"We've developed a way to take non-invasive images of very early plaques, before they're detectable by any other means," says Samuel A. Wickline, M.D., professor of medicine and biomedical engineering and one of the study's senior authors. "This same technology, we think, will allow us to detect very early cancers and other inflammatory events as well."
Patrick M. Winter, Ph.D., research instructor of medicine and first author of the study, presented the team's results Nov. 19 during the Russell Ross Memorial Lecture and New Frontiers in Atherosclerosis at the American Heart Association's Scientific Sessions 2002 in Chicago. Gregory M. Lanza, M.D., Ph.D., assistant professor of medicine and biomedical engineering, is co-senior author.
Wickline also presented an overview of molecular imaging and nanotechnology at the Molecular Basis for Cardiac Imaging session.
Atherosclerosis – the progressive hardening of arteries – results from the accumulation of plaques in key blood vessels. In order for plaques to form, a crowd of smaller vessels, called capillaries, must develop around the diseased site.
In this study, the team used a relatively new imaging method – developed primarily at Washington University – to label growing capillaries, thereby identifying locations where plaques are about to form. They loaded an extremely small particle roughly 200 nanometers long, called a nanoparticle, with about 80,000 atoms of gadolinium, which shows up as a bright spot on a magnetic resonance image (MRI). Other carriers for gadolinium hold only a few such atoms at a time, and therefore result in less bright images.
In order to ensure that gadolinium highlighted only new capillaries, the team also packed the nanoparticle with molecules that specifically detect a protein called avb3, which is abundant in rapidly growing capillaries. In so doing, the nanoparticles mainly latched onto cells that contain avb3.
"You can load these nanoparticles with whatever you want, like a Mr. Potato Head," Wickline explains. "The targeting agent allows us to select where the particle goes, and then we can either add an imaging agent, like gadolinium, or a drug, like plaque stabilizing medications or anticancer agents."
The team injected nanoparticles loaded with avb3 detectors and gadolinium into 13 rabbits. Four of the rabbits had been fed normal diets and nine had been fed high-cholesterol diets for about 80 days. They then took MRI scans of the abdominal aorta – the largest artery in the body – for two hours after injection. The cholesterol-fed rabbits injected with targeted nanoparticles had gadolinium signals in the abdominal aorta more than twice as bright as the other rabbits.
Post-mortem examination confirmed that the cholesterol-fed animals were in fact developing dangerous capillaries around the aorta, in contrast to the control diet rabbits.
"These preliminary results suggest that we can manipulate nanoparticles to image plaques as they are just beginning to form," says Wickline. "Previous research of ours also suggests that this technique can distinguish between patients with stable plaques from those whose plaques are about to rupture and thereby cause a heart attack or stroke."
Because tumors also require new populations of capillaries, the team believes this technique will enable them to detect very early cancers at the beginning stages of tumor development.
The technology used in this study has been licensed to KEREOS Inc., which is devoted to molecular imaging and targeted therapeutics. Gregory M. Lanza, M.D., Ph.D., and Samuel A. Wickline, M.D., are co-founders of KEREOS and both are board members and equity holders.
Winter PM, Caruthers SD, Schmeider A, Harris TD, Chinen L, Williams T, Watkins MP, Allen JS, Wickline SA, Lanza GM. Molecular imaging of angiogenesis in atherosclerotic rabbits by MRI at 1.5T with avb3 targeted nanoparticles, American Heart Association, Nov. 19, 2002.
Wickline SA, Lanza GM. Nanotechnology for molecular imaging and targeted therapeutics. American Heart Association, Nov. 17, 2002.
Funding from the National Heart, Lung and Blood Institute, the National Cancer Institute and Philips Medical Systems supported this research. Bristol-Myers Squibb Medical Imaging provided materials for the study.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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