A New Spin on MRI Contrast
By Beth W. Orenstein
Radiology Today
Vol. 19 No. 11 P. 22

Innovative research looks beyond gadolinium.

Initially, the promise of MRI was to provide a way to make definitive diagnoses noninvasively. Along the way, contrast agents have been used in a growing number of MRI studies to improve the visibility of body structures. Contrast agents alter the local signal in scans by interacting magnetically with nuclear spins—typically of protons on water molecules.

The most common contrast agents used in MRI are gadolinium based; since their introduction in the late 1980s, more than 400 million doses have been administered to patients. In 2013, scientists in Japan spurred safety concerns when they discovered that small amounts of gadolinium accumulate in patients' brains when they undergo repeated enhanced exams. Follow-up studies found similar deposits in bones and other organs. While the deposits haven't definitively been proven to be harmful, the debate rages on and researchers have been busy looking for safe new MRI contrast agents. For a look at some MRI contrast agents that are in development and what could be coming to clinics in the next five to 10 years, Radiology Today speaks with some of the researchers who work at the cutting edge of the field.

Iron Nanoshells
Nanoscientists at Rice University in Houston have been able to load iron chelates inside nanoparticles to create MRI contrast agents that have been shown to outperform gadolinium chelates. The chelating process covers each ion with an organic wrap, reducing exposure and allowing the drug to pass through the body via urination within a few hours. Two weighting techniques are used in MRI: T1, which increases signal, and T2, which reduces signal.

Naomi Halas, PhD, a professor of electrical and computer engineering, chemistry, bioengineering, physics and astronomy, materials science, and nanoengineering, was lead researcher on the project. She says radiologists might be surprised to learn of her group's success with iron, as the metal is known to work for T2 scans but to be impractical for T1 scans. However, her team has found that iron chelates behave differently when engineered on the nanoscale.

"With simple chelates, whether gadolinium or iron, you have only one atom, so the interactions are all short range," Halas says. "But in the nanoparticle, you can have 100,000 or 1 million atoms in a single particle. That allows for long-range interactions that are very significant."

Two decades ago, Halas invented nanoshells, layered nanoparticles that are about 20 times smaller than a red blood cell. She found a way of loading conductive metal and nonconductive silica into nanoshells and concentric layered nanoparticles called nanomatryoshkas, named after the Russian nesting dolls. By varying the thickness of the different layers, Halas' team discovered it could use the nanoparticles to interact with specific wavelengths of light.

In 2016, when Luke Henderson, a graduate chemistry student at Rice, joined Halas' Laboratory for Nanophotonics, they showed that they could add fluorescent dyes to nanomatryoshkas to make them visible in a diagnostic scan. In a 2017 paper published in the Proceedings of the National Academy of Sciences of the United States of America, they showed that gadolinium chelates could be embedded in a silica layer for MRI contrast.

In their earlier work with gadolinium, the researchers noticed that the nanomatryoshka design enhanced the relaxivities of the embedded gadolinium chelates. "Because we were hearing more calls from the medical community for alternatives to gadolinium, we decided to try iron chelates to see if we could have the same enhancement," Henderson says. He says they were surprised when they could not only boost the relaxivities for iron but also observe that the optimal loading of iron into each concentric nanoparticle was four times greater than gadolinium. "That allowed the iron-laden nanomatryoshkas to perform twice as well as clinically available gadolinium chelates," he says.

"It was a pretty easy transition going from gadolinium to iron," Henderson adds. "We were really happy with the results we saw." The researchers are still investigating modifications they can make to their system to improve relaxivities.

Meanwhile, they are collaborating with researchers at MD Anderson Cancer Center in Texas who are using the gold nanoshells Halas invented to treat malignant tumors. The nanoshells are injected into a patient's bloodstream. Because a tumor's blood vessels leak, the nanoparticles accumulate in the tumor and frame it. When the particles are exposed to near-infrared lasers, heat is generated, and this bursts the walls of the cancer cells. Eventually, the nanoshells are eliminated safely from the body.

"Because nanoparticles already have been clinically approved, we anticipate the iron chelates are something that could readily fit into clinical trials as we move forward," Halas says. "We see it not only being used for diagnostics in MRI but also for monitoring patients and engaging in some sort of treatment."

Erasable Contrast
MRI researchers have had success with magnetic nanoparticles that can be directed specifically to sites of interest such as tumors. However, when reading the scans, it's not always clear whether a dark patch near a tumor represents a contrast agent that has bound to a tumor or an unrelated signal from surrounding tissue. Mikhail Shapiro, PhD, an assistant professor of chemical engineering at the California Institute of Technology, has a promising solution: MRI contrast agents that can be erased with ultrasound, so they can be turned off. George Lu, PhD, a postdoctoral scholar in Shapiro's lab, is the lead author of a study in the May issue of Nature Materials on their erasable MRI scans.

