Abstract
This paper aims to study the thrombolytic effect of low-frequency ultrasound combined with targeted urokinase-containing microbubble contrast agents on treatment of thrombosis in rabbit femoral artery; and to determine the optimal combination of parameters for achieving thrombolysis in this model. A biotinylated-avidin method was used to prepare microbubble contrast agents carrying urokinase and Arg-Gly-Asp-Ser (RGDS) peptides. Following femoral artery thrombosis in New Zealand white rabbits, microbubble contrast agents were injected intravenously, and ultrasonic exposure was applied. A 3 × 2 × 2 factorial table was applied to categorize the experimental animals based on different levels of combination of ultrasonic frequencies (Factor A: 1.6 MHz, 2.2 MHz, 2.8 MHz), doses of urokinase (Factor B: 90,000 IU/Kg, 180,000 IU/Kg) and ultrasound exposure time (Factor C: 30 min, 60 min). A total of 72 experimental animals were randomly divided into 12 groups (n = 6/group). Doppler techniques were used to assess blood flow in the distal end of the thrombotic femoral artery during the 120 minutes thrombolysis experiment. The rate of recanalization following thrombolysis was calculated, and thrombolytic efficacy was evaluated and compared. The thrombolytic recanalization rate for all experimental subjects after thrombolytic therapy was 68.1%. The optimal parameters for thrombolysis were determined to be 1) an ultrasound frequency of 2.2 MHz and 2) a 90,000 IU/kg dose of urokinase. Ultrasound exposure time (30 min vs. 60 min) had no significant effect on the thrombolytic effects. The combination of local low-frequency ultrasound radiation, targeted microbubbles, and thrombolytic urokinase induced thrombolysis of femoral artery thrombosis in a rabbit model. The ultrasonic frequency of 2.2 MHz and urokinase dose of 90,000 IU/kg induced optimal thrombolytic effects, while the application of either 30 min or 60 min of ultrasound exposure had similar effects.
Highlights
The combined use of ultrasound, microbubble contract agent, and thrombolytic drugs has shown potential for clinical application in thrombosis treatment
Acconcia et al [9] applied 1 MHz ultrasonic irradiation to assist with the targeting of microbubble thrombolysis in vitro, and reported that the effects of microbubble contrast agent facilitated ultrasound thrombolysis were related to microbubble size, parameters of ultrasonic irradiation, and specific characteristics of the blood clot(s) targeted
Thrombosis and thrombolysis were assessed by continuously monitoring vessel blood flow using pulsed Doppler flowmetry, and the data were analyzed by use of a professional data analysis system (Power Lab system, AD Instruments Pty Ltd)
Summary
The combined use of ultrasound, microbubble contract agent, and thrombolytic drugs has shown potential for clinical application in thrombosis treatment. The use of thrombus-targeting microbubbles has the potential to improve the safety and efficacy of current clinical thrombolytic therapy [8]. Acconcia et al [9] applied 1 MHz ultrasonic irradiation to assist with the targeting of microbubble thrombolysis in vitro, and reported that the effects of microbubble contrast agent facilitated ultrasound thrombolysis were related to microbubble size, parameters of ultrasonic irradiation, and specific characteristics of the blood clot(s) targeted. The specific factors that could potentially optimize thrombolytic efficacy in vivo, including selection of targeted microbubble contrast agents, ultrasound parameter and drug dosage remain unknown
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