title: Overcoming the blood-brain barrier for delivering drugs into the brain by using adenosine receptor nanoagonist.
abstract: The extremely low permeability of the blood-brain barrier (BBB) poses the greatest impediment in the treatment of central nervous system (CNS) diseases. Recent work indicated that BBB permeability can be up-regulated by activating A2A adenosine receptor (AR), which temporarily increases intercellular spaces between the brain capillary endothelial cells. However, due to transient circulation lifetime of adenosine-based agonists, their capability to enhance brain delivery of drugs, especially macromolecular drugs, is limited. In this work, a series of nanoagonists (NAs) were developed by labeling different copies of A2A AR activating ligands on dendrimers. In vitro transendothelial electrical resistance measurements demonstrated that the NAs increased permeability of the endothelial cell monolayer by compromising the tightness of tight junctions, the key structure that restricts the entry of blood-borne molecules into the brain. In vivo imaging studies indicated the remarkably up-regulated brain uptake of a macromolecular model drug (45 kDa) after intravenous injection of NAs. Autoradiographic imaging showed that the BBB opening time-window can be tuned in a range of 0.5-2.0 h by the NAs labeled with different numbers of AR-activating ligands. By choosing a suitable NA, it is possible to maximize brain drug delivery and minimize the uncontrollable BBB leakage by matching the BBB opening time-window with the pharmacokinetics of a therapeutic agent. The NA-mediated brain drug delivery strategy holds promise for the treatment of CNS diseases with improved therapeutic efficiency and reduced side-effects.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Xihui
authors.initials: X
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.forename: Shuyan
authors.initials: S
authors.lastname: Zheng
authors.forename: Yinzhi
authors.initials: Y
authors.lastname: Changyi
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.forename: Shenghong
authors.initials: S
authors.lastname: Ju
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhu
authors.forename: Cong
authors.initials: C
authors.lastname: Li
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002460:Cell Line; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D051379:Mice; D049329:Nanostructures; D010539:Permeability / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D058908:Adenosine A2 Receptor Agonists; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D043705:Receptor, Adenosine A2A