Recent advances in blood-brain barrier disruption as a CNS delivery strategy

The blood-brain barrier (BBB) is a complex functional barrier composed of endothelial cells, pericytes, astrocytic endfeets and neuronal cells. This highly organized complex express a selective permeability for molecules that bear, amongst other parameters, adequate molecular weight and sufficient liposolubility. Unfortunately, very few therapeutic agents currently available do cross the BBB and enters the CNS. As the BBB limitation is more and more acknowledged, many innovative surgical and pharmacological strategies have been developed to circumvent it. This review focuses particularly on the osmotic opening of the BBB, a well-documented approach intended to breach the BBB. Since its inception by Rapoport in 1972, pre-clinical studies have provided important information on the extent of BBB permeation. Thanks to Neuwelt and colleagues, the osmotic opening of the BBB made its way to the clinic. However, many questions remain as to the detailed physiology of the procedure, and its best application to the clinic. Using different tools, amongst which MRI as a real-time in vivo characterization of the BBB permeability and CNS delivery, we attempt to better define the osmotic BBB permeabilization physiology. These ongoing studies are described, and data related to spatial and temporal distribution of a molecule after osmotic BBB breaching, as well as the window of BBB permeabilization, are discussed. We also summarize recent clinical series highlighting promising results in the application of this procedure to maximize delivery of chemotherapy in the treatment of brain tumor patients.