Ultrasound-enabled delivery of drugs to the brain: Thinking outside the blood–brain barrier

Brain-X Pub Date : 2024-08-16 DOI:10.1002/brx2.73
Zhenghong Gao
{"title":"Ultrasound-enabled delivery of drugs to the brain: Thinking outside the blood–brain barrier","authors":"Zhenghong Gao","doi":"10.1002/brx2.73","DOIUrl":null,"url":null,"abstract":"<p>In a groundbreaking study, Rezai et al. unveiled a promising avenue for treating Alzheimer's disease (AD) using aducanumab and a cutting-edge delivery method<span><sup>1</sup></span> (Figure 1A). The team employed magnetic resonance-guided focused ultrasound (MRgFUS) to transiently open the blood–brain barrier (BBB), facilitating the transport of the drug from the blood circulation to the brain tissue. This resulted in a remarkable reduction in amyloid deposition in the treated cerebral area in three human patients. The study counters the drug delivery barriers of the brain by demonstrating the potential efficacy of this innovative approach in treating Alzheimer's.</p><p>MRgFUS stands out as a pivotal modality in brain drug delivery; it offers distinctive advantages, particularly in achieving high spatiotemporal resolution. This technology selectively and reversibly opens the BBB, primarily through the paracellular pathway. This noninvasive methodology presents a compelling approach to increasing the brain parenchyma's permeability to drugs. One key feature lies in the capacity to engineer the volume, shape, and depth of the focal spot in the brain tissue. This engineered precision caters to the specific requirements of treating diverse neurological diseases. The adaptability and precision of MRgFUS open avenues for targeted and efficacious interventions in the intricate landscape of brain-related pathologies.</p><p>Beyond the anticipated benefits of enhanced aducanumab (an FDA-approved amyloid beta-directed human monoclonal antibody indicated to treat Alzheimer's disease) delivery to the brain, the study implicated the intricate dynamics of drug/toxic complex diffusion and clearance within the human brain parenchyma. Notably, although the scientific discussion around the benefits of aducanumab is ongoing, ultrasound waves not only facilitate BBB opening but also interact with the brain parenchyma beyond the BBB to induce multiple effects<span><sup>2, 3</sup></span> that could account for the overall benefit (Figure 1B).</p><p>Considering the importance of the extracellular space (ECS), perivascular space (PVS), and cerebrospinal fluid flow dynamics in modulating drug diffusion, distribution, and waste clearance,<span><sup>4</sup></span> several questions remain that require further investigation. First, does ultrasound expand the ECS? Second, does it impact the PVS? Third, can ultrasound enhance flow transport, improving the clearance of antibodies and degraded amyloid fragments? Fourth, how does ultrasound interact with brain cells (e.g., neurons, astrocytes, etc.)? Fifth, does any mechanical activation of the signaling pathway have an impact? Finally, how can the technology be translated and extended to increase the efficacy of other treatment modalities enabled by larger particles, such as antibody–drug conjugates, adeno-associated viruses, and lipid nanoparticles?</p><p>Some of these aspects have been studied in the preclinical animals' modes; for instance, pulsed ultrasound has been shown to expand the ECS and PVS in rodents.<span><sup>5</sup></span> However, this has not been thoroughly studied in humans. These considerations will open a new frontier, prompting a reevaluation of the multifaceted effects of ultrasound on brain tissue dynamics and elucidating and improving drug delivery to the brain. Expanding our knowledge in this field will enable the treatment of a broad spectrum of brain diseases, including Alzheimer's and many others. Notably, the ultrasound exposures are characterized by brief bursts lasting 5–10 ms. These bursts occur once per second, constituting a total treatment duration of approximately 2 min. Crucially, despite the brevity of these exposures, the peak intensity of the ultrasound wave is exceptionally high. This high-intensity ultrasound can induce changes in the ECS and PVS when penetrating brain tissue.</p><p>In summary, this scientific breakthrough underscores the potential of ultrasound-mediated drug delivery in revolutionizing Alzheimer's therapy. Further exploration of these mechanisms beyond the BBB promises to refine treatment strategies and pave the way for transformative advancements in the field.</p><p><b>Zhenghong Gao</b>: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; validation; visualization; writing – original draft; writing – review &amp; editing.</p><p>The author declares no conflict of interest in this study.</p><p>The ethics approval was not needed in this study.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.73","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain-X","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/brx2.73","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

