Development and assessment of supercharged platelets as a novel drug delivery mechanism for promoting cardiac regeneration

Ischaemic heart disease is the leading cause of death globally, with post-myocardial infarction heart failure significantly reducing quality of life and life expectancy. Current treatment strategies focus primarily on alleviating symptoms and reducing the burden on the damaged heart, failing to address the root cause—myocardial injury and necrosis. In contrast, a regenerative medicine approach targets underlying causes, aiming to repair or replace damaged cardiac tissue to restore heart functionality. Platelets, small, anucleate and granular cells in the blood, are primarily known for their role in blood clot formation at sites of vessel damage. However, they are also a highly promising vehicle for use in targeted drug delivery. Platelets naturally accumulate in infarcted areas of the heart, and their granules provide an ideal storage compartment for therapeutic proteins. Upon activation, these granules release their contents in a targeted manner, allowing precise, sitespecific delivery. These features possessed by platelets confers upon them the necessary means to store, transport and deliver cardiac regenerative factors to the ischaemic heart. Leveraging these unique features, this project explores the production of ‘supercharged’ platelets loaded with the regenerative factors thymosin β4 (TB4), fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA). These supercharged platelets aim to serve as a novel regenerative treatment for ischaemic heart disease, driving tissue repair and functional recovery in the injured heart by promoting cardiomyocyte proliferation and neovascularisation processes. A lentiviral approach was employed for the genetic engineering of megakaryocytes, the precursor cells of platelets. Lentiviral plasmids, designed for the targeted delivery of proteins to the megakaryocyte and platelet α-granules, were modified to incorporate FGF2, VEGFA and TB4. Subsequently generated lentivirus successfully induced overexpression of the target proteins (FGF2, VEGFA and TB4) in the megakaryocyte and platelet α-granules. These supercharged megakaryocytes and platelets maintained their ability to activate in response to classical agonists, demonstrating release of the therapeutic proteins during degranulation. Utilising an in vivo mouse model of cardiac ischaemia reperfusion, the intravenous administration of supercharged platelets demonstrated a functional recovery effect, highlighting their future potential as a regenerative therapy for ischaemic heart disease. This work illustrates a proof of concept for the use of supercharged platelets as a novel drug delivery system to promote cardiac regeneration following myocardial infarction.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Mason, Samantha

Advisor dc:contributor.advisor

• Ghevaert, Cedric

• platelets
• regenerative medicine
• myocardial infarction
• novel therapeutics

Licence

• https://www.repository.cam.ac.uk/bitstreams/160cb2bc-d8b2-439c-8b39-8b707b4ada58/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.122877

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/391945