An in vitro Model System for Evaluating Remote Magnetic Nanoparticle Movement and Fibrinolysis

Background: Thrombotic events continue to be a major cause of morbidity and mortality worldwide. Tissue plasminogen activator (tPA) is used for the treatment of acute ischemic stroke and other thrombotic disorders. Use of tPA is limited by its narrow therapeutic time window, hemorrhagic complications, and insufficient delivery to the location of the thrombus. Magnetic nanoparticles (MNPs) have been proposed for targeting tPA delivery. It would be advantageous to develop an improved in vitro model of clot formation, to screen thrombolytic therapies that could be enhanced by addition of MNPs, and to test magnetic drug targeting at human-sized distances. Methods: We utilized commercially available blood and endothelial cells to construct 1/8th inch (and larger) biomimetic vascular channels in acrylic trays. MNP clusters were moved at a distance by a rotating permanent magnet and moved along the channels by surface walking. The effect of different transport media on MNP velocity was studied using video photography. MNPs with and without tPA were analyzed to determine their velocities in the channels, and their fibrinolytic effect in wells and the trays. Results: MNP clusters could be moved through fluids including blood, at human-sized distances, down straight or branched channels, using the rotating permanent magnet. The greatest MNP velocity was closest to the magnet: 0.76 +/- 0.03 cm/sec. In serum, the average MNP velocity was 0.10 +/- 0.02 cm/sec. MNPs were found to enhance tPA delivery, and cause fibrinolysis in both static and dynamic studies. Fibrinolysis was observed to occur in 85% of the dynamic MNP + tPA experiments. Conclusion: MNPs hold great promise for use in augmenting delivery of tPA for the treatment of stroke and other thrombotic conditions. This model system facilitates side by side comparisons of MNP-facilitated drug delivery, at a human scale.