IMF Laboratory, CNRS UMR 5231, University of Bordeaux, Bordeaux, Aquitaine, France.
Invest Radiol. 2010 May;45(5):282-7. doi: 10.1097/RLI.0b013e3181dac2a7.
Local drug delivery by ultrasound (US)-induced cavitation is a promising strategy for increasing the drug concentration at the target location and for decreasing the systemic toxicity effects. The presence of microbubbles during sonication at the targeted location improves the likelihood for cavitation that can be exploited to increase the capillary permeability. The objective of this work was to evaluate the magnetic resonance imaging (MRI) contrast changes in hepatic tissue in vivo, induced by US-triggered cavitation and destruction of microbubbles (Sonovue), in the presence of a coinjected blood pool MRI contrast agent (Vistarem) used as a reporter macromolecule. The potential tissue damage induced by microbubbles destruction was also evaluated by histology.
The change in the hepatic distribution of the macromolecular MRI contrast agent associated with cavitation was monitored at 1.5 T with a look-locker fast inversion recovery sequence to map the longitudinal relaxation rates, before and during 1 hour after intravenous administration of Vistarem and Sonovue. In 1 group of rats (n = 5), these microbubbles were immediately destroyed with a clinical echograph, using a high mechanical index (MI = 1.5) at low frequency (2 MHz). The control group (n = 7) received identical injections without application of US. The parametric relaxation rate images were computed, and the changes in time were analyzed to account for the potential effect of microbubble destruction by US on the permeability of the hepatic vessels. The animals were killed 1 day after the experiment for routine histology of the liver.
For both groups of animals, after an initial increase, a transient decay of the longitudinal relaxation rate was observed, followed by a constant plateau after 20 minutes. The analysis of the mean relaxation rates in the liver showed significant (P < 0.01) higher values for the group with destruction of microbubbles as compared with the control group. The US-triggered cavitation and destruction of microbubble with the proposed protocol suggests an increased concentration of Vistarem of a factor 2 in the hepatic tissue. No tissue damage was observed at the microscopic analysis.
The absence of tissue alterations indicates that the destruction of this US contrast agent could be safe in vivo under an appropriate choice of the sonication parameters. This approach opens new perspectives for translation toward clinical applications of local drug delivery. Ultrasound-mediated microbubble destruction may help in increasing the local concentration of a drug currently limited by the endothelial barrier. In addition, it may help in reducing the systemic toxicity to normal cells in standard chemotherapies, because the enhanced capillary permeability effect can be spatially adjusted by selecting the sonicated region.
超声（US）诱导空化的局部药物输送是一种很有前途的策略，可以提高靶位的药物浓度，并降低全身毒性作用。在靶向位置进行超声时存在微泡，可以提高空化的可能性，从而增加毛细血管通透性。本工作的目的是评估在注射血液池 MRI 对比剂（Vistarem）作为报告大分子的情况下，体内超声触发空化和微泡破坏（Sonovue）引起的肝组织的磁共振成像（MRI）对比变化。还通过组织学评估微泡破坏引起的潜在组织损伤。
在 1.5 T 下使用 Look-Locker 快速反转恢复序列监测与空化相关的大分子 MRI 对比剂在肝内的分布变化，在静脉注射 Vistarem 和 Sonovue 前和 1 小时内进行监测。在一组大鼠（n = 5）中，立即使用临床超声仪以高机械指数（MI = 1.5）在低频（2 MHz）下破坏这些微泡。对照组（n = 7）接受相同的注射但不应用 US。计算参数弛豫率图像，并分析时间变化以解释 US 破坏微泡对肝血管通透性的潜在影响。实验后 1 天，动物处死进行肝常规组织学检查。
对于两组动物，在初始增加后，观察到纵向弛豫率的短暂衰减，随后在 20 分钟后达到恒定平台。对肝内平均弛豫率的分析表明，与对照组相比，微泡破坏组的弛豫率显著升高（P < 0.01）。该方案提示，超声触发的空化和微泡破坏导致肝组织中 Vistarem 的浓度增加了 2 倍。微观分析未观察到组织损伤。
组织改变的缺失表明，在适当选择超声参数的情况下，这种 US 造影剂的破坏在体内可能是安全的。这种方法为局部药物输送的临床应用开辟了新的前景。超声介导的微泡破坏可以帮助增加目前受到内皮屏障限制的药物的局部浓度。此外，它还可以帮助降低标准化疗中正常细胞的全身毒性，因为通过选择超声区域可以对增强的毛细血管通透性效应进行空间调整。
