Overcoming the Blood–Brain Barrier for Delivering Drugs into the Brain by Using Adenosine Receptor Nanoagonist
- Xihui Gao
- ,
- Jun Qian
- ,
- Shuyan Zheng
- ,
- Yinzhi Changyi
- ,
- Jianping Zhang
- ,
- Shenghong Ju
- ,
- Jianhua Zhu
- , and
- Cong Li
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.
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