Submicron-bubble-enhanced focused ultrasound for blood-brain barrier disruption and improved CNS drug delivery

Ching Hsiang Fan, Hao Li Liu, Chien Yu Ting, Ya Hsuan Lee, Chih Ying Huang, Ma Yan-Jung, Kuo Chen Wei, Tzu Chen Yen, Chih Kuang Yeh

研究成果: Article同行評審

47 引文 斯高帕斯(Scopus)

摘要

The use of focused ultrasound (FUS) with microbubbles has been proven to induce transient blood-brain barrier opening (BBB-opening). However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1-4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz) can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 μg versus 0.3 μg) by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

原文English
文章編號e96327
期刊PloS one
9
發行號5
DOIs
出版狀態Published - 2014 五月 2

All Science Journal Classification (ASJC) codes

  • 多學科

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