Glycoprotein VI Functionalized Drug Carriers for Targeted Drug Delivery to Atherothrombosis Sites

Cardiovascular disease is one of the leading causes of death in the western world. Atherothrombosis, where a thrombus is formed in atherosclerotic sites, due to collagen exposure followed by platelets adhesion, activation and aggregation. The initial step of platelet adhesion and activation is mediated mainly through the collagen receptor found on platelets, Glycoprotein VI (GPVI). In pre-clinical studies and clinical trials, the soluble, dimeric form of GPVI have been shown to inhibit thrombus formation, with little effect on hemostasis by adhering to collagen at atherothrombotic diseased sites.

Here we engineer GPVI functionalized polymeric nanoparticle-based drug carriers and show that by proper design such GPVI-nanoparticles can efficiently and specifically target atherothrombotic diseased sites while enduring physiological flow.

We first tested the adhesion capabilities of 0.2, 2 µm sized GPVI coated particles under flow in microfluidic devices. We showed that under physiological shear levels (1-40 dyne/cm²), 0.2 and 2 µm particles exhibit more than 60- and 10-fold binding capability compared to control (BSA functionalized particles), respectively. We then studied the 0.2 µm GPVI particle deposition onto collagen in a real size LAD (left anterior descending) stenotic artery in vitro model under pulsatile flow condition and in a mice carotid in vivo injury model with and without a stenosis. We found that the particles adhere better in the stenotic injury conditions where high shear prevail. Altogether our results suggest that GPVI-functionalized nanoparticles can be designed to serve as a potential drug carrier to target specifically atherothrombotic sites.