In a groundbreaking study, Rezai et al. unveiled a promising avenue for treating Alzheimer's disease (AD) using aducanumab and a cutting-edge delivery method1 (Figure 1A). The team employed magnetic resonance-guided focused ultrasound (MRgFUS) to transiently open the blood–brain barrier (BBB), facilitating the transport of the drug from the blood circulation to the brain tissue. This resulted in a remarkable reduction in amyloid deposition in the treated cerebral area in three human patients. The study counters the drug delivery barriers of the brain by demonstrating the potential efficacy of this innovative approach in treating Alzheimer's.

MRgFUS stands out as a pivotal modality in brain drug delivery; it offers distinctive advantages, particularly in achieving high spatiotemporal resolution. This technology selectively and reversibly opens the BBB, primarily through the paracellular pathway. This noninvasive methodology presents a compelling approach to increasing the brain parenchyma's permeability to drugs. One key feature lies in the capacity to engineer the volume, shape, and depth of the focal spot in the brain tissue. This engineered precision caters to the specific requirements of treating diverse neurological diseases. The adaptability and precision of MRgFUS open avenues for targeted and efficacious interventions in the intricate landscape of brain-related pathologies.

Beyond the anticipated benefits of enhanced aducanumab (an FDA-approved amyloid beta-directed human monoclonal antibody indicated to treat Alzheimer's disease) delivery to the brain, the study implicated the intricate dynamics of drug/toxic complex diffusion and clearance within the human brain parenchyma. Notably, although the scientific discussion around the benefits of aducanumab is ongoing, ultrasound waves not only facilitate BBB opening but also interact with the brain parenchyma beyond the BBB to induce multiple effects2, 3 that could account for the overall benefit (Figure 1B).

Considering the importance of the extracellular space (ECS), perivascular space (PVS), and cerebrospinal fluid flow dynamics in modulating drug diffusion, distribution, and waste clearance,4 several questions remain that require further investigation. First, does ultrasound expand the ECS? Second, does it impact the PVS? Third, can ultrasound enhance flow transport, improving the clearance of antibodies and degraded amyloid fragments? Fourth, how does ultrasound interact with brain cells (e.g., neurons, astrocytes, etc.)? Fifth, does any mechanical activation of the signaling pathway have an impact? Finally, how can the technology be translated and extended to increase the efficacy of other treatment modalities enabled by larger particles, such as antibody–drug conjugates, adeno-associated viruses, and lipid nanoparticles?

Some of these aspects have been studied in the preclinical animals' modes; for instance, pulsed ultrasound has been shown to expand the ECS and PVS in rodents.5 However, this has not been thoroughly studied in humans. These considerations will open a new frontier, prompting a reevaluation of the multifaceted effects of ultrasound on brain tissue dynamics and elucidating and improving drug delivery to the brain. Expanding our knowledge in this field will enable the treatment of a broad spectrum of brain diseases, including Alzheimer's and many others. Notably, the ultrasound exposures are characterized by brief bursts lasting 5–10 ms. These bursts occur once per second, constituting a total treatment duration of approximately 2 min. Crucially, despite the brevity of these exposures, the peak intensity of the ultrasound wave is exceptionally high. This high-intensity ultrasound can induce changes in the ECS and PVS when penetrating brain tissue.

In summary, this scientific breakthrough underscores the potential of ultrasound-mediated drug delivery in revolutionizing Alzheimer's therapy. Further exploration of these mechanisms beyond the BBB promises to refine treatment strategies and pave the way for transformative advancements in the field.

