Plasminogen Activator Loaded Magnetic Carriers for Stroke Therapy: A Mass Balance Feasibility Evaluation

Systemic or catheter-induced thrombolysis is current standards employed in acute stroke therapy; however, significant side effects reduce both the benefit-risk ratio for the individually-treated person as well as the broader applicability of these potentially life-saving procedures. The new thrombolysis method proposed here, based on nanoscale bioengineering, has the potential to improve clot lysis efficiency, reduce side effects, and extend the therapeutic time window in which stroke patients are eligible for treatment. In this system, tissue plasminogen activator (tPA)-loaded magnetic carriers are injected intravenously, and concentrated at the vascular occlusion site via external magnetic fields. Triggered tPA release from the carriers is then induced through focal ultrasound inducing focal clot lysis. Using clinical and engineering boundary parameters, we have investigated the theoretical feasibility of magnetic carriers releasing sufficient amounts of tPA to achieve focal clot lysis concentrations currently observed after systemic tPA infusion. We applied conservative assumptions to our proposed system, using tPA as either Activase^®, or in a concentrated form. Simulating common human stroke syndromes, our models employ tPA-loaded magnetic carriers concentrated at the origins of the middle cerebral and internal carotid arteries to achieve the local free tPA concentrations of 1 to 4 g/mL typically obtained with current tPA therapy. We then applied our preliminary tPA encapsulation and release values, obtained from magnetic poly-lactide-co-glycolide (PLGA) carriers synthesized in our laboratories, to produce experimentally-supported simulations. Our results demonstrate that a single 100 mg intravenous injection of tPA-loaded magnetic carriers can readily exceed the local 4 g/mL tPA concentration necessary to achieve clot lysis. Furthermore, the injected total dosage of nanocrystalline iron oxide remains below the iron toxicity level for humans. Our data supports the concept that targeted, non-invasive thrombolysis using tPA-loaded magnetic carriers is a feasible treatment for stroke therapy.