Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain

Koki Ogawa; Naoya Kato; Michiharu Yoshida; Takeshi Hiu; Takayuki Matsuo; Shusaku Mizukami; Daiki Omata; Ryo Suzuki; Kazuo Maruyama; Hidefumi Mukai; Shigeru Kawakami

doi:10.1016/j.jconrel.2022.05.042

Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain

J Control Release. 2022 Aug:348:34-41. doi: 10.1016/j.jconrel.2022.05.042. Epub 2022 Jun 1.

Authors

Affiliations

¹ Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki, Japan.
² Department of Neurosurgery, Nagasaki University, School of Medicine, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki, Japan.
³ Department of Immune Regulation, Shionogi Global Infectious Diseases Division, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki-shi, Nagasaki, Japan.
⁴ Laboratory of Drug and Gene Delivery Research, Faculty of Pharma-Science, Teikyo University, 2-11-1 Kaga Itabashi-ku Tokyo, Japan.
⁵ Laboratory of Drug and Gene Delivery Research, Faculty of Pharma-Science, Teikyo University, 2-11-1 Kaga Itabashi-ku Tokyo, Japan; Advanced Comprehensive Research Organization (ACRO), Teikyo University, 2-11-1 Kaga Itabashi-ku Tokyo, Japan.
⁶ Laboratory of Theranostics, Faculty of Pharma-Science, Teikyo University, 2-11-1 Kaga Itabashi-ku Tokyo, Japan; Advanced Comprehensive Research Organization (ACRO), Teikyo University, 2-11-1 Kaga Itabashi-ku Tokyo, Japan.
⁷ Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki, Japan; Laboratory for Molecular Delivery and Imaging Technology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, Japan.
⁸ Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki, Japan. Electronic address: skawakam@nagasaki-u.ac.jp.

PMID: 35640764
DOI: 10.1016/j.jconrel.2022.05.042

Abstract

Messenger RNA (mRNA) medicine has become a new therapeutic approach owing to the progress in mRNA delivery technology, especially with lipid nanoparticles (LNP). However, mRNA encapsulated-LNP (mRNA-LNP) cannot spontaneously cross the blood-brain barrier (BBB) which prevents the expression of foreign proteins in the brain. Microbubble-assisted focused ultrasound (FUS) BBB opening is an emerging technology that can transiently enhance BBB permeability. In this study, FUS/microbubble-assisted BBB opening was investigated for the intravenous delivery of mRNA-LNP to the brain. The intensity of FUS irradiation was optimized to 1.5 kW/cm², at which BBB opening occurred efficiently without hemorrhage or edema. Exogenous protein (luciferase) expression by mRNA-LNP, specifically at the FUS-irradiated side of the brain, occurred only when FUS and microbubbles were applied. This exogenous protein expression was faster but shorter than that of plasmid DNA delivery. Furthermore, foreign protein expression was observed in the microglia, along with CD31-positive endothelial cells, whereas no expression was observed in astrocytes or neurons. These results support the addition of mRNA-LNP to the lineup of nanoparticles delivered by BBB opening.

Keywords: Blood-brain barrier (BBB); Focused ultrasound (FUS); Lipid nanoparticles (LNP); Messenger RNA (mRNA); Microbubble.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood-Brain Barrier* / metabolism
Brain / metabolism
Drug Delivery Systems / methods
Endothelial Cells
Liposomes
Magnetic Resonance Imaging
Microbubbles*
Nanoparticles
RNA, Messenger / genetics
RNA, Messenger / metabolism
Rats
Rats, Sprague-Dawley

Substances

Lipid Nanoparticles
Liposomes
RNA, Messenger