Nano-ghosts for selective drug delivery across the blood-brain barrier

Many central nervous system disorders, including neuroinflammatory and malignant diseases, are severely undertreated due to the pharmacological limitations posed by the blood-brain barrier (BBB). The BBB is formed by impermeable tight junctions between brain capillary endothelial cells (BCEC) and serves as a selective barrier, regulating the homeostasis of the brain and protecting it from toxic substances. Unfortunately, in many cases the BBB also disrupts the passage of drugs from the blood to the brain.

In order to overcome these limitations, we aim to modify our mesenchymal stem cell (MSC) nano-ghost (NG) drug delivery system to allow transport across the BBB. The NGs are nano-vesicles produced from the plasma membrane of human mesenchymal stem cells which possess membrane-associated targeting and migratory abilities to and through the BBB, and towards sites of inflammation. The NGs are expected to retain the cell surface moieties and encompass their unique targeting capabilities, and therefore may serve as an effective drug delivery system for targeting neuroinflammatory disorders. Our primary hypothesis is, therefore, that brain targeting of a healthy or diseased BBB can be accomplished by NGs.

Our results show that NGs pass the BBB, both in vitro and in vivo. Transport of NGs through an in vitro BBB model was almost identical to that through a control transwell. In vitro results also show that NGs selectively target microglial cells as well as glioma cells. Biodistribution studies on EAE mice show that NGs selectively accumulated in the animals’ brains and spinal cords and could be detected in and around sclerotic lesions. We were able to show that prednisolone-loaded NGs which were injected to EAE mice improved their clinical scores over time, while control groups eventually deteriorated. Preliminary results in a glioblastoma mouse model suggest that the NGs can be affective for treating brain tumors as well.