MRI contrast agents are metal-based and have been used by radiologists for more than 30 years. Currently, gadolinium is the most commonly used metal in MRI contrast agents. Existing gadolinium agents are small molecules that, after a time, are cleared from the body relatively quickly through the kidneys. However, radiologists cannot use it with certain high-risk groups, primarily patients with kidney disease and those who have allergic reactions to it. While recent studies have shown that gadolinium from MRI procedures can be found in brain and bone tissue even years after its application, at this time the U.S. Food and Drug Administration says the agent has not been proven to be harmful based on existing studies.

In their study, published July 12, 2017 in ACS Central Science, the researchers who developed this new organic-based contrast agent contend that a non-metal alternative would most benefit patients who cannot currently tolerate the metal-based agents but its use could be broadened to all patients needing MRI contrast agents. This approach would minimize concerns about contrast agent accumulation as clinically viable, nanoparticle-based MRI contrast agents are developed.  

The researchers developed the metal-free agent through a collaboration among research labs. The team from University of Nebraska, who design and produce a variety of organic radical molecules, shared their organic compound with MIT researchers who specialize in the synthesis of complex polymer architectures. Polymers are made from various types of molecules that assemble into shapes that affect how they interact within biological systems.

Jeremiah Johnson, Ph.D., is the Firmenich Career Development Associate Professor of Chemistry at MIT and senior author of the study. His team designed a polymer shape they call the bottle brush because of its resemblance to the kitchen tool. By configuring multiple bottle-brush polymers into a spherical shape, they produced a variation on the bottle brush polymer they called a brush-arm star polymer, or BASP.

“This BASP nanostructure has useful features, including excellent scalability,” Johnson said. Johnson’s team previously published studies in which they described how BASPs can be designed with attached drug molecules and contrast agents, including the organic radical compound, nitroxide. “We had already been making our polymers with nitroxide attached,” he said, “but this is the first time we were able to attach this new nitroxide molecule that works much better as an MRI contrast agent.” The molecule was developed in the laboratory of co-author Andrzej Rajca, Ph.D., the Charles Bessey Professor of Chemistry at the University of Nebraska, Lincoln.

The BASP polymer structure plays a key role in how the organic compound enhances imaging for tumor tissue and then is eliminated from the body. Nitroxides are normally broken down by chemicals in living systems before they can help to create MRI images. Putting them on BASP polymers protected them, allowing them to circulate in the bloodstream long enough to accumulate in mouse tumors, and to generate contrast in MRI scans. The researchers found that the nitroxide BASP nanoparticles are stable enough to last for up to 20 hours in mice, where they accumulated in the mouse tumors. They also showed that the particles are not harmful to mice, even at high doses.

“There’s a need right now for good, safe MRI contrast agents,” Johnson said. “We think the best could be an entirely organic one that has no metal and therefore no potential metal-induced toxicity.” While there are many types of cancer and tumor types, their research has not yet focused on how to target specific tumors. “We’re working right now on the fundamentals, asking how we get enough contrast from these agents but in the future plan to test ways to target specific tumor types.”

The study was funded in part by NIBIB (EB018529, EB019950) and the National Institute of Neurological Disorders and Stroke (NS090451).

Editor’s note: Study co-author Mike Boska, Ph.D., professor in the UNMC Department of Radiology, director of the bioimaging core, and vice chairman of radiology research provided clinical perspective and animal dosing expertise for the study. Sadly, he died in May. His research focused on the development and application of magnetic resonance imaging and spectroscopy methods. The co-authors dedicated the work described in their article to his memory.

Nitroxide-Based Macromolecular Contrast Agents with Unprecedented Transverse Relaxivity and Stability for Magnetic Resonance Imaging of Tumors. Nguyen HV, Chen Q, Paletta JT, Harvey P, Jiang Y, Zhang H, Boska MD, Ottaviani MF, Jasanoff A, Rajca A, Johnson JA. ACS Cent Sci. 2017 Jul 26.

 

 

 

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