Imperial researchers have designed drug delivery nanocapsules
that could reduce the side effects of a major blood clot
dissolving drug.
Tested on human blood in the lab, the selective nanocapsules
could reduce the side effects of a major blood clot dissolving
drug, which include bleeding on the brain. If confirmed with
animal tests, the nanocapsules could also make the drug more
effective at lower doses.
Blood clots, also known as thrombi, are a key cause of strokes
and heart attacks which are leading causes of death and
ill-health worldwide. They can be treated with a clot dissolving
drug called tissue plasminogen activator (tPA) which disrupts
clots to clear the blocked blood vessel and re-establish blood
flow.
However, tPA can cause life-threatening off-target bleeding, and
lasts only a few minutes in circulation, so often requires
repeated doses, which further increases the risk of bleeding.
Consequently, it is only used for a minority of potentially
eligible patients.
Now, researchers at Imperial College London have found that by
encasing tPA in newly designed tiny capsules, it can be targeted
more specifically to harmful blood clots with an increased
circulation time. They designed the nanocapsules to attach to
activated platelets present in thrombi, release the tPA payload
and dissolve clots.
Lead author Dr Rongjun Chen of Imperial’s Department of Chemical
Engineering said: “tPA has a narrow window between desired effect
and side effects, so we have wrapped it in a package that extends
this therapeutic window and minimises the required dose. Our
results are exciting but animal and clinical studies are required
for validation.”
Blood clots are made of blood cells called platelets which link
together when activated. These platelets are held together with
proteins called fibrinogen which bind to activated platelets and
form ‘bridges’ between them. The new nanocapsule, called
tPA-cRGD-PEG-NV, mimics fibrinogen so that it seeks out clots
within blood vessels.
The researchers tested this on healthy human blood under both
static conditions, where still blood was tested in petri dishes,
and physiological flow conditions in a simulated blood vessel. To
test flow conditions, they designed a computer model to simulate
how the encapsulated tPA might act in circulating blood.
They found that the nanocapsules were highly selective in binding
to activated platelets and that the time it took to dissolve
clots was similar to that with unencapsulated tPA.
Co-corresponding author Professor Xiao Yun Xu of Imperial’s
Department of Chemical Engineering said: “We combined
experimental and computational work to characterise this
nanocapsule. To build our computer model we needed a mechanistic
understanding of the interplay between the physical and
biochemical processes of blood clot dissolving. The model could
be very useful in animal and clinical trials of this potential
nanomedicine, as well as in predicting optimal dosing for
patients.”
The purpose-built computer model was able to simulate nanocapsule
transport to the clot site, its release of tPA, and its
dissolution of clots. Professor Xu added: “Our simulation
illustrated the potential in predicting the outcome of blood clot
treatments in clinically relevant scenarios.”
Co-author Professor Simon Thom of Imperial’s National Heart and
Lung Institute said: “We’ve found a way to make a clot-busting
drug more precisely targeted, potentially enhancing efficacy and
reducing catastrophic side effects. This promising work
demonstrates the activity of nano-encapsulated tPA in a
laboratory setting and paves the way for safer delivery of drugs
with otherwise harmful side effects. Research is now needed in
whole organisms to determine the capsule’s effectiveness in a
more realistic setting.”
Next the researchers will test the encapsulated tPA in animals to
see how it performs in whole organisms, especially for increasing
circulation time and checking the computer model’s ability to
predict clot busting in a realistic setting. Dr Chen added: “Once
fully validated, the selective nanocapsules and the computer
model could serve as powerful platforms for developing
clot-busting nanomedicines.”
This work was funded by the National Institute for Health
Research (NIHR) Imperial Biomedical Research Centre based at
Imperial College Healthcare NHS Trust, Imperial College London,
Department of Health and Social Care, and the Engineering and
Physical Sciences Research Council (EPSRC).
