An efficient drug delivery system crossing the blood-brain barrier in response to glycemic control

We are developing an efficient blood-brain barrier(BBB)-crossing drug delivery system utilizing a physiological glucose transport pathway via glucose transporter-1(GLUT1). Several drug carriers targeting GLUT1 by incorporating glucose as the ligand have been tried, but none of them was transported into the brain at a high level upon intravenous administration. Thus, we adopted an original biological strategy of glycemic control. We constructed a self-assembled supramolecular micellar nanoparticle, having a property as a drug carrier, decorated with glucose ligands on the surface. Intravenously injected glucose-decorated nanoparticle accumulated highly in the brains of mice in response to an increase of glycemic concentration after a prior fasting condition. We observed the transport of glucose-decorated nanoparticle from cerebral blood vessels into brain parenchyma in real time, and identified the delivery of glucose-decorated nanoparticle into neurons and microglia. The BBB-crossing delivery is considered to occur along with the phenomenon of intracellular recycling of GLUT1 in the brain microvascular endothelial cells. Our novel BBB-crossing technology introducing glycemic control as an animal-side conditioning is expected to become a powerful tool for delivering high molecular drugs such as oligonucleotide and monoclonal antibody drugs, to achieve effective disease modifying therapy in the brain.