St.
Louis, July 27, 2006 -- In laboratory tests, one
very low dose of a drug was enough to show an effect
on notoriously tenacious artery-clogging plaques.
What kind of drug is that potent?
It's not so much the drug itself as how it was delivered.
Fumagillin -- a drug that can inhibit the growth
of new blood vessels that feed atherosclerotic plaques
-- was sent directly to the base of plaques by microscopically
small spheres called nanoparticles developed by researchers
at Washington University School of Medicine in St.
Louis.
"Previously we reported that we can visualize plaques
using our nanoparticle technology, but this is the
first time we've demonstrated that the nanoparticles
can also deliver a drug to a disease site in a living
organism," says Patrick Winter, Ph.D., research assistant
professor of medicine. "After a single dose in laboratory
rabbits, fumagillin nanoparticles markedly reduced
the growth of new blood vessels that feed plaques."
The researchers report their findings in the September
issue of the journal Arteriosclerosis, Thrombosis,
and Vascular Biology, and the article is now available
on line.
An atherosclerosis plaque results when a buildup
of cholesterol, inflammatory cells and fibrous tissue
forms inside an artery. If a plaque ruptures, it
can block blood flow to the heart or brain, causing
heart attack or stroke.
While growing, plaques require an influx of nutrients,
fats and cells, so they develop their own blood supply
-- minute blood vessels that grow within the wall
of arteries and penetrate the plaque. Many believe
that cutting off this blood supply could stabilize
or reduce plaques. In previous studies, fumagillin
has been shown to be an effective agent for stopping
the process that creates new blood vessels.
Riding on the nanoparticles, fumagillin is carried
to the site of new blood vessel formation and stays
there thanks to a fellow nanoparticle passenger --
a component that fastens the nanoparticles to cells
found in newly developing blood vessels. Stuck in
this position, the nanoparticle drops its load of
fumagillin, concentrating it at the site of the atherosclerotic
plaque.
In this study, the single dosage of fumagillin each
rabbit received was 50,000 times lower than the total
fumagillin dose used in an earlier experiment by
another research group and yet reduced the growth
of new blood vessels in plaques by 60 to 80 percent.
"Fumagillin can have neurocognitive side effects,
causing injury to the brain at high doses," Winter
says. "The ability of the nanoparticles to concentrate
the drug at the disease site allows the dose to be
lowered. This could open the door for a lot of drugs
that have failed to be approved because they caused
too many side effects at a higher dose. It might
pay to look at these drugs again and ask if placing
them on these nanoparticles can help them be effective
at a lower dose and clinically useful."
The nanoparticles are the invention of Samuel Wickline,
M.D., professor of medicine, of biomedical engineering,
of physics and of cell biology and physiology, and
Gregory Lanza, M.D., Ph.D., associate professor of
medicine and biomedical engineering. Both are heart
specialists at Barnes-Jewish Hospital.
The microscopic spheres are capable of carrying
a variety of components at the same time and can
be detected with standard MRI scans, making them
useful for imaging disease sites while simultaneously
treating them. Using the nanoparticles, a physician
can confirm a drug has reached the desired location,
measure the amount of drug at the site, and later
check to see if the drug has affected the disease.
In the current study, the researchers fed rabbits
a high-cholesterol diet for 80 days before treatment
with fumagillin nanoparticles. The diet caused numerous
small plaques in the rabbits' aortas, but the plaques
were considered to be at an early stage of growth.
By demonstrating the utility of the nanoparticles
for early intervention of atherosclerosis, the research
group hopes that they can help alleviate the need
for more invasive treatment of later-stage atherosclerosis.
"We wanted to go after the early stages of the disease
when patients don't yet need immediate intervention
to prevent serious cardiac problems," Winter says. "We
think fumagillin nanoparticles potentially could
be incorporated into a protocol that includes lipid-lowering
statin drugs or dietary changes." Next, the research
group plans to study the effect of fumagillin nanoparticles
in the treatment of cancerous tumors. According to
Winter, the use of inhibitors of blood vessel growth
is a well-accepted therapy for cancer, suggesting
the nanotechnology may prove beneficial in cancer
therapy.
Winter PM, Neubauer AM, Caruthers SD, Harris TD,
Robertson JD, Williams TA, Schmieder AH, Hu G, Allen
JS, Lacy EK, Wickline SA, Lanza GM. Endothelial áíâ3
integrin-targeted fumagillin nanoparticles inhibit
angiogenesis in atherosclerosis. Arteriosclerosis,
Thrombosis, and Vascular Biology September 2006,
available on line ahead of print.
Funding from the National Institutes of Health,
the American Heart Association and Philips Medical
Systems supported this research.
Washington University School of Medicine's full-time
and volunteer faculty physicians also are the medical
staff 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, currently ranked fourth in the nation
by U.S. News & World Report. Through its affiliations
with Barnes-Jewish and St. Louis Children's hospitals,
the School of Medicine is linked to BJC HealthCare. Contact:
Gwen Ericson
ericsong@wustl.edu
314-286-0141
Washington University School of Medicine
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