RT Journal Article
SR Electronic
T1 Calcium-Mediated Modulation of Blood-Brain Barrier Permeability by Laser Stimulation of Endothelial-Targeted Nanoparticles
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.02.494541
DO 10.1101/2022.06.02.494541
A1 Xiaoqing Li
A1 Qi Cai
A1 Blake A. Wilson
A1 Hanwen Fan
A1 Monica Giannotta
A1 Robert Bachoo
A1 Zhenpeng Qin
YR 2022
UL http://biorxiv.org/content/early/2022/06/04/2022.06.02.494541.abstract
AB The blood-brain barrier (BBB) maintains an optimal environment for brain homeostasis but excludes most therapeutics from entering the brain. Strategies that can reversibly increase BBB permeability will be essential for treating brain diseases and is the focus of significant preclinical and translational interest. Recently, we reported that picosecond laser excitation of molecular-targeted gold nanoparticles (AuNPs) induced a graded and reversible increase in BBB permeability in vivo (OptoBBB). Here we investigate how to increase the targeting efficiency and how picosecond lase stimulation of AuNP leads to an increase in endothelial paracellular permeability. Our results suggest that targeting brain endothelial glycoproteins leads to >20-fold higher targeting efficiency compared with tight junction targeting. We report that OptoBBB is associated with a transient elevation of Ca2+ that propagates to adjacent endothelial cells after laser excitation and extends the region of BBB opening. The Ca2+ response involves both internal Ca2+ depletion and Ca2+ influx. Furthermore, we demonstrate that the involvement of actin polymerization and Ca2+-dependent phosphorylation of ERK1/2 lead to cytoskeletal activation, increasing paracellular permeability. Taken together, we provide mechanistic insight into how excitation of endothelial targeted AuNPs leads to an increase in BBB permeability. These insights will be critical for guiding the future developments of this technology for brain disease treatment.Competing Interest StatementA patent has been filed related to the technology described in this work (US 2021/0252151 A1)