(238e) Polymeric Drug Carriers Modulate Platelet Adhesion in Thromboinflammation

Introduction: Platelets contribute to health through maintaining hemostasis by plugging interruptions in vasculature and disease through contributing to dysregulated, pathogenic thrombosis. While platelets have long been known to play a significant role in thrombus development, more recent work identified other cell types, including cells lining blood vessels (endothelial cells) and different white blood cell (leukocyte) populations, that also play a role in thrombus formation. More specifically, over the past two decades, the intersection of thrombosis and inflammation has developed into a singular concept of ‘thromboinflammation’ to better characterize conditions like sickle cell disease, acute lung injury in COVID-19, and venous thrombosis. Under thromboinflammatory conditions, leukocytes and platelets can form aggregates and be recruited to growing thrombi either through interactions between leukocytes and the endothelium or between platelets and the endothelium or subendothelium.

Previous work demonstrated that model particulate drug carriers can be utilized to decrease leukocyte adhesion to an inflamed endothelium in vitro and in vivo in a murine model of acute lung injury. However, polymeric particles’ impact on platelet adhesion in blood flow under thromboinflammatory conditions has yet to be fully explored.

Materials and methods: We developed an in vitro flow-based system to best represent the thromboinflammatory environment in vivo. Human whole blood is perfused via a syringe pump over an activated, damaged endothelial cell monolayer in a parallel-plate flow channel, representing vascular injury with underlying inflammation. Before blood flow, platelets are stained and activated to facilitate the development of leukocyte-platelet aggregates. Immediately before blood flow, model nano- or micro-sized particulate drug carriers are added to whole blood. After blood flow, the flow chamber is rinsed, and both platelet and leukocyte adhesion to the damaged endothelium quantified using fluorescent and transmitted light microscopy. Platelet and leukocyte adhesion is compared to controls containing no particles.

Results and conclusions: The inclusion of particulate drug carriers in blood flow can decrease the level of platelet adhesion in a model of thromboinflammation, and the magnitude of platelet adhesion decrease is dependent on several particle variables, including particle size, concentration, and inclusion of endothelium-specific targeting ligands. Further, we demonstrated that platelet adhesion reduction with drug carrier particles is due to interactions between particles and leukocytes. Overall, this study helped elucidate new information on the interactions between particles and platelets in blood flow. Further, this study can help develop a novel method of modulating platelet adhesion in blood flow under inflammatory conditions.