OC 53.1 - Magnetically Powered Microwheels Enhance Thrombolysis in a Murine Model of Ischemic Stroke

Background: We previously developed magnetically powered microbots called microwheels (Tasci., Nat. Commun., 2016). They consist of superparamagnetic microparticles that assemble into disc like shapes in the presence of rotating magnetic fields (1-10 mT) and roll along surfaces at high speeds (>100 µm/s). Recently we showed microwheels that co-deliver tPA and plasminogen enhance the rate of fibrinolysis in vitro by 50-fold compared to therapeutic concentrations of tPA (Disharoon, JTH, 2021).

Aims: The objective of this study is to demonstrate the efficacy of tPA-microwheels in vivo.

Methods: Mice were injected with Rose Bengal and the proximal branch of the middle cerebral artery was exposed to a 530nm LED for 10 min to form a thrombus. Then tPA functionalized superparamagnetic particles (1 µm) were injected into the tail vein and targeted to the thrombus using an external magnetic field. Reperfusion time was measured by laser doppler. The size of the infarct was measured with 2,3,5-triphenyltetrazolium chloride (TTC) 24 h after thrombus formation.

Results: The reperfusion time and degree of reperfusion show that tPA-microwheels can lyse thrombi at 1/10th the typical soluble tPA dose (25 µg) (Figure 1A). Concentrating the tPA-microwheels proximal to the thrombi with a magnetic field reduces the reperfusion times by half. By rotating the magnetic field, and thereby the microwheels, lysis rate was further enhanced. Infarct volumes were reduced by 18.4% when treated with tPA-microwheels compared to no treatment (Figure 1B).

Conclusion(s): tPA-functionalized microwheels can lyse thrombi in a murine model of ischemic stroke. Using magnetic fields to concentrate tPA-microwheels at the thrombus interface allows for a systemic dose well below the therapeutic dose of tPA, which may reduce bleeding risk. Rotating magnetic fields further enhanced thrombolysis, which we speculate based in our in vitro experiments, is a function of improved penetration into the thrombus.