Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
Int J Nanomedicine. 2012;7:2573-82. doi: 10.2147/IJN.S31675. Epub 2012 May 23.
We evaluated the delivery efficiency of intravenously injected large molecular agents, before and after disruption of the blood-brain barrier (BBB-D), induced by focused ultrasound (FUS) using various acoustic parameters.
Male Sprague-Dawley rats were injected intravenously with Evans blue (EB) before or after BBB-D induction by pulsed FUS. We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA) at four different doses to induce BBB-D resulting from cavitation. The permeability of the BBB was assessed quantitatively based on the extravasation of EB. Contrast enhanced magnetic resonance imaging (MRI) was used to monitor the gadolinium deposition associated with FUS. Histological analysis was performed to examine tissue damage.
The accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D. Administration of EB followed by sonication resulted in greater EB extravasation than that for rats subjected to sonication prior to EB injection. To reduce tissue damage, EB extravasation was enhanced by first administering EB by intravenous injection, followed by sonication at reduced acoustic power or UCA dosage. The normalized signal intensity change in rat brains that received the same dose of UCA and sonicated after gadolinium injection was significantly greater than in rats undergoing sonication followed by gadolinium administration. Moreover, contrast enhanced MRI showed a more precise distribution of gadolinium in the brain when gadolinium was administered before sonication.
We demonstrated that a compound administered prior to sonication treatment promotes extravasation of the sonicated region. Thus, it is possible to optimize ultrasound parameters for lower sonication and reduced UCA doses, to induce BBB-D while minimizing damage to normal brain tissue.
我们评估了在使用各种声参数破坏血脑屏障（BBB-D）前后，静脉内注射的大分子量药物的输送效率。
雄性 Sprague-Dawley 大鼠在经脉冲聚焦超声（FUS）诱导 BBB-D 前后静脉内注射 Evans 蓝（EB）。我们使用 1.0 MHz 脉冲 FUS 进行实验，设置了四个声功率水平，并使用四种不同剂量的超声造影剂（UCA）来诱导由空化引起的 BBB-D。基于 EB 的外渗，定量评估 BBB 的通透性。对比增强磁共振成像（MRI）用于监测与 FUS 相关的钆沉积。进行组织学分析以检查组织损伤。
发现 EB 在大鼠脑中的积累取决于声功率和 UCA 剂量，而与 EB 给药是在 FUS 诱导的 BBB-D 之前还是之后无关。与先进行 FUS 再给予 EB 相比，先给予 EB 再进行超声处理导致 EB 外渗更多。为了减少组织损伤，通过先静脉内给予 EB，然后在降低声功率或 UCA 剂量下进行超声处理，增强 EB 外渗。在给予相同剂量的 UCA 并在注射钆后进行超声处理的大鼠脑中，归一化信号强度变化明显大于先进行超声处理再给予钆的大鼠。此外，对比增强 MRI 显示，当在超声处理之前给予钆时，钆在大脑中的分布更精确。
我们证明了在超声处理治疗之前给予的化合物可促进超声处理区域的外渗。因此，可以优化超声参数以降低声功率和减少 UCA 剂量，同时最小化对正常脑组织的损伤，来诱导 BBB-D。
