Intravenous Targeted Microbubbles Carrying Urokinase versus Urokinase Alone in Acute Peripheral Arterial Thrombosis in a Porcine Model

Abstract

Standard therapy in acute peripheral arterial occlusion consists of intra-arterial catheter-guided thrombolysis. As microbubbles may be used as a carrier for fibrinolytic agents and targeted to adhere to the thrombus, we can theoretically deliver the thrombolytic medication locally following simple intravenous injection. In this intervention-controlled feasibility study, we compared intravenously administered targeted microbubbles incorporating urokinase and locally applied ultrasound, with intravenous urokinase and ultrasound alone. In 9 pigs, a thrombus was created in the left external iliac artery, after which animals were assigned to either receive targeted microbubbles and urokinase (UK+tMB group) or urokinase alone (UK group). In both groups, ultrasound was applied at the site of the occlusion. Blood flow through the iliac artery and microcirculation of the affected limb were monitored and the animals were euthanized 1 hr after treatment. Autopsy was performed to determine the weight of the thrombus and to check for adverse effects. In the UK+tMB group (n=5), median improvement in arterial blood flow was 5mL/min (range 0-216). Improvement was seen in 3 of these 5 pigs at conclusion of the experiment. In the UK group (n=4), median improvement in arterial blood flow was 0mL/min (-10 to 18), with slight improvement in 1 of 4 pigs. Thrombus weight was significantly lower in the UK+tMB group (median 0.9383g, range 0.885-1.2809) versus 1.5399g (1.337-1.7628; P=0.017). No adverse effects were seen. Based on this experiment, minimally invasive thrombolysis using intravenously administered targeted microbubbles carrying urokinase combined with local application of ultrasound is feasible and might accelerate thrombolysis compared with treatment with urokinase and ultrasound alone.