Clots can be treated with a drug called tissue plasminogen activator (tPA) which dissolves them to clear blocked blood vessels and re-establish blood flow. However, tPA can cause life-threatening off-target bleeding – including on the brain - and lasts only a few minutes in circulation. This means it often requires repeated doses, further increasing the risks involved.
The Imperial team found that by encasing tPA in the newly developed nanocapsules, the drug 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 clots, release the tPA payload and dissolve the blockage. The work, published in Science Advances, detailed the success of the technique in the lab, with further investigation required to establish its viability in living organisms.
"We've found a way to make a clot-busting drug more precisely targeted, potentially enhancing efficacy and reducing catastrophic side effect,” said study co-author Professor Simon Thom, from Imperial's National Heart and Lung Institute.
“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."
Blood clots are formed of platelets which link together when activated. They are held together with proteins called fibrinogen that bind to activated platelets and form 'bridges' between them. The new nanocapsule, snappily titled tPA-cRGD-PEG-NV, mimics fibrinogen so that it seeks out clots within blood vessels.
The researchers tested it on healthy human blood both in petri dishes and simulated blood vessels. 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.
"We combined experimental and computational work to characterise this nanocapsule,” said co-corresponding author Professor Xiao Yun Xu, from Imperial's Department of Chemical Engineering.
“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."