Encapsulation and release of plasminogen activator from biodegradable magnetic microcarriers

There are a number of therapies available to recanalize occluded arteries. However, even though proven beneficial, these approaches are not without significant shortcomings. Previous research showed that by encapsulating therapeutic thrombolytic enzymes in liposomic formulations, the reperfusion times in vivo were significantly lower than for administration of free thrombolytic. Like liposomes, biodegradable, diblock polymers of poly(lactic acid)–poly(ethylene glycol) (PLA–PEG) have been shown to have therapeutic benefit as delivery vehicles for a variety of drug delivery concepts. We report on new formulations based on tissue plasminogen activator (tPA) encapsulated in magnetic, PLA–PEG microcarriers. We studied the tPA encapsulation efficiency, loading, and release after varying the molecular weight of polymer, carrier size, tPA solution composition, and use of ultrasound to enhance release. We loaded 3.3–9.4 wt% tPA and 12–17 wt% magnetite into the carriers, depending on the exact formulation. The release of tPA was complete 20 min after reconstitution. Ultrasound insonation failed to enhance tPA release rates in smaller carriers but significantly enhanced release in larger carriers. With these formulations, we should be able to achieve lytic concentrations if we can magnetically concentrate 5 mg of carrier within about 11 ml of blood volume near the clot.