Advanced Imaging Approaches in Drug Discovery: Exploring Macromolecular Biodistribution to Brain Targets.

One of the greatest challenges to developing effective therapeutics targeting neurological disease lies in clearly understanding drug biodistribution and delivery mechanisms. The blood-brain barrier is a highly organized and nearly impermeable border made up of tightly packed endothelial cells that line the blood vessels and separate circulating blood from the brain's tissues and extracellular fluid in the central nervous system (CNS). A potential strategy for the delivery of large molecule therapeutics to the brain via systemic administration relies upon brain endothelial cell receptor-targeted approaches that allow for crossing the blood-brain barrier. Advanced imaging techniques are employed in order to evaluate the efficacy of such approaches. Using super resolution scanning laser microscopy, we are able to assess the cell-type specificity and subcellular distribution of both the receptor targets and the transport vehicle itself in the brain in vivo and thus better understand the kinetics of target engagement. To evaluate the larger scale biodistribution of potential therapeutics, we employ light sheet microscopy for whole brain imaging in cleared samples. Ongoing efforts are focused on improving both the throughput and reproducibility of these approaches in order to integrate image-based screening for drug delivery and target engagement into the neurodegenerative drug development workflow.