Submicron-bubble-enhanced focused ultrasound for blood-brain barrier disruption and improved CNS drug delivery.
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.
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
Ching-Hsiang
CH
Fan
Department of Electrical Engineering, Chang-Gung University, Tao-Yuan, Taiwan.
Hao-Li
HL
Liu
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
Chien-Yu
CY
Ting
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
Ya-Hsuan
YH
Lee
Department of Electrical Engineering, Chang-Gung University, Tao-Yuan, Taiwan.
Chih-Ying
CY
Huang
Department of Electrical Engineering, Chang-Gung University, Tao-Yuan, Taiwan.
Yan-Jung
YJ
Ma
Department of Neurosurgery, Chang Gung University College of Medicine and Memorial Hospital, Tao-Yuan, Taiwan.
Kuo-Chen
KC
Wei
Department of Nuclear Medicine, Chang Gung University College of Medicine and Memorial Hospital, Tao-Yuan, Taiwan; Molecular Imaging Center, Chang Gung University College of Medicine and Memorial Hospital, Tao-Yuan, Taiwan.
Tzu-Chen
TC
Yen
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
Chih-Kuang
CK
Yeh
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002330:Carmustine / Q000008:administration & dosage / Q000493:pharmacokinetics; D003287:Contrast Media; D016503:Drug Delivery Systems / Q000379:methods*; D008279:Magnetic Resonance Imaging; D008297:Male; D045423:Microbubbles; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013010:Sonication / Q000379:methods; D014465:Ultrasonics / Q000379:methods*
D018906:Antineoplastic Agents, Alkylating; D003287:Contrast Media; D002330:Carmustine