07 June 2021

A new method of delivery developed by British scientists could avoid the risk of side effects from tissue plasminogen activator (tPA).

tPA is currently the most widely used thrombolytic drug, used to prevent strokes and heart attacks. However, the clinical use of tPA is limited by haemorrhagic side effects, and a short window of effectiveness.

Dr Rongjun Chen of Imperial College London and colleagues created a nano-vesicle that specifically delivers the drug to the thrombus, or blood clot. It was inspired by fibrinogen binding to activated platelets, they write.

When a thrombus forms, platelets are activated and molecules on their surface can bind to specific peptide sequences of fibrinogen. The scientists packaged up tPA into lipid nanovesicles coated with this peptide sequence, and a biocompatible version of polyethylene to increase its stability.

The team showed, using human blood in microfluidic devices in the lab, that the nanovesicles bind specifically to activated platelets and release their tPA cargo at the site of the blood clot. This led to the breakup of the fibrinogen and the thrombi.

"Our experiments with human blood demonstrated its highly selective binding to activated platelets and efficient tissue plasminogen activator release at a thrombus site," they write in the journal Science Advances.

Dr Chen commented: “Tissue plasminogen activator 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.”

As well as their experimental research, the team developed a computer model to simulate how the encapsulated tPA might act in circulating blood. Using this model, they determined that the time it took to dissolve clots with the nanovesicle-encapsulated tPA was similar to that with unencapsulated tPA.

Co-author Professor Xiao Yun Xu added: “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.”


Source:

Huang Y, Gu B, Salles-Crawley II, Taylor KA, Yu L, Ren J, Liu X, Emerson M, Longstaff C, Hughes AD, Thom SA, Xu XY, Chen R. (2021) “Fibrinogen-mimicking, multiarm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy.” Science Advances, doi: 10.1126/sciadv.abf9033

 

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