"With this method, like lights on a bike or astronomical images followed over time in the sky, the contrast agents blink off, resulting in a before-and-after signal that makes them easier to see," Shapiro says.

Like Halas' team, Shapiro's team uses nanoscale structures, but Shapiro's are gas vesicles, which some microbes naturally produce. Gas vesicles have a protein shell with a hollow interior. Microbes use them as flotation devices to regulate access to light and nutrients. The hollow chambers of the vesicles reflect sound waves in distinctive ways. They also stand out on MRI scans because the air in their chambers reacts differently to magnetic fields than the watery tissues around them. As a result, when gas vesicles are present, they appear dark on MRI images.

Using mice, the researchers showed that gas vesicles could be detected with MRI in certain tissues and organs such as the brain and the liver. They also showed that gas vesicles could be turned off when hit with ultrasound waves that had enough pressure.

"If you take an MRI image and see a set of dark spots, you can apply a form of energy that will erase anything coming from the contrast agent," Shapiro says. "The dark spots due to contrast agents will disappear, and you will know whether the dark spots you saw were from the contrast agent or from something else." The key here, Shapiro adds, is that "you don't look at one image but rather at something that is changing, and that change gives you more information." It's a concept that is well established in the scientific community, Shapiro says. "What we're doing is taking that concept and applying it to MR."

Previous research showed that these protein structures can be genetically modified to target receptors on specific cells such as tumor cells. Gas vesicles could be engineered so that one group might target a tumor and another group stay in the bloodstream to outline blood vessels, Shapiro says. That way, doctors could visualize two types of tissue at the same time.

"We've done this previously in ultrasound imaging," Shapiro adds. "Now we have a whole new application in MRI."

Erasing adds little time to the acquisition of the images, he says. "Maybe a few seconds. It adds some time because you have to take before-and-after images, but erasing itself is not particularly long."

The method is compatible with any MR scanner, he says. "You would need to put an MR together with a special ultrasound transducer that is MRI compatible, but those have existed for quite a while."

While the researchers have shown that their method works in mice, Shapiro says, "We still have a few years of work before we would consider doing something in humans."

Low Dose to No Dose
Dennis Durmis, senior vice president, head of Americas Region, Bayer Radiology, says, "[T]he trend in the industry is looking at more organ-specific contrast agents."

Gadolinium-based contrast agents are divided into two categories based on their molecular structure: linear and macrocyclic. Linear agents coil around the gadolinium like a snake around an egg. Macrocyclic agents form a clamshell-like wrap around the gadolinium. Macrocyclic agents are more stable and have a tighter casing. Durmis says the industry is focusing more on macrocyclic agents because of their stability.

"You want to make sure you have a more stable product because it means a high-quality image," he says. "And you want to do it at the lowest possible dose."

Rather than "safe" contrast, what about no contrast? Researchers at Purdue University in Lafayette, Indiana, are looking at a way to detect vascular disorders and brain injuries using MR without contrast agents. Yunjie Tong, PhD, an assistant professor in Purdue's Weldon School of Biomedical Engineering, is developing the technology along with Blaise Frederick, PhD, a biophysicist and associate professor at Harvard Medical School.

In healthy subjects, Tong says, blood flow should be symmetric in arteries and veins in both hemispheres of the brain and in the neck. Functional MRI can be used to show intrinsic signals, for example, from the internal carotid artery and the internal jugular vein. Traditionally, contrast agents have been injected into patients to calculate the cerebral circulation time.

"The gold standard is with gadolinium," Tong says. "To understand how blood flows and get an accurate measurement, you inject gadolinium and watch with functional MRI how it goes through the brain."

However, Tong has found that a spontaneous natural oscillation produces something similar to contrast. "We try to use this intrinsic oscillation as a natural bolus," he says. "You can use it to map how blood flows through brain and get similar parameters as bolus MRI can give you." It can show a delay in the cerebral circulation time. A delay would indicate a blood flow disturbance in the brain that could be caused by a tumor, traumatic brain injury, or other brain disorder or disease, he says.

Tong says his new method could even be applied on some existing MRI data to calculate cerebral circulation time. It could prove to be beneficial to football players who suffer head injuries or in quickly assessing the severity of a patient's stroke, he says. As an engineer, Tong believes his method is ready for prime time, but "physicians may have a different take," he says with a laugh.

— Beth W. Orenstein, of Northampton, Pennsylvania, is a freelance medical writer and regular contributor to Radiology Today.