The shear-activated nanotherapeutic breaks apart and releases its drug when it encounters regions of vascular narrowing. |
Researchers
at the Wyss Institute for Biologically Inspired Engineering at Harvard
University have developed a novel biomimetic strategy that delivers
life-saving nanotherapeutics directly to obstructed blood vessels,
dissolving blood clots before they cause serious damage or even death.
This new approach enables thrombus dissolution while using only a
fraction of the drug dose normally required, thereby minimizing bleeding
side effects that currently limit widespread use of clot-busting drugs.
The research findings, which were published online today in the journal Science,
have significant implications for treating major causes of death, such
as heart attack, stroke and pulmonary embolism, that are caused by acute
vascular blockage by blood thrombi.
The
inspiration for the targeted vascular nanotherapeutic approach came
from the way in which normal blood platelets rapidly adhere to the
lining of narrowed vessels, contributing to the development of
atherosclerotic plaques. When vessels narrow, high shear stresses
provide a physical cue for circulating platelets to stick to the vessel
wall selectively in these regions. The vascular nanotherapeutic is
similarly about the size of a platelet, but it is an aggregate of
biodegradable nanoparticles that have been coated with the clot-busting
drug, tissue plasminogen activator (tPA). Much like when a wet ball of
sand breaks up into individual grains when it is sheared between two
hands, the aggregates selectively dissociate and release tPA-coated
nanoparticles that bind to clots and degrade them when they sense high
shear stress in regions of vascular narrowing, such as caused by blood
clot formation.
Disruption
of normal blood flow to the heart, lung, and brain due to thrombosis is
one of the leading causes of death and long-term adult disability in
the developing world. Today, patients with pulmonary embolism, strokes,
heart attacks and other types of acute thrombosis leading to
near-complete vascular occlusion, are most frequently treated in an
acute care hospital setting using systemic dosages of powerful
clot-dissolving drugs. Because these drugs can cause severe and often
fatal bleeding as they circulate freely throughout the body, the size of
the dosage given to any patient is limited because efficacy must be
balanced against risk.
The
new shear-activated nanotherapeutic has the potential to overcome these
efficacy limitations. By targeting and concentrating drug at the
precise site of the blood vessel obstruction, the Wyss team has been
able to achieve improved survival in mice with occluded lung vessels
with less than 1/50th of the normal therapeutic dose, which should
translate into fewer side effects and greater safety. This raises the
possibility that, in the future, an emergency technician might be able
immediately administer this nanotherapeutic to anyone suspected of
having a life-threatening blood clot in a vital organ before the patient
even reached the hospital.
Commenting
on the work, Ingber noted that “the vascular nanotherapeutic we
developed that selectively becomes activated in regions of high shear
stress, much like living platelets do, is a wonderful example of how we
at the Wyss Institute take inspiration from biology, and how biomimetic
strategies can lead to new and unexpected solutions to age-old problems
that existing technologies can’t address.”
Shear-Activated Nanotherapeutics for Drug Targeting to Obstructed Blood Vessels
Source: Harvard University
Filed Under: Drug Discovery
