Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
Ultrasound Med Biol. 2011 Jun;37(6):949-57. doi: 10.1016/j.ultrasmedbio.2011.03.005. Epub 2011 May 5.
Ultrasound-triggered microbubble destruction (UTMD) is essential for targeted drug delivery but currently there is no agreed gold standard for its real-time monitoring. This study used a clinical diagnostic ultrasound scanner to quantify the destruction effects of different values of mechanical index (MI) on microbubble. This was achieved by measuring the signal intensity of peripheral vessels, which is representative of systemic microbubble concentration. Twenty-four male Sprague-Dawley rats and SonoVue contrast agent were used for this study, six for the determination of signal saturation and 18 for the study of microbubble destruction. In the first part of the experiment, four different SonoVue doses (200, 400, 600 and 800 μL/kg) were injected into each of six rats and the signal intensity in their right femoral arteries were recorded using a diagnostic ultrasound scanner. This data was used to plot time-intensity curves (TIC) to determine at which concentration the signal reaches saturation. Then UTMD studies were performed using the 400 μL/kg dose as its peak signal intensity (PSI) was safely within the linear portion of the intensity-concentration curve. The remaining 18 rats were divided into three MI groups (0.2, 0.6 and 1.0) and for each rat, the following was performed: TIC recording of a sham exposure without sonication was performed first using the same scanner from signal saturation study. Simultaneously, another ultrasound scanner was applied to the adductor muscles of left hind limb for sonication later. Then, a sonication TIC recording was performed, with both ultrasound scanners activated. A TIC recording of second sonication was also obtained for comparison. The TICs showed that the area under the curve and the enhancement duration were reduced after sonication in the groups MI = 0.6 and MI = 1.0 but not for the group MI = 0.2. The PSI in the groups with MI of 0.6 and 1.0 were slightly lowered after sonication, although it is not statistically significant. No significant difference of TIC exists between the first and the second sonication for each group. Pharmacokinetic analysis was performed with estimated concentration-time curve derived from TIC curve and found that SonoVue had faster clearance and decreased half-life in the groups MI = 0.6 and MI = 1.0. In conclusion, this study shows that sonographic signal measured from peripheral vessels is a feasible indicator of systemic microbubble concentration and may be used to quantify ultrasound-triggered microbubble destruction at target site.
超声触发微泡破坏（UTMD）是靶向药物递送的关键，但目前尚无公认的实时监测金标准。本研究使用临床诊断超声扫描仪定量测量不同机械指数（MI）对微泡破坏的影响。这是通过测量外周血管的信号强度来实现的，外周血管的信号强度代表全身微泡浓度。本研究使用了 24 只雄性 Sprague-Dawley 大鼠和 SonoVue 造影剂，其中 6 只为确定信号饱和，18 只为研究微泡破坏。在实验的第一部分，将 4 种不同剂量的 SonoVue（200、400、600 和 800 μL/kg）分别注射到 6 只大鼠体内，使用诊断超声扫描仪记录其右侧股动脉的信号强度。该数据用于绘制时间-强度曲线（TIC），以确定信号达到饱和的浓度。然后，使用 400 μL/kg 剂量进行 UTMD 研究，因为其峰值信号强度（PSI）安全地处于强度-浓度曲线的线性部分内。其余 18 只大鼠分为 3 个 MI 组（0.2、0.6 和 1.0），对每只大鼠进行以下操作：首先使用来自信号饱和研究的相同扫描仪记录无超声照射的假暴露 TIC。同时，另一个超声扫描仪应用于左后肢的内收肌进行随后的超声照射。然后，激活两个超声扫描仪以进行超声 TIC 记录。还获得了第二次超声 TIC 记录以进行比较。TIC 显示，MI = 0.6 和 MI = 1.0 组的曲线下面积和增强持续时间在超声照射后减少，但 MI = 0.2 组则不然。MI = 0.6 和 MI = 1.0 组的 PSI 在超声照射后略有降低，尽管这并不具有统计学意义。每个组的第一次和第二次超声 TIC 之间没有明显差异。使用 TIC 曲线推导的估计浓度-时间曲线进行药代动力学分析，发现 SonoVue 在 MI = 0.6 和 MI = 1.0 组中的清除速度更快，半衰期更短。总之，本研究表明，从外周血管测量的超声信号是全身微泡浓度的可行指标，可用于定量测量靶向部位的超声触发微泡破坏。
