Drug Discovery and the BBBModulating the paracellular pathway at the blood-brain barrier: current and future approaches for drug delivery to the CNS

The blood-brain barrier (BBB) is the tightly regulated point of entry by which any neuro-targeting therapy must pass through. BBB modulation is a means to loosen the size exclusion properties of the barrier by temporarily interfering with the formation of intercellular tight junction (TJ) or adheren junction (AJ) complexes, allowing for diffusion of small molecule therapeutics from blood to brain. Several technologies, such as RNAi, peptidomimetics, high frequency ultrasound and nanoparticles, have been developed and refined over the years, paving the way for barrier modulation to become an effective part of conventional central nervous system therapies. Here, we review the current and future approaches aimed at facilitating enhanced drug delivery to the central nervous system (CNS).