Zhenghong Gao: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; validation; visualization; writing – original draft; writing – review & editing.

The author declares no conflict of interest in this study.

The ethics approval was not needed in this study.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
通过超声波向大脑输送药物:突破血脑屏障
在一项开创性的研究中,Rezai 等人揭示了利用阿杜单抗和最先进的给药方法1 治疗阿尔茨海默病(AD)的前景(图 1A)。研究小组利用磁共振引导聚焦超声(MRgFUS)瞬时打开血脑屏障(BBB),促进药物从血液循环运输到脑组织。这使得三名人类患者接受治疗的脑区淀粉样蛋白沉积明显减少。这项研究打破了大脑的药物输送障碍,证明了这一创新方法在治疗阿尔茨海默氏症方面的潜在疗效。MRgFUS 是大脑药物输送的关键模式;它具有独特的优势,尤其是在实现高时空分辨率方面。该技术主要通过细胞旁通路选择性地、可逆地打开 BBB。这种无创方法为提高脑实质对药物的通透性提供了一种令人信服的方法。它的一个主要特点是能够设计脑组织中焦点的体积、形状和深度。这种工程设计的精确性满足了治疗各种神经系统疾病的特殊要求。MRgFUS的适应性和精确性为在错综复杂的脑相关病症中进行有针对性的有效干预开辟了道路。除了增强阿杜单抗(美国食品及药物管理局批准的淀粉样蛋白β定向人类单克隆抗体,用于治疗阿尔茨海默病)向大脑输送的预期益处外,该研究还涉及药物/毒性复合物在人脑实质内扩散和清除的复杂动态。值得注意的是,尽管围绕阿杜单抗益处的科学讨论仍在继续,但超声波不仅能促进BBB开放,还能与BBB以外的脑实质相互作用,诱发多种效应2、3,这可能是总体益处的原因(图1B)。考虑到细胞外空间(ECS)、血管周围空间(PVS)和脑脊液流动动力学在调节药物扩散、分布和废物清除方面的重要性4,仍有几个问题需要进一步研究。首先,超声是否会扩大 ECS?第二,超声是否会影响 PVS?第三,超声是否能增强血流传输,改善抗体和降解淀粉样蛋白片段的清除?第四,超声波如何与脑细胞(如神经元、星形胶质细胞等)相互作用?第五,机械激活信号通路是否会产生影响?最后,如何转化和扩展该技术,以提高由较大颗粒(如抗体-药物共轭物、腺相关病毒和脂质纳米颗粒)促成的其他治疗方式的疗效?其中一些方面已在临床前动物模式中进行了研究;例如,脉冲超声已被证明可扩大啮齿动物的 ECS 和 PVS。这些考虑因素将开辟一个新的领域,促使我们重新评估超声波对脑组织动力学的多方面影响,并阐明和改进向大脑的药物输送。拓展这一领域的知识将有助于治疗包括阿尔茨海默氏症在内的多种脑部疾病。值得注意的是,超声波照射的特点是持续 5-10 毫秒的短暂爆发。这些爆发每秒一次,总治疗时间约为 2 分钟。最重要的是,尽管照射时间很短,但超声波的峰值强度却非常高。总之,这一科学突破凸显了超声波介导的药物输送在阿尔茨海默氏症治疗中的革命性潜力。对这些超越 BBB 的机制的进一步探索有望完善治疗策略,并为该领域的变革性进步铺平道路:构思;数据整理;形式分析;资金获取;调查;方法论;项目管理;资源;验证;可视化;写作-原稿;写作-审稿&;编辑。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Issue Information Research progress and applications of optoelectronic synaptic devices based on 2D materials Mechanosensitive Piezo channels and their potential roles in peripheral auditory perception Brain perfusion alterations in patients and survivors of COVID-19 infection using arterial spin labeling: A systematic review Microbiome-gut-brain axis as a novel hotspot in depression
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1