Exceeding the biochemical speed limit of fibrinolysis using magnetically powered microwheels

Abstract

The biochemical lysis of blood clots, or thrombolysis, using tissue plasminogen activator (tPA) is an effective treatment option for some types of clots, but its use has been limited by its rate of transport to and dissolution of thrombi. This thesis develops a technology that could broaden the indications for thrombolytic therapy using rotating magnetic fields to assemble and direct drug-bearing microwheels (μwheels) to target and lyse blood clots.μWheels driven by rotating magnetic fields translate because of friction against a surface. The translational velocity of μwheels depends on the thickness of the liquid gap separating them from the surface, which can be controlled by applying magnetic load and colloidal forces. μWheel rolling is characterized by stick-slip behavior where μwheels near the surface “stick” and translate rapidly and μwheels farther from the surface “slip” and translate slowly. μWheels functionalized with tPA (tPA-μwheels) can be targeted to plasma clots formed in vitro, demonstrating their utility as drug delivery vehicles. tPA-μwheels are five- to tenfold more effective than therapeutic concentrations of free tPA because they translate more rapidly than diffusion and localize near the clot at concentrations two orders-of-magnitude above the bulk. However, at high tPA concentrations, fibrinolysis rates are limited by the concentration of tPA’s substrate, plasminogen. To address this biochemical limitation, plasminogen-laden mesoporous silica nanoparticles are conjugated to tPA-μwheels (pgn-tPA-μwheels) to co-deliver both molecules. Pgn-tPA-μwheels match the maximum lysis rate achieved using artificially high concentrations of free plasminogen and tPA. By tuning the ratio of tPA to plasminogen and combining co-delivery with magnetically-driven mechanical action, we achieve lysis rates beyond what are possible using fibrinolytic agents alone.