Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers.
Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers.
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DOI：
10.1038/s41467-020-18059-7
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发表时间：
2020-10-01
影响因子：
16.6
通讯作者：
Yanik MF
中科院分区：
文献类型：
--
作者：
Ozdas MS;Shah AS;Johnson PM;Patel N;Marks M;Yasar TB;Stalder U;Bigler L;von der Behrens W;Sirsi SR;Yanik MF
非侵入性的、分子特异性的、具有低脱靶效应的脑回路的局部调制可以导致脑疾病治疗的突破。我们全身注射工程超声可控药物载体，随后在大脑内的所需靶点应用新型双组分聚集和解锁聚焦超声序列（AU-FUS）。第一个序列以毫米级的精度聚集药物载体。第二个序列在局部撑开载体的货物，以实现高靶特异性，而不损害血脑屏障（BBB）。在从载体释放后，药物局部穿过完整的BBB。我们展示了在大鼠运动皮层中通过局部集中和从超声控制的载体释放GABAA受体激动剂对感觉信号的回路特异性操纵。我们的方法使用的药物数量级（1300倍）低于全身注射所需的药物数量级，并且需要非常低的超声压力（低于FDA诊断成像安全限值的20倍）。我们表明，BBB保持完整，使用被动空化检测（PCD），MRI造影剂，重要的是，还通过敏感的荧光染料外渗和免疫组织化学。具有分子和空间特异性的脑回路的非侵入性操纵可能会彻底改变脑疾病的治疗。在这里，作者远程集中和提供药物的局灶性脑区，而不损害血脑屏障使用新的超声序列和药物载体。
Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry. Non-invasive manipulation of brain circuits with molecular and spatial specificity could revolutionize the treatment of brain disorders. Here, the authors remotely concentrate and deliver drugs to focal brain regions without compromising the blood-brain barrier using novel ultrasound sequences and drug carriers.
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影响因子：
19.7
作者：
Hynynen, K;McDannold, N;Jolesz, FA
通讯作者：
Jolesz, FA
影响因子：
25
作者：
Gordon, Joshua A.
通讯作者：
Gordon, Joshua A.
影响因子：
10.8
作者：
Airan RD;Meyer RA;Ellens NP;Rhodes KR;Farahani K;Pomper MG;Kadam SD;Green JJ
通讯作者：
Green JJ
影响因子：
16.6
作者：
Iturria-Medina Y;Sotero RC;Toussaint PJ;Mateos-Pérez JM;Evans AC;Alzheimer’s Disease Neuroimaging Initiative
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
DOI：
10.1088/0960-1317/21/5/054004
发表时间：
2011-05
期刊：
Journal of micromechanics and microengineering : structures, devices, and systems
影响因子：
--
作者：
Khuri-Yakub BT;Oralkan O
通讯作者：
Oralkan O