Magnetic resonance imaging (MRI) has become an indispensable medical diagnostic tool because of its ability to produce detailed, 3D pictures of tissue in the body. Radiologists often inject patients with contrast agents to make certain tissues, such as tumors, stand out more on the final image. Now, researchers have synthesized an MRI contrast agent that is 15 times more sensitive than the compounds currently used. This could allow less contrast agent to be used, thus reducing the potential for harmful side effects.
The researchers created the new compound by chemically linking gadolinium ions to nanodiamonds--tiny clusters of carbon atoms just a few nanometers in diameter. Gadolinium, a rare-earth metal, is used in MRI contrast agents because of its strong paramagnetic properties (magnetism in response to an applied magnetic field). But alone, gadolinium is toxic, so it has to be bonded to other, biocompatible molecules to be used clinically. Many groups have been trying to improve the properties of gadolinium-based contrast agents by attaching the metal to a variety of materials, ranging from large organic molecules to nanoparticles.
"We've done this with many classes of nanoparticles and have never seen this extraordinary increase in sensitivity," says Thomas J. Meade, professor of chemistry and director of the Center for Advanced Molecular Imaging at Northwestern University. He and his colleagues published their findings online in Nano Letters last month.
Meade collaborated with Dean Ho, assistant professor of biomedical and mechanical engineering at Northwestern, and his group, which has been studying nanodiamonds as vehicles for drug delivery. Ho says that nanodiamonds, unlike some carbon nanomaterials, are well-tolerated by cells and do not change cells' gene expression in undesirable ways. The researchers coupled the nanodiamonds to gadolinium and tested the properties of the resulting complex to assess how good of an MRI contrast agent it might be.
MRI works by surrounding a patient with a powerful magnetic field, which aligns the nuclei of hydrogen atoms in the body. Radio wave pulses systematically probe small sections of tissues, knocking those atoms out of alignment. When they relax back into their previous state, the atoms emit a radio frequency signal that can be detected and translated into an image.
Because of its strong paramagnetic properties, gadolinium alters the relaxation of hydrogen atoms when it's nearby. Contrast agents containing gadolinium can be designed to collect preferentially in tumors, thus enhancing the contrast between the tumor and the surrounding tissue. The contrast agent's ability to alter the relaxation of hydrogen atoms is expressed as "relaxivity", which accounts for the relaxation time and the concentration of gadolinium in the tissues.
The high relaxivity of the gadolinium-nanodiamond compound can be partly attributed to its ability to attract water, which helps boost the MRI signal. "If you look at the shape of a nanodiamond, it's like a soccer ball but more angular around the faces," Ho says. "It's not totally round." The different faces have alternating positive and negative charges, which helps to orient water molecules opposite to each other, creating a tight shell of water around the nanodiamond.
The researchers tested the gadolinium-nanodiamond on different types of cells in the lab and did not find evidence of toxicity. The next step, Ho says, is to test the compound's safety and effectiveness as a contrast agent in animals. "We're excited to see what kind of increased performance we can get," Ho says.
"I think it's a very interesting system," says Kenneth N. Raymond, professor of chemistry at the University of California at Berkeley. "They've obviously got a one order of magnitude increase in relaxivity that's quite significant." Many researchers have tried to attach gadolinium ions to high molecular weight compounds, like proteins and dendrimers, he says. "The little nanodiamond, as far as I know, is quite novel, and, I think, a very clever thing to do."
Currently, radiologists need to inject what amounts to several grams of gadolinium into a patient to get good contrast on an MRI. By increasing the sensitivity of the contrast agent ten-fold, "you could use one-tenth as much gadolinium," Raymond says. "There's a lot of concern in the clinic for certain classes of patients about gadolinium toxicity. Toxicity is very closely connected to dose."
By Corinna Wu