| Miniscule,
carefully engineered particles can detect the very beginning
stages of clogged arteries in animals, thanks in large
part to research at Washington University School of
Medicine in St. Louis. With a new five-year, $7.3 million
grant, School of Medicine researchers will begin to
translate this breakthrough into clinical advances.
Funded by the National Heart,
Lung and Blood Institute, the grant will support a
Biomedical Research Partnership between the School
of Medicine and several commercial partners, including
Kereos Inc, Philips Medical Systems, Bristol-Myers
Squibb Medical Imaging and Dow Chemical. The grant
is an advancement of the School of Medicine's BioMed
21 initiatives, which focus in part on translational
research and biomedical imaging.
"We've developed a way
to take images of very early arterial plaques, before
they're detectable by any other means," says
principal investigator Samuel A. Wickline, M.D., professor
of medicine and of biomedical engineering at the School
of Medicine and a Washington University heart specialist
at Barnes-Jewish Hospital. "With this grant we
will bridge the gap between fundamental laboratory
research and the development of new, investigational
drugs."
Wickline and co-investigator
Gregory M. Lanza, M.D., Ph.D., associate professor
of medicine and biomedical engineering, are cofounders
of Kereos Inc.
Hardened or clogged arteries,
a condition called atherosclerosis, result from the
accumulation of fatty plaques on the interior walls
of blood vessels. As a plaque begins to form, a crowd
of small blood vessels, called capillaries, develops
around the site. Wickline and his colleagues designed
a way to take images of those young capillaries, thereby
predicting locations that will soon fall prey to atherosclerosis.
Their technique uses specially
engineered nanoparticles that serve as mailmen — researchers
tell the extremely small particles exactly what kind
of cell to find and give them a package to deliver
when they arrive.
In a study published in 2003,
Wickline's team packed nanoparticles with two components:
molecules that latch onto small, rapidly growing capillaries
and an imaging agent called gadolinium, which shows
up as a bright spot on a magnetic resonance image
(MRI). Using rabbits, they found that arteries that
were developing dangerous capillaries had gadolinium
signals twice as bright as normal arteries.
The researchers have shown
that this technique also can help distinguish between
stable plaques and those that are about to break apart.
Fragments of plaques are a common cause of heart attacks
or strokes.
Now that their technique has
been proven effective in animals, the researchers
will use the new grant to develop imaging agents that
can be used in humans. They also hope to design drugs
that can be delivered on nanoparticles to prevent
a future heart attack or stroke.
"Our ultimate goal is
to change the usual course of atherosclerosis by using
imaging techniques to determine who is likely to have
a stroke or heart attack and then targeting drugs
to the site of the very earliest stages of disease,"
Wickline says.
Although this grant does not
directly fund clinical trials, Wickline believes the
team's research will be ready to be tested on patients
in the next two to three years. And, because tumors
also require new populations of capillaries, the team
believes these techniques also may help detect very
early cancers at the beginning stages of tumor development.
Editor's note: Samuel A. Wickline,
M.D., is a co-founder of Kereos Inc and is a board
member and equity holder.
Lanza GM, Yu X, Winter PM,
Abendschein DR, Karukstis KK, Scott MJ, Chinen LK,
Fuhrhop RW, Scherrer DE, Wickline SA. Targeted antiproliferative
drug delivery to vascular smooth muscle cells with
a magnetic resonance imaging nanoparticle contrast
agent: implications for rational therapy of restenosis.
Circulation, vol. 106, pp. 2842-2847, 2002.
Wickline SA, Lanza GM. Nanotechnology
for molecular imaging and targeted therapy. Circulation,
vol. 107, pp. 1092-1095, 2003.
Winter PM, Morawski AM, Caruthers
SD, Fuhrhop RW, Zhang H, Williams TA, Allen JS, Lacy
EK, Robertson JD, Lanza G, Wickline SA. Molecular
imaging of angiogenesis in early-stage atherosclerosis
with alpha-v-beta-3-integrin-targeted nanoparticles.
Circulation, vol. 108, pp. 2270-2274, 2003.
Buxton DB, Lee SC, Wickline
SA, Ferrari M. Recommendations of the National Heart,
Lung and Blood Institute Nanotechnology Working Group.
Circulation, vol. 108, pp. 2737-2742, 2003.
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 second 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.
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