Improvement of in vitro thrombolysis employing magnetically-guided microspheres

Significant shortcomings in clinical thrombolysis efficiencies and arterial recanalization rates still exist to date necessitating the development of additional thrombolysis-enhancing technologies. For example, to improve tPA-induced systemic clot lysis several supplementary treatment methods have been proposed, among them ultrasound-enhanced tissue plasminogen activator (tPA) thrombolysis which has already found some clinical applicability. The rationale of this study was to investigate whether biodegradable, magnetic spheres can be a useful adjuvant to currently existing tPA-induced thrombolysis and further enhance clot lysis results. Based on an envisioned, novel thrombolysis technology--magnetically-guided, tPA-loaded nanocarriers with triggered release of the shielded drug at an intravascular target site--we evaluated the lysis efficiencies of magnetically-guided, non-medicated magnetic spheres in various combinations with tPA and ultrasound. When tPA was used in conjunction with magnetic spheres and a magnetic field, the lysis efficiency under static, no-flow conditions improved by 1.7 and 2.7 fold for red and white clots, respectively. In dynamic lysis studies, the addition of ultrasound and magnetically-guided spheres to lytic tPA dosages resulted in both maximum clot lysis efficiency and shortest reperfusion time corresponding to a 2-fold increase in lysis and 7-fold reduction in recanalization time, respectively. Serial microscopic evaluations on histochemical sections reconfirmed that tPA penetration into and fragmentation of the clot increased with escalating exposure time to tPA and magnetic spheres/field. These results delineate the effectiveness of magnetic spheres as an adjuvant to tPA therapy accelerating in vitro lysis efficiencies beyond values found for tPA with and without ultrasound. We demonstrated that the supplementary use of magnetically-guided, non-medicated magnetic spheres significantly enhances in vitro static and dynamic lysis of red and white blood clots.