Researchers at Imperial College London have designed drug delivery nanocapsules that could reduce side effects of a major blood clot dissolving drug.
Blood clots, also known as thrombi, can be treated with a drug called tissue plasminogen activator (tPA), which dissolves clots to clear the blocked blood vessel and re-establish blood flow.
Life-threatening off-target bleeding, including on the brain, can be a side effect of tPA. The drug only lasts a few minutes in circulation, often requiring repeated doses, which further increases risk. Due to this, tPA is only used for a minority of eligible patients.
By encasing tPA in its newly designed capsules, Imperial found that the drug can be targeted more specifically to harmful blood clots with an increased circulation time.
Blood clots are made of blood cells called platelets which link together when activated. They are held together with proteins called fibrinogen which bind to activated platelets and form ‘bridges’ between them.
The new nanocapsules have been designed to attach to activated platelets present in thrombi, release the tPA payload and dissolve clots. Named tPA-cRGD-PEG-NV, the nanocapsule mimics fibrinogen so that it can seek out clots within blood vessels.
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.”
Researchers tested the nanocapsules on healthy human blood under both static conditions in petri dishes, and physiological flow conditions in a simulated blood vessel. This involved designing a computer model to simulate how the encapsulated tPA might act in circulating blood.
“We combined experimental and computational work to characterise this nanocapsule,” said Imperial Department of Chemical Engineering professor Xiao Yun Xu, co-corresponding author. “To build our computer model we needed a mechanistic understanding of the interplay between the physical and biochemical processes of blood clot dissolving.”
According to the team, the nanocapsules were found to be highly selective in binding to activated platelets, with a similar time taken to dissolve clots to that of unencapsulated tPA. Next, researchers will test the nanocapsules in animals to see how they perform in whole organisms, particularly for increasing circulation time and checking the computer model’s ability to predict clot busting in a realistic setting.