A platelet-mediated paradigm for the targeted delivery of microencapsulated, clot-augmenting biotherapeutics

Abstract

Reported herein is a paradigm-shifting, targeted drug delivery system that leverages the patient’s own platelets to sense and actuate targeted delivery of a clot-augmenting therapeutic to a site of vascular injury. In this system, platelets target microencapsulated drugs through their natural aggregation behavior in the clot formation process and then deliver the drug by physically rupturing the microcapsule through contractile forces exerted during clot contraction. This cell-mediated, targeted drug delivery system utilizes polyelectrolyte multilayer capsules that hybridize with the patient’s own platelets upon intravenous administration and rupture upon platelet contraction, enabling the targeted and controlled “burst” release of an encapsulated biotherapeutics. As platelets are the “first responders” in the blood clot formation process, this platelet-hybridized system is ideal for the targeted delivery of clot augmenting biotherapeutics wherein immediate therapeutic efficacy is required. As proof-of-concept, we tailored this system to deliver the pro-clotting biotherapeutic, factor VIII (fVIII) for hemophilia A patients who have developed inhibitory anti-fVIII antibodies. The polyelectrolyte multilayer capsules physically shield the encapsulated fVIII from the patient’s inhibitors during circulation, preserving its bioactivity until it is delivered at the target site via platelet contractile force. Using an in vitro microfluidic vascular injury model with fVIII-inhibited blood, we demonstrate a 3.8x increase in induced fibrin formation using capsules loaded with fVIII at a concentration an order of magnitude lower than that used in systemic delivery. We further demonstrate that clot formation occurs 18 minutes faster when fVIII loaded capsules are used compared to systemic delivery at the same concentration. Because platelets are integral in the pathophysiology of thrombotic disorders, cancer, and innate immunity, this paradigm-shifting smart drug delivery system can be similarly applied to these diseases.