When people are contaminated with certain radioactive materials, they can be treated with diethylene triamine pentaacetic acid (DTPA), which binds to the radioactive material in the body, allowing it to be expelled through urine.

The interest in DTPA has increased in recent years as fears about dirty bombs have spiked since 9/11. A dirty bomb — an explosive device designed to disperse radioactive material — has not yet been detonated, but significant and verifiable threats have been reported in the US and abroad, and experts believe such a device is not likely to be powerful enough to cause mass destruction. However, if a dirty bomb is set off, the fear of radioactive contamination could cause public panic. For this reason, dirty bombs are sometimes referred to as “weapons of mass disruption.”

Michael Jay, PhD, a professor at the UNC Eshelman School of Pharmacy, is conducting research to make DTPA more readily available to people exposed to radioactive material by an accident or a dirty bomb. He is working on an oral form of the drug, which, if successful, will be added to the Center for Disease Control and Prevention’s Strategic National Stockpile.

When administered within hours after contamination, DTPA is very effective in eliminating radioactive material from the body. However, the drug is currently only available in IV form, which makes producing, storing, and administering the drug more complicated.

“Injectable forms don’t make good products for a national stockpile because they are expensive to make,” Jay says. “They also have to be sterile, the shelf life is shorter, and you need a professional to administer it.

“Everything is easier with an oral form. Administering would be easier, storing it would be easier, manufacturing would be cheaper.”

However, the challenge in producing an oral dose of DTPA has been its low bioavailability—the percentage of a dose that gets absorbed, unchanged, into the blood. An IV dose has a 100 percent bioavailability, whereas less than 1 percent of an orally administered dose of DTPA gets absorbed.

Since 2005, Jay has received a $5.2 million grant from the National Institute of Allergy and Infectious Diseases to develop an oral form of DTPA. The goal: raise bioavailability significantly so that it can be used as an effective radionuclide decorporation agent.

In the past three-plus years, Jay and researchers in his lab have solved the bioavailability problem. Their solution was to develop a DTPA prodrug—a drug that is not active when administered but becomes active after it enters the body. One of these prodrugs has shown 100 percent bioavailability in rats.

“We designed it so that it would have the right permeability,” Jay says. “The reason DTPA itself is not well-absorbed is because it’s very ionic, very highly charged, so it has high solubility and low permeability. We wanted high permeability and reasonable solubility, so we designed it to have this property.”

Jay is collaborating with several colleagues on the project. Russ Mumper, PhD, the John A McNeill Distinguished Professor at the School, is providing expertise in formulation and product development. Bill Zamboni, PhD, an associate professor at the School, directs the bioavailability studies. He is also director of the GLP Analytical Facility at UNC-Chapel Hill, which will conduct the bioassay work. One of Jay’s former colleagues at the University of Kentucky, Pat McNamara, PhD, is participating in the study design and pharmacokinetic analysis.

The researchers are now tackling the next hurdle: developing easy-to-administer adult and pediatric formulations for the prodrug.

“The problem is that it’s a bit of a challenging molecule to work with,” Jay says. “We want to make an oral dosage form. We initially wanted to make a solid out of it, but it is a viscous oil and we can’t crystallize it. It’s also very hydroscopic. And on top of that, it’s sensitive to water, air, and a number of things—a really uncooperative compound. Thus, we have to make formulations that deal with these issues.”

Jay also anticipates that significant taste-masking will be required for this prodrug.

Nanoparticles for Tumor Imaging and Therapy

Another area of Jay’s research aims to use nanoparticles to improve the imaging and treatment of tumors. Jay is creating nanoparticles that contain gadolinium, a substance commonly used as an MRI contrast agent.

“The standard MRI imaging agents are water-soluble, so if you inject them into people, they tend to go where water goes,” Jay says. “So if you are trying to look at blood flow, or if you’ve got a little leakage in a blood vessel in the brain, that’s fine. But we want to look at tumors.

“As the current agents make their first pass through a tumor, you might be able to image it if you move fast enough. But what we want to do is to deliver the gadolinium selectively to tumors, so when you image a patient you can tell where and how big the tumor is.”

Jay is also planning to bind radioisotopes on the nanoparticles to enable nuclear imaging by PET or SPECT,. While MRI is better at providing an anatomical image of the whole body and doesn’t involve radioactive material, nuclear imaging is much more sensitive.

The nanoparticles are also designed to carry a drug to treat the tumor, giving them a therapeutic function as well.

“So ultimately what we want to do is have the image as a guide to tell us how much drug needs to be delivered,” Jay says. “If you are going to give a nanomedicine as treatment for a tumor, one of the big questions will be how much medicine do you actually need to treat the tumor. So that will help guide future dosing regimens.

“If this works out, we would have the patient come in for an initial scan, where they would be injected with this nanoparticle and take a scan. Based on the image, we can determine what’s the likely dose to reach that tumor, and then you can determine your pharmacokinetic doses based on that image. So we would have individualized therapy for specific tumors.”

Entrepreneurial Ventures

Much of Jay’s research is based on a novel process for making nanoparticles, which he and Mumper, one of Jay’s former students, developed while they were both at the University of Kentucky.

“Russ joined the faculty at Kentucky in 1999,” Jay says. “He had just come out of working at a small company that was working on delivering DNA, and the nano world was just starting to explode at the time. So we thought about some ideas on how this could work, and from those little lunch-time discussions, we tried stuff. When we found this process that was pretty unique, we said, ‘One day we are going to start a company based on this.’

“Then we said, ‘Well, why not today?’ We couldn’t think of a reason why not.”

So in 2000, they cofounded NanoMed Pharmaceuticals, a company dedicated to developing improved therapeutic products to treat cancer and other serious diseases. The company is applying its Nanotemplate Engineering technology to reformulate FDA-approved drugs to impart unique pharmaceutical and/or pharmacological competitive advantages. The company’s lead oncology product, NMP-139, is targeted for an Investigational New Drug Application submission in 2010.

In addition to NanoMed, Jay, who admits to having “a little entrepreneurial streak in me”, has also started Cherry Orchard Products LLC. The company, which he calls a “mom-and-pop-and-friend operation”, is developing a compound to relieve discomfort from wearing braces.

“We’ve invested some money and we are in the process of raising more,” Jay says. “We have a patent on the product. The patent actually belongs to the University of Kentucky and we’ve licensed the patent. We’ve been to visit the FDA a couple times to figure out what we have to do to get this product approved. The pathway to market is actually much easier than most drugs. But it still takes time and money.”