Angolano Cleide, Hansen Emily, Ajjawi Hala, Nowlin Paige, Zhang Yongzhi, Thunemann Natalie, Ferran Christiane, Todd Nick
Division of Vascular and Endovascular Surgery, Center for Vascular Biology Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
Harvard University, Cambridge, MA, United States.
Biomed Pharmacother. 2025 Jan;182:117762. doi: 10.1016/j.biopha.2024.117762. Epub 2024 Dec 23.
The technology of focused ultrasound-mediated disruption of the blood-brain barrier (FUS-BBB opening) has now been used in over 20 Phase 1 clinical trials to validate the safety and feasibility of BBB opening for drug delivery in patients with brain tumors and neurodegenerative diseases. The primary treatment parameters, FUS intensity and microbubble dose, are chosen to balance sufficient BBB disruption to achieve drug delivery against potential acute vessel damage leading to microhemorrhage. However, other safety considerations due to second order effects caused by BBB disruption, such as inflammation and alteration of neurovascular function, are only beginning to be understood. This study builds on previous work that has investigated the inflammatory response following FUS-BBB opening. In this study, we characterize the effect of FUS intensity, microbubble dose and single vs multiple treatments on the extent of BBB disruption, observed level of microhemorrhage, and degree of inflammatory response at acute post-treatment time points in the wild-type mouse brain. Results show that upregulation of pro-inflammatory markers is primarily driven by microbubble dose, with peak effects seen at 24 hours post-treatment. We additionally saw significantly elevated levels of cytokine and chemokine markers in female vs male mice, despite no sex differences in level of BBB disruption or microglia activation. Multiple treatments did not result in increased levels of pro-inflammatory markers compared to single treatment baseline. However, we did see an interesting elevation of the anti-inflammatory molecule eNOS after multiple treatments, indicating active mechanisms were at work to restore homeostasis in the brain environment.
聚焦超声介导的血脑屏障破坏技术（FUS-BBB开放）现已用于20多项1期临床试验，以验证在脑肿瘤和神经退行性疾病患者中开放血脑屏障用于药物递送的安全性和可行性。主要治疗参数，即FUS强度和微泡剂量，是为了在充分破坏血脑屏障以实现药物递送与可能导致微出血的潜在急性血管损伤之间取得平衡而选择的。然而，由于血脑屏障破坏引起的二阶效应，如炎症和神经血管功能改变等其他安全考虑因素才刚刚开始被了解。本研究建立在先前对FUS-BBB开放后炎症反应进行研究的基础之上。在本研究中，我们在野生型小鼠脑中，在治疗后急性时间点，表征了FUS强度、微泡剂量以及单次与多次治疗对血脑屏障破坏程度、观察到的微出血水平和炎症反应程度的影响。结果表明，促炎标志物的上调主要由微泡剂量驱动，在治疗后24小时出现峰值效应。我们还发现，雌性小鼠与雄性小鼠相比，细胞因子和趋化因子标志物水平显著升高，尽管在血脑屏障破坏水平或小胶质细胞激活方面不存在性别差异。与单次治疗基线相比，多次治疗并未导致促炎标志物水平升高。然而，我们确实在多次治疗后看到抗炎分子eNOS出现有趣的升高，表明有活跃机制在发挥作用以恢复脑环境中的内稳态。
