TY - JOUR
T1 - Characterization of focused ultrasound-mediated brainstem delivery of intranasally administered agents
AU - Ye, Dezhuang
AU - Luan, Jingyi
AU - Pang, Hannah
AU - Yang, Yaoheng
AU - Nazeri, Arash
AU - Rubin, Joshua B.
AU - Chen, Hong
N1 - Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/12/10
Y1 - 2020/12/10
N2 - Focused ultrasound-mediated intranasal (FUSIN) delivery is a recently proposed technique that bypasses the blood-brain barrier to achieve noninvasive and localized brain drug delivery. The goal of this study was to characterize FUSIN drug delivery outcome in mice with regard to its dependency on several critical experimental factors, including the time interval between IN administration and FUS sonication (Tlag1), the FUS pressure, and the time for sacrificing the mice post-FUS (Tlag2). Wild-type mice were treated by FUSIN delivery of near-infrared fluorescent dye-labeled bovine serum albumin (800CW-BSA, used as a model agent). 800CW-BSA was intranasally administered to the mice in vivo, followed by intravenous injection of microbubbles and FUS sonication at the brainstem. Fluorescence imaging of ex vivo mouse brain slices was used to quantify the delivery outcomes of 800CW-BSA. Major organs, along with the nasal tissue and trigeminal nerve, were harvested to assess the biodistribution of 800CW-BSA. The delivery outcome of 800CW-BSA was the highest at the brainstem when Tlag1 was 0.5 h, which was on average 24.5-fold, 5.4-fold, and 21.6-fold higher than those of the IN only, Tlag1 = 1.5 h, and Tlag1 = 4.0 h, respectively. The FUSIN delivery outcome at the lowest pressure level, 0.43 MPa, was on average 1.8-fold and 3.7-fold higher than those at 0.56 MPa and 0.70 MPa, respectively. The mean concentration of 800CW-BSA in the brainstem after FUSIN delivery decreased from 0.5 h to 4.0 h post-FUS. The accumulation of 800CW-BSA was low in the heart, lung, spleen, kidneys, and liver, but high in the stomach and intestines. This study revealed the unique characteristics of FUSIN as a noninvasive, efficient, and localized brain drug delivery technique.
AB - Focused ultrasound-mediated intranasal (FUSIN) delivery is a recently proposed technique that bypasses the blood-brain barrier to achieve noninvasive and localized brain drug delivery. The goal of this study was to characterize FUSIN drug delivery outcome in mice with regard to its dependency on several critical experimental factors, including the time interval between IN administration and FUS sonication (Tlag1), the FUS pressure, and the time for sacrificing the mice post-FUS (Tlag2). Wild-type mice were treated by FUSIN delivery of near-infrared fluorescent dye-labeled bovine serum albumin (800CW-BSA, used as a model agent). 800CW-BSA was intranasally administered to the mice in vivo, followed by intravenous injection of microbubbles and FUS sonication at the brainstem. Fluorescence imaging of ex vivo mouse brain slices was used to quantify the delivery outcomes of 800CW-BSA. Major organs, along with the nasal tissue and trigeminal nerve, were harvested to assess the biodistribution of 800CW-BSA. The delivery outcome of 800CW-BSA was the highest at the brainstem when Tlag1 was 0.5 h, which was on average 24.5-fold, 5.4-fold, and 21.6-fold higher than those of the IN only, Tlag1 = 1.5 h, and Tlag1 = 4.0 h, respectively. The FUSIN delivery outcome at the lowest pressure level, 0.43 MPa, was on average 1.8-fold and 3.7-fold higher than those at 0.56 MPa and 0.70 MPa, respectively. The mean concentration of 800CW-BSA in the brainstem after FUSIN delivery decreased from 0.5 h to 4.0 h post-FUS. The accumulation of 800CW-BSA was low in the heart, lung, spleen, kidneys, and liver, but high in the stomach and intestines. This study revealed the unique characteristics of FUSIN as a noninvasive, efficient, and localized brain drug delivery technique.
KW - Blood-brain barrier
KW - Brain drug delivery
KW - Brainstem
KW - Focused ultrasound
KW - Intranasal delivery
UR - http://www.scopus.com/inward/record.url?scp=85090406489&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2020.08.053
DO - 10.1016/j.jconrel.2020.08.053
M3 - Article
C2 - 32871204
AN - SCOPUS:85090406489
SN - 0168-3659
VL - 328
SP - 276
EP - 285
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -