Brigham Hospital. US: Nanometer-sized “drones” that deliver a special type of healing
molecule to fat deposits in arteries could become a new way to prevent
heart attacks caused
by atherosclerosis, according to a study in pre-clinical models by
scientists at Brigham and Women’s Hospital (BWH) and Columbia University
Medical Center.
These findings are published in the February 18th online issue of Science Translational Medicine.
Although current treatments have reduced the number of deaths from
atherosclerosis-related disease, atherosclerosis remains a dangerous
health problem:
Atherosclerosis of the coronary arteries is the #1 killer of women
and men in the U.S., resulting in one out of every four deaths. In the
study, targeted
biodegradable nano ‘drones’ that delivered a special type of drug
that promotes healing ('resolution') successfully restructured
atherosclerotic plaques in
mice to make them more stable. This remodeling of the plaque
environment would be predicted in humans to block plaque rupture and
thrombosis and thereby
prevent heart attacks and strokes.
“This is the first example of a targeted nanoparticle technology
that reduces atherosclerosis in an animal model,” said co-senior author
Omid Farokhzad,
MD, associate professor and director of the Laboratory of
Nanomedicine and Biomaterials at BWH and Harvard Medical School (HMS).
“Years of research and
collaboration have culminated in our ability to use nanotechnology
to resolve inflammation, remodel and stabilize plaques in a model of
advanced
atherosclerosis.”
In this study, targeted nanomedicines made from polymeric building
blocks that are utilized in numerous FDA approved products to date, were
nanoengineered
to carry an anti-inflammatory drug payload in the form of a
biomimetic peptide. Furthermore, this peptide was derived from one of
the body’s own natural
inflammatory-resolving proteins called Annexin A1. The way the
nanomedicines were designed enabled this biological therapeutic to be
released at the target
site, the atherosclerotic plaque, in a controlled manner.
In mouse models with advanced atherosclerosis, researchers
administered nanomedicines and relevant controls. Following five weeks
of treatment with the
nanomedicines, damage to the arteries was significantly repaired and
plaque was stabilized.
Specifically, researchers observed a reduction of reactive oxygen
species; increase in collagen, which strengthens the fibrous cap; and
reduction of the
plaque necrotic core, and these changes were not observed in
comparison with the free peptide or empty nanoparticles.
“Many researchers are trying to develop drugs that prevent heart
attacks by tamping down inflammation, but that approach has some
downsides,” said
co-senior author Ira Tabas, MD, Richard J. Stock professor of
Medicine (Immunology) and professor of Pathology & Cell Biology at
Columbia. “One is that
atherosclerosis is a chronic disease, so drugs are taken for years,
even decades. An anti-inflammatory drug that is distributed throughout
the entire body
will also impair the immune system’s ability to fight infection.”
That might be acceptable for conditions that severely affect quality of
life, like
rheumatoid arthritis, but “using this approach to prevent a heart
attack that may never happen may not be worth the risk.”
In addition, it’s not enough to deliver an anti-inflammatory drug to
the plaques, said Columbia associate research scientist Gabrielle
Fredman, PhD, one of
the study’s lead co-authors. “Atherosclerosis is not only
inflammation; there’s also damage to the arterial wall. If the damage
isn’t repaired, you may not
prevent heart attacks.”
The targeted nanomedicines used in this current study were
engineered by researchers at BWH. Following preliminary
proof-of-principle studies at Columbia
University in models of inflammation, they were further tested in a
clinically relevant disease model in mice and were shown to be capable
of maneuvering
through the blood circulation, and traversing leaky regions through
to the inside of the plaques, as was demonstrated by fluorescence
microscopy imaging of
the plaque lesions.
Researchers note that in addition to their specific ‘sticky’
surfaces, their small sub-100 nanometer size is also a key property that
facilitates the
retention and accumulation of these nanoparticles within the
plaques. These nanoparticles are 1000 times smaller than the tip of a
single human-hair
strand.
“These nanomedicines are developed using biodegradable polymers that
can break-up over time in the body using the bodies natural mechanisms,
and can be
nanoengineered using scale-able chemistries and nanotechnologies,
which ultimately can facilitate their rapid translation to the clinic,”
said co-lead
author Nazila Kamaly, PhD, instructor in the Laboratory of
Nanomedicine and Biomaterials at BWH and HMS.
Researchers caution that although plaques in mice look a lot like
human plaques, mice do not have heart attacks, so the real test of the
nanoparticles will
not come until they are tested in humans. “In this study, we’ve
shown, for the first time, that a drug that promotes resolution of
inflammation and repair
is a viable option, when the drug is delivered directly to plaques
via nanoparticles,” said Tabas. To be ready for testing in humans, the
team plans to
fine-tune the nanoparticles to optimize drug delivery and to package
them with more potent resolution-inducing drugs. "We think that we can
obtain even
better delivery to plaques and improve healing more than with the
current peptides,” , he said.
Farokhzad and colleagues have considerable expertise with
bench-to-bedside translation of nanotechnologies for medical
applications, and foundational work
done in part by his team has led to the development and first in
human testing of a targeted nanoparticle capable of controlling drug
release for treatment
of cancers, and the first in human testing of a targeted
nanoparticle vaccine capable of orchestrating an immune response to
facilitate smoking cessation
and relapse prevention.
“The inflammation resolving targeted nanoparticles have shown
exciting potential not only for the potential treatment of
atherosclerosis as described here,
but also other therapeutic areas including wound repair, for example, as
described in the Feb. 9 online issue of Journal of Clinical Investigation,
in addition to other applications currently underway with our
collaborators,” Farokhzad said. “I’m optimistic
that with additional animal validation we will also consider the
human testing of the inflammation resolving targeted nanoparticles for a
myriad of unmet
medical needs—these are exciting times in medicine and the future of
nanomedicine is incredibly bright.”
This work was supported by a Program of Excellence in Nanotechnology
(PEN) Award, HHSN268201000045C, from the NIH (O.C.F., I.T.); NIH
Pathway to
Independence K99 grant HL119587 (G.F.); the Welcome Trust Programme
Grant (086867/Z/08); NIH grants CA151884 and the David Koch-Prostate
Cancer Foundation
Award in Nanotherapeutics (O.C.F.); and NIH grants
HL106019
,
HL075662
, and
HL054591
(I.T.). Other contributing authors include Mauro Perretti, Jaclyn
Milton, Stefano Spolitu, Devram Ghorpade, Raymond Chiasson and George
Kuriakose.
O.C.F. discloses his financial interest in BIND Biosciences, Selecta
Biosciences, and Blend Therapeutics, three biotechnology companies
developing
nanoparticle technologies for medical applications. BIND, Selecta,
and Blend did not support the research in this study, and currently
these companies have
no rights to any technology or intellectual property developed as
part of this research.