title: Nanoagonist-mediated endothelial tight junction opening: A strategy for safely increasing brain drug delivery in mice.
abstract: 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.
authors.affiliation: 1 Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Xihui
authors.initials: X
authors.lastname: Gao
authors.affiliation: 2 Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
authors.forename: Yuan-Cheng
authors.initials: YC
authors.lastname: Wang
authors.affiliation: 3 Department of Biomedical Engineering, The Pennsylvania State University, Philadelphia, PA, USA.
authors.forename: Yikang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 4 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yue
authors.affiliation: 1 Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Zining
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 1 Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Mengjing
authors.initials: M
authors.lastname: Ke
authors.affiliation: 1 Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Shengyuan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: 1 Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Li
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000648:ultrastructure; D002199:Capillary Permeability / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000648:ultrastructure; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D046529:Microscopy, Electron, Transmission; D049329:Nanostructures / Q000737:chemistry*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D058908:Adenosine A2 Receptor Agonists; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D043705:Receptor, Adenosine A2A
keywords: Nanoagonist; blood–brain barrier; brain drug delivery; dynamic contrast enhanced-magnetic resonance imaging; vascular permeability