August 11, 2003
The Trojan Clot-Buster: Drug-Coated
Red Blood Cells Destroy Blood Clots From Within
(Philadelphia, PA) - Thrombosis -
the formation of internal blood clots - is a common
cause of complications and even death following surgery.
To create a better means of preventing thrombosis, researchers
at University of Pennsylvania School of Medicine coated
red blood cells (RBCs) with tissue plasminogen activator
(tPA), a clot-dissolving drug commonly used as an emergency
treatment for stroke. When given alone, tPA has a short
life span in circulation and has the potential to cause
serious bleeding as it diffuses out of the bloodstream.
The RBC/tPA combo, however, lasts ten times longer in
the bloodstream than free-floating tPA and decreases
the likelihood of excess bleeding, according to a new
study.
"The idea of coating red blood cells with tPA was to
create a Trojan Horse, a vehicle for sneaking tPA into
the bloodstream that could not only add to the drug's
longevity, but would also allow it to be incorporated
into a growing blood clot. RBC/tPA can dissolve blood
clots from within," said Vladimir R, Muzykantov, MD,
PhD, associate professor in Penn's Department of Pharmacology
and author of the study. "Our research shows that the
Trojan Horse approach converts tPA into a potent killer
of nascent blood clots, one that would pose a much smaller
risk of causing internal bleeding."
In the August issue of Nature Biotechnology, Muzykantov
and his colleagues demonstrate in animal models how
the marriage of red blood cells and tPA has the potential
of safely preventing thrombosis following surgery and
as a therapeutic for victims of heart attack or stoke.
"If developed for humans, the RBC/tPA method could
provide an ideal way of delivering clot-busting drugs,
with fewer side effects," said Muzykantov. "In theory,
patients could donate blood before surgery and receive
their own cells bound to tPA following surgery, providing
a safer alternative to blood-thinning medication."
Research has shown that preventing thrombosis helps
to reduce mortality and morbidity in many diseases.
Unfortunately, current clot-busting drugs have the tendency
to cause excessive bleeding, either by causing bleeding
outside of the blood vessels or by removing pre-existing
and, perhaps, beneficial blood clots. According to the
Penn researchers, RCB/tPA spares existing blood clots
and is too large to cause damage outside of the bloodstream.
To coat red blood cells with tPA, Muzykantov and his
colleagues capitalized on the 'stickiness' of streptavidin-biotin,
a protein complex used in laboratories to study molecular
interactions. Streptavidin forms an incredibly tight
bond to a tiny molecule called biotin, so the researchers
'biotinylated' tPA and RBCs and used streptavidin to
link them together. According to the researchers, the
technique may provide a safe way of extending the longevity
and safety of drugs within the circulatory system.
"Red blood cells can travel hundreds of kilometers
throughout the blood vessels during their 100-or so
day life-span. That fact alone makes the idea of RBC-bound
therapeutics very interesting," said Muzykantov. "Moreover,
red blood cells are relatively large, which makes it
very difficult for drugs bound to them to burrow their
way out of the bloodstream where they could potentially
do damage."
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