Thrombus-targeted perfluorocarbon-containing liposomal bubbles for enhancement of ultrasonic thrombolysis: in vitro and in vivo study.

BACKGROUND: External low-frequency ultrasound (USD) in combination with microbubbles has been reported to recanalize thrombotically occluded arteries in animal models. OBJECTIVE: The purpose of this study was to examine the enhancing effect of thrombus-targeted bubble liposomes (BLs) developed for fresh thrombus imaging during ultrasonic thrombolysis. METHODS: In vitro: after the administration of thrombus-targeted BLs or non-targeted BLs, the clot was exposed to low-frequency (27 kHz) USD for 5 min. In vivo: Rabbit iliofemoral arteries were thrombotically occluded, and an intravenous injection of either targeted BLs (n = 22) or non-targeted BLs (n = 22) was delivered. External low-frequency USD (low intensity, 1.4 W cm(-2) , to 12 arteries, and high intensity, 4.0 W cm(-2) , to 10 arteries, for both the targeted BL group and the non-targeted BL group) was applied to the thrombotically occluded arteries for 60 min. In another 10 rabbits, recombinant tissue-type plasminogen activator (rt-PA) was intravenously administered. RESULTS: In vitro: the weight reduction rate of the clot with targeted BLs was significantly higher than that of the clot with non-targeted BLs. In vivo: TIMI grade 3 flow was present in a significantly higher number of rabbits with USD and targeted BLs than rabbits with USD and non-targeted BLs, or with rt-PA monotherapy. High-intensity USD exposure with targeted BLs achieved arterial recanalization in 90% of arteries, and the time to reperfusion was shorter than with rt-PA treatment (targeted BLs, 16.7 ± 5.0 min; rt-PA, 41.3 ± 14.4 min). CONCLUSIONS: Thrombus-targeted BLs developed for USD thrombus imaging enhance ultrasonic disruption of thrombus both in vitro and in vivo.