TY - JOUR
T1 - Nanoagonist-mediated endothelial tight junction opening
T2 - A strategy for safely increasing brain drug delivery in mice
AU - Gao, Xihui
AU - Wang, Yuan Cheng
AU - Liu, Yikang
AU - Yue, Qi
AU - Liu, Zining
AU - Ke, Mengjing
AU - Zhao, Shengyuan
AU - Li, Cong
N1 - Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Basic Research Program of China (973 Program, 2013CB733801, 2013CB932500), the National Natural Science Foundation of China (Nos. 81371624, 81571741, 81301875), New Century Excellent Talents in University Award and the Shanghai Foundation for Development of Science and Technology (Nos. 13NM1400400, 15140901300) and the Opening Foundation of State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics (Nos. T151108).
Publisher Copyright:
© Author(s) 2016.
PY - 2017/4
Y1 - 2017/4
N2 - Even though opening endothelial tight junctions is an efficient way to up-regulate brain drug delivery, the extravasation of blood-borne components from the compromised tight junctions can result in adverse consequences such as edema and neuronal injuries. In this work, we developed a nanoagonist that temporarily opened tight junctions by signaling adenosine 2A receptor, a type of G protein-coupled receptor expressed on brain capillary endothelial cells. Magnetic resonance imaging demonstrated remarkable blood-brain barrier permeability enhancements and significantly increased brain uptakes of both small molecular and macromolecular paramagnetic agents after nanoagonist administration. Gamma ray imaging and transmission electron microscope observed tight junction opening followed by spontaneous recovery after nanoagonist treatment. Immunofluorescence staining showed the unspoiled basal membrane, pericytes and astrocyte endfeet that enwrapped the vascular endothelium. Importantly, edema, apoptosis and neuronal injuries observed after hypertonic agent mediated tight junction-opening were not observed after nanoagonist intervention. The uncompromised neurovascular units may prevent the leakage of blood-borne constituents into brain parenchyma and accelerate tight junction recovery. Considering blood-brain barrier impermeability is a major obstacle in the treatment of central nervous system diseases, nanoagonist-mediated tight junction opening provides a promising strategy to enhance brain drug delivery with minimized adverse effects.
AB - Even though opening endothelial tight junctions is an efficient way to up-regulate brain drug delivery, the extravasation of blood-borne components from the compromised tight junctions can result in adverse consequences such as edema and neuronal injuries. In this work, we developed a nanoagonist that temporarily opened tight junctions by signaling adenosine 2A receptor, a type of G protein-coupled receptor expressed on brain capillary endothelial cells. Magnetic resonance imaging demonstrated remarkable blood-brain barrier permeability enhancements and significantly increased brain uptakes of both small molecular and macromolecular paramagnetic agents after nanoagonist administration. Gamma ray imaging and transmission electron microscope observed tight junction opening followed by spontaneous recovery after nanoagonist treatment. Immunofluorescence staining showed the unspoiled basal membrane, pericytes and astrocyte endfeet that enwrapped the vascular endothelium. Importantly, edema, apoptosis and neuronal injuries observed after hypertonic agent mediated tight junction-opening were not observed after nanoagonist intervention. The uncompromised neurovascular units may prevent the leakage of blood-borne constituents into brain parenchyma and accelerate tight junction recovery. Considering blood-brain barrier impermeability is a major obstacle in the treatment of central nervous system diseases, nanoagonist-mediated tight junction opening provides a promising strategy to enhance brain drug delivery with minimized adverse effects.
KW - Blood-brain barrier
KW - Brain drug delivery
KW - Dynamic contrast enhanced-magnetic resonance imaging
KW - Nanoagonist
KW - Vascular permeability
UR - http://www.scopus.com/inward/record.url?scp=85021826989&partnerID=8YFLogxK
U2 - 10.1177/0271678X16656198
DO - 10.1177/0271678X16656198
M3 - Article
C2 - 27342320
AN - SCOPUS:85021826989
SN - 0271-678X
VL - 37
SP - 1410
EP - 1424
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
IS - 4
ER -