FEATURE — Summer 2007

Professors Samuel Wickline (above) and Gregory Lanza (see below) invented a nanoemulsion for molecular imaging and drug delivery. They use it to treat cancer and cardiovascular disease.
Thinking Small May Lead To Big Results in Medical Care

Professors Samuel Wickline and Gregory Lanza are combing the nano-landscape discovering better ways to detect, diagnose, and treat cancer and heart disease.

by Janni Simner

In the 1960s film Fantastic Voyage, five travelers are reduced to microscopic size and injected into the bloodstream of an ailing scientist. Their mission? Find a blood clot in the scientist's brain and destroy it with a targeted laser. Four decades later, "miniaturizer" beams remain the stuff of science fiction, but Washington University researchers are developing targeted techniques to find and destroy blood clots, tumors, and more—using particles no larger than those fictional travelers.

"We're trying to change the way drugs are delivered," explains Samuel Wickline, professor of medicine and of biomedical engineering, physics, and cellular biology. Along with Gregory Lanza, associate professor of medicine and of biomedical engineering, Wickline leads a team of medical researchers working in the growing field of nanotechnology.

The prefix nano- means one billionth; Wickline and Lanza's work focuses on particles that are around 200 nanometers, or 200 billionths of a meter, wide. A strand of human hair, by comparison, is about 80,000 nanometers wide; even a single red blood cell is around 7,500 nanometers wide. What makes Wickline and Lanza's nanoparticles so valuable is not just that they're so small, though; it's that groups of very small particles, taken together, have a very large surface area. That might seem like a contradiction, but imagine trying to stuff a basketball into a small cardboard box. You could probably only fit one basketball into that box, but you could pack dozens of golf balls into the same space. What's more, the golf balls, taken together, have a larger surface area than the basketball taken alone.

A collection of nanoparticles has a larger surface area still—millions of times larger. Wickline and Lanza are developing ways to load all that extra space with combinations of molecules that larger particles wouldn't have room for, in hopes that those particles then can be injected into the bloodstream and sent on a voyage of their own to locate, image, and treat disease.

"What's the point of doing this research if we're not trying to change the standards of care?"

One of their primary focuses is cancer diagnosis and treatment, thanks in part to the National Cancer Institute, funder of the University's Siteman Center of Cancer Nanotechnology Excellence. Wickline and Lanza are using nanoparticles to attack cancer in two basic ways. First, they're designing particles that carry both targeting molecules and tumor imaging agents. The targeting molecules locate and "latch on" to tumors; the imaging agents then provide a detailed picture of those tumors when viewed by an MRI or CAT scan—and they do so at an earlier stage than most cancers currently can be detected.

Second, the researchers are designing particles that carry both targeting molecules and cancer drugs. Again, the targeting molecules latch on to tumors, with the result that medication gets delivered directly to the cancerous tissue, and not to the rest of the body, in much the way the travelers in Fantastic Voyage delivered their laser to a single blood clot, leaving their patient otherwise unharmed. Currently, chemotherapy drugs often do harm to more than just the tumor they're attacking; some of those drugs have life-threatening side effects. Targeted drugs also can be given at far lower doses than untargeted ones. "And if you can give 10 or 100 times less drug over the course of chemotherapy, you'll have less toxicity," Wickline says.

"We don't like the fact that cancer treatment can be as horrific as the disease," Lanza adds. He envisions a future where early detection and targeted therapy are the norm, and where both surgery and system-wide medication delivery become a secondary line of cancer defense.

Gregory Lanza is an associate professor of medicine and of biomedical engineering.

Wickline, Lanza, and their colleagues also have been using nanoparticles to attack the causes of heart disease. Patrick Winter, research assistant professor of medicine, used Wickline and Lanza's work to deliver a drug called fumagillin directly to the blood vessels that feed artery-clogging plaques. Winter's study was conducted in rabbits, and he found that the drug successfully inhibited the growth of new blood vessels, and did so at doses 50,000 times lower than the doses used in previous, more traditional fumagillin trials.

Neither fumagillin nor its analogue, TNP-470, are FDA approved for systemic use in patients due to toxicity, but Wickline and Lanza's work may one day allow researchers to revisit the use of many drugs like these, drugs that are effective but that also carry intolerable side effects at high doses.

Wickline and Lanza agree that cancer and heart disease are just a starting point. Nanotechnology can be applied to other diseases as well, especially diseases where inflammation plays a role, such as rheumatoid arthritis and macular degeneration. Ultimately, Wickline says, "Our goal is to prevent disease from getting to the point where patients become symptomatic."

Wickline and Lanza have worked together since the early 1990s, when Lanza was a cardiovascular fellow in Wickline's lab. From the start, they brought complementary skills to their work. Wickline had a physics, engineering, and medical imaging background; Lanza had a genetics and chemistry background, along with pharmaceutical experience he acquired as a research manager at Monsanto Co. They both saw a need for better ways to find and image diseased tissue, and that need led them to start experimenting with nanoparticles. "When you look at a regular chest X-ray or MRI, you get a good idea about the shape and size of organs," Wickline says. "But we needed agents that would identify specific molecules and markers. We needed a technology that would let us work at the molecular level."

From the start, Wickline and Lanza relied not only on their own partnership, but on the collaboration and teamwork of everyone in their lab, which includes a mix of technicians, graduate students, and postdocs. "Great ideas, like great music, come from people working together and playing off each other," Lanza says of that team.

Wickline adds: "I like our ability to think outside of the box while still putting something together that works for patients. When you put different kinds of people together, you can think broadly and range widely, while at the same time not losing focus on our patients."

Wickline and Lanza both say that in the end their work is always about the patients; they're committed not only to conducting research, but also to seeing the results of that research reach the public. When they first tried to interest drug companies in developing nanotechnology-based products, though, they met some resistance; companies were wary of investing in a new technology without a long track record. Wickline and Lanza finally decided to found their own company, Wickline says, "in order to move this work out of the lab and into clinical trials."

That company became Kereos, Inc. Wickline and Lanza do not run Kereos, but they do play an ongoing advisory role: Wickline as a board member, Lanza as chief scientific officer. Wickline and Lanza work with Robert A. Beardsley, president and CEO, and others to transfer their research and knowledge to Kereos' pharmaceutical setting. Kereos works with other companies in turn, such as Bristol-Myers Squibb and Philips Medical Systems, to develop products for doctors and patients. Some of those products may reach the public within just a few years; the first trials of a tumor imaging agent are scheduled to begin later in 2007.

"Our real purpose is to reach the clinic," Lanza says. "What's the point of doing this research if we're not trying to change the standards of care?" Wickline adds, "The definition of innovation in a practical sense is to change the way we practice medicine—that is our goal."

Wickline and Lanza continue to occasionally treat clinic patients themselves; Lanza says seeing those patients helps keep their research in perspective. "We work on breast cancer, and I hate that disease because I've taken care of patients, 42-year-old women, with terminal breast cancer," Lanza says. "We work on a lot of problems that really annoy me. My dad died of cancer. My mom died of a stroke. Who hasn't known someone who has had a heart attack? The idea that we can maybe hit some of these things and change how they go for people—that's plenty of motivation."

The work itself continues to provide motivation as well, Wickline says, precisely because nanotechnology is still in its infancy. "It's fulfilling to answer one question, but it's even more exciting to get to choose among the 10 new questions that pop up when you do. It's never ending, and that's the fun part. It's always new, and that's a delight."

Janni Simner, A.B. '89, is a free-lance writer based in Tucson, Arizona.

For more information on Kereos, visit: http://www.kereos.com/.