Figure 2.

The Blood Brain Barrier. (A) Schematic of the BBB shown in cross-section. Main cellular components are shown. Endothelial cells are fused together by tight junctions, and surrounded by pericytes and astrocytic end feet. Figure adapted from (59). (B) Transport pathways across the Blood Brain Barrier. Ions, water and other small molecules necessary to maintain CNS homeostasis (such as glucose for metabolic support) can cross the BBB using a variety of mechanisms, including those based on passive diffusion, from high to low concentrations, and active transport, requiring ATP hydrolysis. Molecules can cross the BBB using either paracellular (between cells) or transcellular (across cells) pathways. Receptor-mediated transcytosis (RMT) allows selective uptake of macromolecules, including plasma proteins, enzymes, hormones and growth factors, via receptors expressed on the luminal side of the BBB. Trojan horse antibody strategies exploit RMT to enable delivery of conjugated drugs within the CNS. Adsorptive-mediated transport (AMT) relies on the electrostatic interaction between positively charged molecules (in general charged peptide moieties) and the negatively charged plasma membrane. Carrier-mediated transport (CMT) is an energy-dependent mechanism, allowing co-transport of molecules, either in the same direction (symport) or in the opposite direction (antiport). Active efflux transport (AET) is involved in the clearance of molecules, including drugs, from the brain. Due to the general impermeability of the BBB and the reliance on specialized and specific transport mechanisms for transport of molecules into the CNS, high molecular weight therapeutics, such as mAbs and their derivatives, are largely excluded from the CNS. Figure adapted from (60).