Facilitated brain delivery of poly (ethylene glycol)-poly (lactic acid) nanoparticles by microbubble-enhanced unfocused ultrasound.
Nanotechnology plays a unique instrumental role in the revolutionary development of brain-specific drug delivery, imaging, and diagnosis, but is highly limited by the existence of blood-brain barrier (BBB). In this study, microbubble-enhanced unfocused ultrasound (MEUUS) was developed as an approach to mediate an extensive brain delivery of poly (ethylene glycol) - poly (lactic acid) (PEG-PLA) nanoparticles. Following the MEUUS treatment, the nanoparticles signals were found to penetrate through the vascular walls and distributed deeply into the parenchyma at a significantly higher level (more than 250%) than those of the non-MEUUS treated control. Such effect was reversible and dependent on nanoparticles injection timing, sonication mode and mechanical index. Together with the transmission electron microscopy analysis, the increased brain accumulation of nanoparticles was claimed to be largely mediated by an ultrasound-induced stable cavitation of the microbubble which resulted in mechanical stretching of the vessel wall and consequently induced cellular transcytosis of the nanoparticles. The MEUUS technique was also used to facilitate the brain delivery of PEG-PLA nanoparticles functionalized with amyloid beta-specific antibody 6E10 for enabling the recognition of the hallmarks of Alzheimer's disease that widely distributed in the brain. No erythrocytes extravasation and other visible damages in the brain were detected following the MEUUS treatment. These findings together indicated that unfocused ultrasound with the aid of microbubble could effectively improve the brain delivery of nanoparticles, and this approach might serve as a safe and flexible platform for the potential application of nanoparticles in the diagnosis and therapy of brain diseases.
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
Lei
L
Yao
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
Qingxiang
Q
Song
Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Institute of Ultrasound in Medicine, 600 Yishan Road, Shanghai 200233, PR China.
Wenkun
W
Bai
Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Institute of Ultrasound in Medicine, 600 Yishan Road, Shanghai 200233, PR China.
Jizhen
J
Zhang
Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
Deyu
D
Miao
Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
Mengyin
M
Jiang
Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Institute of Ultrasound in Medicine, 600 Yishan Road, Shanghai 200233, PR China.
Yu
Y
Wang
Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Institute of Ultrasound in Medicine, 600 Yishan Road, Shanghai 200233, PR China.
Zhiyong
Z
Shen
Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
Quanyin
Q
Hu
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
Xiao
X
Gu
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
Meng
M
Huang
Department of Medical Biophysics and Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Gang
G
Zheng
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China. Electronic address: shellygao1@sjtu.edu.cn.
Xiaoling
X
Gao
Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Institute of Ultrasound in Medicine, 600 Yishan Road, Shanghai 200233, PR China. Electronic address: binghu_stephen@163.com.
Bing
B
Hu
Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China. Electronic address: chenjun@fudan.edu.cn.
Jun
J
Chen
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China. Electronic address: hongzhuan_chen@hotmail.com.
Hongzhuan
H
Chen
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D003374:Coumarins / Q000493:pharmacokinetics; D005456:Fluorescent Dyes; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014465:Ultrasonics
D003374:Coumarins; D005456:Fluorescent Dyes; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols
Brain delivery; Microbubble; Nanoparticles; Unfocused ultrasound