Barnes-Jewish Hospital Research 1997 Annual Report: A Tiny Particle With Far-Reaching Significance

Reprinted with permission.

A site-targeted imaging agent, consisting of a particle 200 nanometers in diameter, has the potential of profoundly affecting the ability of physicians to detect cancer or blood clots at earlier stages than now possible. There’s a flurry of excitement about the tiny particle’s far-reaching significance. And the researchers who invented it are medical faculty members of Barnes-Jewish Hospital.

Samuel A. Wickline, MD, co-director of the cardiovascular division at Barnes-Jewish Hospital, hesitates in calling the particle developed and patented by himself and Gregory M. Lanza, MD, PhD, a “better mousetrap” to image tumors or cardiovascular pathologies. But the data to date is encouraging, and others knowledgeable about these things are excited, including a number of pharmaceutical companies eager to establish joint ventures.

“The concept of specifically targeting and imaging an area of the body, or targeting and treating an area, has been around for 20 years or more,” says Dr. Wickline. “We simply approached it in a different way. Previous attempts have involved using specific antibodies connected to radioactive imaging agents, or microbubbles injected into the bloodstream in the case of ultrasound imaging. Both methods have a problem with the contrast agents remaining in the blood’s circulation long enough to obtain quality images.”

Drs. Wickline and Lanza’s formulation uses an emulsion, a concept that has been known for thousands of years (think salad dressing or a mixture of oil and water), but before now had never been applied as an imaging agent with the capability for drug delivery.

“We attach the nanoparticle to a monoclonal antibody that is targeted to some pathologic site of interest, such as a particular kind of cancer or a blood clot,” explains Dr. Lanza. “Unlike other methods in which a single contrast mechanism is bound to the antibody, we can bind thousands of the nanoparticles, which results in a much brighter image when the antibody reaches its targeted site.”

Breast cancer: a pertinent example

That brightness is especially important in diagnosing cancer, which is difficult to detect in early stages because its appearance may be quite similar to surrounding tissue. Breast cancer is a good example of the particle’s potential diagnostic ability. Although monthly self-examination is helpful, it is still difficult to discover small lumps. Further improvements in the ability of screening tests such as mammography to detect very early tumors also is necessary. Attaching the particle to an antibody that targets breast cancer and imaging it through magnetic resonance imaging (MRI) or ultrasound methods may prove an effective resolution to these difficulties.

The particle also may be useful in treating disease, providing the proof needed that a drug dose is reaching its target. “Combined imaging and drug delivery will be the cornerstone of diagnosis and therapy during the next 20 years,” says Dr. Wickline. “Finding out early that there is a problem, treating it specifically, and watching the problem resolve – those are the keys to diagnosis and therapy.”

He adds, “This discovery has the possibility of doing all that with any imaging modality you care to use, based on whatever modality is most applicable for a certain pathology. Its potential use is incredibly broad, and hundreds of products may be developed from it.”

Patenting the discovery – and proving it

“Our concentration right now is on three major imaging modalities: ultrasound, MRI and nuclear imaging,” says Dr. Lanza. “The first two are important because neither produces harmful side effects. And since nuclear imaging is the standard right now for identifying and targeting pathologies, we feel it is important to address that imaging modality quickly.”

A patent covering the use of the site-targeted contrast agent in ultrasound was issued in November 1997, and patents are pending for its use in MRI and nuclear imaging. Other patents related to drug delivery and diagnosis are under development.

“Our task now is proving that our particle works using different antibodies supplied by various pharmaceutical companies. Once that is accomplished, we can help develop the specific products that will have the potential of benefiting thousands of patients,” says Dr. Wickline.

That is being accomplished through an almost “factory line” approach, accepting antibodies from various companies, attaching them to the particle, and proving in vivo that the combined molecule is arriving at the designated site. Once this is demonstrated, clinical trials can begin.

Discoveries through cooperative research

Discovery of such new imaging methods has come through close cooperation between Washington University School of Medicine’s cardiovascular medicine division and Washington University’s department of physics, a research relationship established more than 20 years ago. Overseen by Dr. Wickline and James G. Miller, PhD, professor of physics and research professor of medicine, the collaboration enables graduate students in physics to learn and study while participating in cutting-edge research set in a medical environment. The ability to communicate ideas back and forth between the basic science of physics and a clinical endeavor like cardiovascular medicine has resulted in major breakthroughs over the years, especially in the area of ultrasound imaging.

Over the past several years, the same type of cooperative effort has begun to flourish between cardiovascular medicine and the university’s department of biomedical engineering in its School of Engineering and Applied Sciences. Frank Yin, MD, PhD, is director of the department.

“The university and medical school have put together a large consortium of individuals interested in cardiovascular medicine, biophysics and biomedical engineering, and that growth has been exponential. As clinical problems mount that can be addressed by quantitative approaches, and as funding to support these activities increases, so does the number of principal investigators interested in these multidisciplinary problems,” says Dr. Wickline.

Both undergraduate and graduate biomedical engineering students work on projects in the labs housed at Barnes-Jewish Hospital, giving them an opportunity to see how their designs work in clinical practice.

“Advances in biomedical engineering occur through an interactive process,” explains Dr. Wickline. “For example, you can build a device that you think will improve imaging, but the proof comes only when the image is actually made and can be evaluated by those caring for patients. That’s the best way for students to learn, and the fastest way to advance technology.”

The worth of that process is seen in advances being made in cardiac MRI. “We’re devoting a lot of effort to using cardiac MRI to learn new physiology, new anatomy and new functions of the heart, things that haven’t been measurable before,” comments Dr. Wickline. “The cooperative effort between researchers and clinicians in cardiovascular medicine, biomedical engineering and physics is having significant results in the form of patents issued and pending, and commercial interest.”

And while advances are made in the way cardiac MRI may be used, the tiny particle discovered by Drs. Wickline and Lanza will contribute to making the technique’s images more revealing and useful.