Harvard University. 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
preclinical models by scientists at Harvard Medical School, Brigham and
Women’s Hospital and Columbia University. These findings were published
Feb. 18 in Science Translational Medicine.
Although current treatments have reduced the number of deaths from
atherosclerosis-related disease, the condition remains a dangerous
health problem. Atherosclerosis of the coronary arteries is the leading
killer of women and men in the U.S., accounting for one out of every
four deaths. In this study, targeted biodegradable nano “drones” that
delivered a special type of drug to promote healing successfully
restructured atherosclerotic plaques in mice to make them more stable.
This remodeling of the plaque environment is predicted in humans to
block plaque rupture and thrombosis, thereby preventing 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, HMS associate professor of anaesthesia at Brigham and
Women’s Hospital. “Years of research and collaboration have culminated
in our ability to use nanotechnology to resolve inflammation and remodel
and stabilize plaques in a model of advanced atherosclerosis.”
Farokhzad is also director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women’s.
In this study, targeted nanomedicines made from polymeric building
blocks that are used in numerous FDA-approved products to date, were
nanoengineered to carry an anti-inflammatory drug payload in the form of
a biomimetic peptide, a molecule that resembles naturally occurring
building blocks of proteins already found in the body. Furthermore, this
peptide was derived from one of the body’s own natural
inflammatory-resolving proteins, Annexin A1. The nanomedicines were
designed to enable 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; an increase in collagen, which strengthens the fibrous cap; and
a reduction of the plaque necrotic core. 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,
the Richard J. Stock Professor of Medicine (Immunology) and professor
of pathology and cell biology at Columbia University. “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, Tabas said, 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, 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 Brigham and Women’s. Following preliminary
proof-of-principle studies at Columbia 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 of traversing leaky regions 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, the nanomedicines’ 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 1,000 times
smaller than the tip of a single strand of human hair.
“These nanomedicines are developed using biodegradable polymers that
can break up over time in the body using the body’s natural mechanisms,
and can be nanoengineered using scalable chemistries and
nanotechnologies, which ultimately can facilitate their rapid
translation to the clinic,” said co-lead author Nazila Kamaly, HMS instructor in anaesthesia in the Laboratory of Nanomedicine.
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,” Tabas said.
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.
“The inflammation-resolving targeted nanoparticles have shown
exciting potential not only for the treatment of atherosclerosis as
described here, but also in other therapeutic areas including wound
repair, 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 Wellcome 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.).
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.
Adapted from a Brigham and Women’s Hospital and Columbia University Medical Center news release.