Transport of nanomedicines across the blood-brain barrier: Challenges and opportunities for imaging and therapy.

The blood-brain barrier (BBB) is a protective and semipermeable border of endothelial cells that prevents toxins and foreign bodies to enter and damage the brain. Unfortunately, the BBB also hampers the development of pharmaceuticals targeting receptors, enzymes, or other proteins that lie beyond this barrier. Especially large molecules, such as monoclonal antibodies (mAbs) or nanoparticles, are prevented to enter the brain. The limited passage of these molecules partly explains why nanomedicines - targeting brain diseases - have not made it into the clinic to a great extent. As nanomedicines can target a wide range of targets including protein isoforms and oligomers or potentially deliver cytotoxic drugs safely to their targets, a pathway to smuggle nanomedicines into the brain would allow to treat brain diseases that are currently considered 'undruggable'. In this review, strategies to transport nanomedicines over the BBB will be discussed. Their challenges and opportunities will be highlighted with respect to their use for molecular imaging or therapies. Several strategies have been explored for this thus far. For example, carrier-mediated and receptor-mediated transcytosis (RMT), techniques to disrupt the BBB, nasal drug delivery or administering nanomedicines directly into the brain have been explored. RMT has been the most widely and successfully explored strategy. Recent work on the use of focused ultrasound based BBB opening has shown great promise. For example, successful delivery of mAbs into the brain has been achieved, even in a clinical setting. As nanomedicines bear the potential to treat incurable brain diseases, drug delivery technologies that can deliver nanomedicines into the brain will play an essential role for future treatment options.