Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound
Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound
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DOI：
10.1002/ijc.22732
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发表时间：
2007-08-15
影响因子：
6.4
通讯作者：
Hynynen, Kullervo
中科院分区：
文献类型：
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作者：
Treat, Lisa H.;McDannold, Nathan;Hynynen, Kullervo
由于抗肿瘤药物通常无法穿透完整的血脑屏障（BBB），因此脑肿瘤化疗的临床应用受到严重限制。虽然阿霉素（DOX）已被认为是中枢神经系统（CNS）化疗的有力候选药物，但血脑屏障通常会阻止其达到细胞毒性水平。在这项研究中，我们展示了一种通过血脑屏障靶向递送DOX的非侵入性方法，从而在正常大鼠脑中达到对人类肿瘤具有治疗作用的药物水平。使用mri引导的聚焦超声与预先形成的微泡（option）局部破坏血脑屏障和DOX的全身给药，我们在最小的组织效应下实现了脑组织中DOX浓度为886 +/- 327 ng/g。在较高的optionson剂量下，组织DOX浓度可达5,366 +/- 659 ng/g，但组织损伤更严重。相比之下，在所有配对样本中，非靶向对侧脑组织中的DOX积累仍显着降低（p < 0.001）。这些结果表明，尽管先前存在可及性限制，但聚焦超声靶向递送可能使DOX化疗成为针对中枢神经系统肿瘤的可行治疗选择。此外，超声区MRI信号增强与组织DOX浓度密切相关（r = 0.87），表明MRI增强可能表明在图像引导干预过程中药物渗透。我们的技术使用mri引导聚焦超声来达到脑内DOX的治疗水平，为使用化疗治疗中枢神经系统恶性肿瘤患者提供了一大步。(c) 2007 Wiley-Liss, Inc。
The clinical application of chemotherapy to brain tumors has been severely limited because antitumor agents are typically unable to penetrate an intact blood-brain barrier (BBB). Although doxorubicin (DOX) has been named as a strong candidate for chemotherapy of the central nervous system (CNS), the BBB often prevents cytotoxic levels from being achieved. In this study, we demonstrate a noninvasive method for the targeted delivery of DOX through the BBB, such that drug levels shown to be therapeutic in human tumors are achieved in the normal rat brain. Using MRI-guided focused ultrasound with preformed microbubbles (Optison) to locally disrupt the BBB and systemic administration of DOX, we achieved DOX concentrations of 886 +/- 327 ng/g tissue in the brain with minimal tissue effects. Tissue DOX concentrations of up to 5,366 +/- 659 ng/g tissue were achieved with higher Optison doses, but with more significant tissue damage. In contrast, DOX accumulation in nontargeted contralateral brain tissue remained significantly lower for all paired samples (p < 0.001). These results suggest that targeted delivery by focused ultrasound may render DOX chemotherapy a viable treatment option against CNS tumors, despite previous accessibility limitations. In addition, MRI signal enhancement in the sonicated region correlated strongly with tissue DOX concentration (r = 0.87), suggesting that contrast-enhanced MRI could perhaps indicate drug penetration during image-guided interventions. Our technique using MRI-guided focused ultrasound to achieve therapeutic levels of DOX in the brain offers a large step forward in the use of chemotherapy to treat patients with CNS malignancies. (c) 2007 Wiley-Liss, Inc.