This report originally appeared in the September 2011 issue of DOTmed Business News

Dr. Dean Ho’s experiment began with a bang. His mixture of TNT and RDX was just the right combination of chemicals to get his experiment going. But while composition B is known for being the main ingredient in hand grenades and artillery, Ho was more interested in the leftovers of the explosion: nanoparticles.

In this case, the particles, called nanodiamonds, are a type of nanoparticle being used in imaging. Nanodiamonds are anywhere between two and eight nanometers wide, and have multiple facets that act as loading docks for other molecules. Ho and his colleague, Dr. Thomas Meade, combined the particles with gadolinium, a commonly used—and highly toxic—magnetic resonance imaging (MRI) contrast agent. The results, according to Ho, were surprising.

“We observed an immense increase in the efficacy of the contrast agent,” explains Ho, who is an associate professor of biomedical engineering and mechanical engineering at Northwestern University and also plays a role at the university’s Robert H. Lurie Comprehensive Cancer Center. “We got numbers that were among the highest ever recorded.”

Diamonds in the rough
The difference between a nanodiamond-bound gadolinium and a free-floating gadolinium was dramatic. In their study, which was published in the January 2010 issue of Nano Letters, the group described a 12-fold increase in a gadolinium’s relaxivity, or relative brightness, when bound to a nanodiamond. The nanoparticle-gadolinium combination resulted in enhanced signal intensity and significantly more vivid images. More recently, Ho and his colleagues published an article in Science Translational Medicine describing the success of nanodiamonds bound to cancer drugs in vivo using mice. The next step, says Ho, is larger animal models.

Meade, the lead author of the study, has been fine-tuning the nanoparticle-gadolinium combination for years. His goal has been to address one of the weaknesses of MRI, which is its low sensitivity. By combining contrast agents with nanodiamonds, Meade has been able to produce very bright particles. This, in turn, may let radiologists to use lower doses to achieve the same relaxivity.

“The goal is to treat patients with significantly reduced doses,” says Ho. “You can really improve efficiency and sensitivity, and reduce toxicity.”
Sensitivity and toxicity, according to Meade, are key for MRI. “It is the field’s biggest Achilles’ heel,” says Meade. In this context, he explains, nanodiamonds are like hitting the jackpot.

Nanotubules deliver the goods
Meade and Ho’s group at Northwestern is not the only lab to be pursuing this line of research. Dr. Lon J. Wilson, a professor of chemistry at Rice University, has been working with a different kind of nanoparticle called nanotubules. Wilson’s nanotubules are hollow and measure only one nanometer in length. While nanodiamonds carry gadolinium on the outside, Wilson and his group placed the gadolinium ions on the inside of these tubules.

Wilson calls this combination of nanotubes and gadolinium gadonanotubes. He says the benefit of the nanotubule is that it acts as a sheath, protecting patients from the toxicity associated with gadolinium. The gadonanotubes produced images that were at least 40 times more effective than the best clinical agents.

Wilson attributes this improvement to the scale at which nanoparticles operate. With five to ten gadolinium ions confined in the small space of a nanotubule, the contrast agent’s effect is amplified.

“The success of the gadonanotubes is really an effect of nanotechnology,” explains Wilson. “The nanotechnological approach to imaging is a new paradigm in contrast agent design and execution.”

According to Meade, the advantage of nanoparticles is not limited to reducing dosages and toxicity. Nanoparticles also offer the opportunity to combine two fields that had previously been separate in imaging: therapeutics and diagnostics.

Meade compares nanodiamonds to UPS trucks, a nontoxic delivery system for his choice of contrast agents and therapeutics. “They give us a platform on which to decorate a material with both diagnostics and therapeutics,” says Meade, a professor of chemistry, molecular biosciences, neurobiology and radiology at Northwestern.

This feature of nanoparticles—their seemingly unlimited ability to bind to and deliver a range of compounds simultaneously—is what makes them so intriguing for use in imaging. By covalently bonding nanoparticles to contrast agents and therapeutic compounds at the same time, physicians gain a new perspective.
“We call this theranostics, the combination of therapeutics and diagnostics,” Meade says. This combination may allow clinicians to “fate-map,” or follow, therapeutic compounds—like cancer drugs—as they move through the body. Wilson’s group is also headed in the same direction. They are researching the potential of cancer therapy where nanoparticles deposit therapeutics at specific sites while providing clinicians an opportunity to monitor their progress using MRI.
By offering a multi-modal platform, nanodiamonds would offer a new way to treat and diagnose patients. “They are the perfect carrier,” says Meade. “We can now make smarter, target-specific products that are more efficient. There is no limit to what nanoparticles can do.”

Baby steps for a medical revolution
Although research in the field is steadily growing, the specialty is still in its infancy. Very few ventures have transitioned from the lab bench to clinical settings, and even fewer are close to receiving FDA approval. But given nanotechnology’s potential, Meade believes that this is bound to change in the near future.

“The landscape is changing,” explains Meade. “But it will take a while to get this to a doctor’s office. Whenever new technology comes out, people are going to be anxious.”

Dr. Daniel S. Kohane, a senior associate in critical care medicine at Boston’s Children’s Hospital, compares nanotechnology to the field of chemistry four hundred years ago. Like nanotechnology, chemistry held immense potential and eventually, it changed the world, but not without a few obstacles.

No limits – except for some challenges
In March 2011, Kohane and his colleagues conducted a review of nanotechnology and its implications in surgery. And that was just the tip of the iceberg, explains Kohane.

“There really are no limits,” says Kohane, an associate professor of anesthesia at Harvard Medical School. “And given the range of particle sizes, you can imagine what this field can accomplish.”

But to begin with, researchers will have to overcome lingering concerns regarding the safety of nanotechnology. “It’s the black box of nanotechnology,” Kohane says. “We don’t know what their toxicity is, and what they will do in the body.”

Currently, several research groups are conducting larger animal safety studies to investigate how nanoparticles are removed from the body. According to Ho, these studies will hold the key to addressing some of the safety concerns. “Different nanoparticles perform differently. Even the same material has different properties in different environments,” says Ho. “So we need to examine each one carefully before we move ahead.”

From an investor’s standpoint, researchers will also have to show that nanotechnology has a favorable cost-benefit ratio. “We need to prove that we can indeed make reproducible, new material, that give us advantages that we can get no other way,” says Meade. National initiatives like the NIH’s National Cancer Institute’s Nanotechnology program have played a large role in moving research towards clinical settings and the market.

For Meade, nanoparticles are the next logical step in molecular imaging research. He predicts that the future of nanoparticle-based imaging research will only grow in the future. Meade points to the history of MRI as evidence.
“Twenty years ago, MRI was at 10 millimeters, and now we’re down to 10 microns,” Meade says. “Imagine where we could be in 20 more years.”