Designing nanomedicine to combat diseases is a
hot area of scientific research, primarily for
treating cancer, but very little is known in the
context of atherosclerotic disease. Scientists have
engineered a microchip coated with blood vessel
cells to learn more about the conditions under
which nanoparticles accumulate in the plaque-
filled arteries of patients with atherosclerosis, the
underlying cause of myocardial infarction and
stroke.
Atlanta, GA | Posted on February 4th, 2014
In the research, microchips were coated with a
thin layer of endothelial cells, which make up the
interior surface of blood vessels. In healthy blood
vessels, endothelial cells act as a barrier to keep
foreign objects out of the bloodstream. But at
sites prone to atherosclerosis, the endothelial
barrier breaks down, allowing things to move in
and out of arteries that shouldn't.
In a new study, nanoparticles were able to cross
the endothelial cell layer on the microchip under
conditions that mimic the permeable layer in
atherosclerosis. The results on the microfluidic
device correlated well with nanoparticle
accumulation in the arteries of an animal model
with atherosclerosis, demonstrating the device's
capability to help screen nanoparticles and
optimize their design.
"It's a simple model — a microchip, not cell
culture dish — which means that a simple
endothelialized microchip with microelectrodes
can show some yet important prediction of what's
happening in a large animal model," said YongTae
(Tony) Kim, an assistant professor in
bioengineering in the George W. Woodruff School
of Mechanical Engineering at the Georgia Institute
of Technology.
The research was published in January online in
the journal Proceedings of the National Academy
of Sciences. This work represents a
multidisciplinary effort of researchers that are
collaborating within the Program of Excellence in
Nanotechnology funded by the National Heart,
Lung, and Blood Institute, the National Institutes
of Health (NIH). The team includes researchers at
the David H. Koch Institute for Integrative Cancer
Research at MIT, the Icahn School of Medicine at
Mount Sinai, the Academic Medical Center in
Amsterdam, Kyushu Institute of Technology in
Japan, and the Boston University School of
Medicine and Harvard Medical School.
Kim began the work as his post-doctoral fellow
at the Massachusetts Institute of Technology
(MIT) in the lab of Robert Langer.
"This is a wonderful example of developing a
novel nanotechnology approach to address an
important medical problem," said Robert Langer,
the David H. Koch Institute Professor at
Massachusetts Institute of Technology, who is
renowned for his work in tissue engineering and
drug delivery.
Kim and Langer teamed up with researchers from
Icahn School of Medicine at Mount Sinai in New
York. Mark Lobatto, co-lead author works in the
laboratories of Willem Mulder, an expert in
cardiovascular nanomedicine and Zahi Fayad, the
director of Mount Sinai's Translational and
Molecular Imaging Institute.
"The work represents a unique integration of
microfluidic technology, cardiovascular
nanomedicine, vascular biology and in vivo
imaging. We now better understand how
nanoparticle targeting in atherosclerosis works."
Lobatto says.
The researchers hope that their microchip can
accelerate the nanomedicine development process
by better predicting therapeutic nanoparticles'
performance in larger animal models, such as
rabbits. Such a complimentary in vitro model
would save time and money and require fewer
animals.
Few nanoparticle-based drug delivery systems,
compared to proposed studies, have been
approved by the U.S. Food and Drug
Administration, Kim said. The entire process
developing one nanomedicine platform can take
15 years to go from idea to synthesis to testing
in vitro to testing in vivo to approval.
"That's a frustrating process," Kim said. "Often
what works in cell culture dishes doesn't work in
animal models."
To help speed up nanomedicine research by
improving the predictive capabilities of in vitro
testing, Kim and colleagues designed their
microchip to mimic what's going on in the body
better than what is currently possible through
routine cell culture.
"In the future, we can make microchips that are
much more similar to what's going on in animal
models, or even human beings, compared to the
conventional cell culture dish studies," Kim said.
On their microchip, scientists can control the
permeability of the endothelial cell layer by
altering the rate of blood flow across the cells or
by introducing a chemical that is released by the
body during inflammation. The researchers
discovered that the permeability of the cells on
the microchip correlated well with the
permeability of microvessels in a large animal
model of atherosclerosis.
The microchips allows for precise control of the
mechanical and chemical environment around the
living cells. By using the microchip, the
researchers can create physiologically relevant
conditions to cells by altering the rate of blood
flow across the cells or by introducing a chemical
that is released by the body during inflammation.
Kim said that while this microchip-based system
offers better predictability than current cell culture
experiments, it won't replace the need for the
animal studies, which provide a relatively more
complete picture of how well a particular
nanomedicine might work in humans.
"This is better than an in vitro dish experiment,
but it's not going to perfectly replicate what's
going on inside the body in near future," Kim said.
"It will help make this whole process faster and
save a number of animals."
###
This research is supported by the National Heart,
Lung, and Blood Institute as a Program of
Excellence in Nanotechnology Award
(HHSN268201000045C), the National Cancer
Institute (NCI) (CA151884); the David H. Koch
Prostate Cancer Foundation Award in
Nanotherapeutics, and the National Institutes of
Health (NIH) (R01 EB009638 and R01CA155432).
Any conclusions or opinions are those of the
authors and do not necessarily represent the
official views of the sponsoring agencies.
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