The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound.
The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound.
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DOI：
10.1016/j.jconrel.2012.06.012
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发表时间：
2012-08-20
期刊：
影响因子：
--
通讯作者：
McDannold NJ
中科院分区：
文献类型：
--
作者：
Park J;Zhang Y;Vykhodtseva N;Jolesz FA;McDannold NJ
聚焦超声（FUS）结合循环微泡剂是一种有前途的策略，可以非侵入性地破坏血脑屏障（BBB），并可以实现通常不会离开脑血管系统的治疗药物的靶向递送。本研究使用动态对比增强MRI（DCE-MRI）和化疗药物阿霉素（DOX）的有效载荷研究了血脑屏障通透性的动力学。我们还研究了如何破坏和药物输送的影响，由双超声（DS）与两个不同的时间间隔（10或120分钟）。使用690 kHz FUS换能器对20只大鼠大脑的一个半球中的两个位置进行经颅超声处理;另一个半球作为对照。对于BBB破坏，以1 Hz施加10 ms脉冲串60 s，并结合静脉注射微泡超声造影剂（Depletion; 10 μl/kg）。在第二个位置超声处理后立即注射DOX。使用DCE-MRI在超声处理后30 min至7.5 h的4-5个时间点连续估计MRI造影剂（Gd-DTPA）的转移系数（Ktranss）。单次超声处理（SS）后，30分钟时的平均Ktrans为0.0142±0.006 min-1，比未超声处理的目标高两个或更多个数量级。其随时间呈指数下降，估计半衰期为2.22小时（95%置信区间（CI）：1.06-3.39小时）。添加第二次超声处理增加Ktranss，并且超声处理之间的间隔为120 min，延长了BBB破坏的持续时间。延迟10分钟和120分钟的DS后，平均Ktranss估计值分别为0.0205（CI：0.016-0.025）和0.0216（CI：0.013-0.030）min-1。当屏障恢复时发生的Ktrans衰变的半衰期为1.8小时（CI：1.20- 2.41小时），超声处理之间的间隔为10分钟，并增加到3.34小时（CI：0.84-5.84小时），间隔为120分钟。对于所有实验组，DOX浓度显著高于非超声处理的脑中的浓度（p<0.0001），并且对于超声处理之间间隔10分钟的DS，DOX浓度高1.5倍。在超声处理后30分钟所获得的DOX浓度和测量的Ktranss之间发现线性相关性（R：0.7）。这些数据表明，可以使用Gd-DTPA作为替代示踪剂来估计在FUS诱导的BBB破坏后DOX向脑的递送。本研究的结果提供了考虑FUS后BBB随时间的动态破坏所需的信息。
Focused ultrasound (FUS) combined with a circulating microbubble agent is a promising strategy to non-invasively disrupt the blood-brain barrier (BBB) and could enable targeted delivery of therapeutics that normally do not leave the brain vasculature. This study investigated the kinetics of the BBB permeability using dynamic contrast-enhanced MRI (DCE-MRI) and the resulting payload of the chemotherapy agent, doxorubicin (DOX). We also investigated how the disruption and drug delivery were affected by a double sonication (DS) with two different time intervals (10 or 120 min). Two locations were sonicated transcranially in one hemisphere of the brain in 20 rats using a 690 kHz FUS transducer; the other hemisphere served as a control. For BBB disruption, 10 ms bursts were applied at 1 Hz for 60 s and combined with IV injection of a microbubble ultrasound contrast agent (Definity; 10 μl/kg). DOX was injected immediately after the second location was sonicated. The transfer coefficient (Ktrans) for an MRI contrast agent (Gd-DTPA) was estimated serially at 4–5 time points ranging from 30 min to 7.5 hr after sonication using DCE-MRI. After a single sonication (SS), the mean Ktrans was 0.0142±0.006 min−1 at 30 min and was two or more orders of magnitude higher than the non-sonicated targets. It decreased exponentially as a function of time with an estimated half-life of 2.22 hr (95% confidence intervals (CI): 1.06–3.39 hr). Adding a second sonication increased Ktrans, and with a 120 min interval between sonications, prolonged the duration of the BBB disruption. Mean Ktrans estimates of 0.0205 (CI: 0.016–0.025) and 0.0216 (CI: 0.013–0.030) min−1 were achieved after DS with 10 and 120 min delays, respectively. The half-life of the Ktrans decay that occurred as the barrier was restored was 1.8 hr (CI: 1.20– 2.41 hr) for a 10 min interval between sonications and increased to 3.34 hr (CI: 0.84–5.84 hr) for a 120 min interval. DOX concentrations were significantly greater than in the non-sonicated brain for all experimental groups (p<0.0001), and 1.5-fold higher for DS with a 10 min interval between sonications. A linear correlation was found between the DOX concentration achieved and the Ktrans measured at 30 min after sonication (R: 0.7). These data suggest that one may be able to use Gd-DTPA as a surrogate tracer to estimate DOX delivery to the brain after FUS-induced BBB disruption. The results of this study provide information needed to take into account the dynamics BBB disruption over time after FUS.
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影响因子：
19.7
作者：
Hynynen, K;McDannold, N;Jolesz, FA
通讯作者：
Jolesz, FA
DOI：
10.1109/tbme.2009.2034533
发表时间：
2010-01
期刊：
IEEE transactions on bio-medical engineering
影响因子：
--
作者：
Choi JJ;Feshitan JA;Baseri B;Wang S;Tung YS;Borden MA;Konofagou EE
通讯作者：
Konofagou EE
影响因子：
2.9
作者：
McDannold, Nathan;Vykhodtseva, Natalia;Hynynen, Kullervo
通讯作者：
Hynynen, Kullervo
影响因子：
3.5
作者：
McDannold, N;Vykhodtseva, N;Hynynen, K
通讯作者：
Hynynen, K
影响因子：
5.7
作者：
Hynynen, K;McDannold, N;Vykhodtseva, N
通讯作者：
Vykhodtseva, N