The blood-brain barrier (BBB) is a highly selective semipermeable border that separates the circulating blood from the brain's extracellular fluid. Its primary function is to protect the brain by preventing the entry of harmful substances. However, this protective feature also poses a significant challenge for drug delivery to the brain. Here, we explore the different mechanisms by which small molecule drugs and larger biologic drugs can be transported across the BBB.
Small Molecule Drugs
Small molecule drugs typically cross the BBB through passive diffusion or facilitated transport:
Passive Diffusion: This is the most common mechanism for small lipophilic molecules. Drugs that are non-polar and have a low molecular weight can dissolve in the lipid bilayer of the endothelial cells that form the BBB and diffuse across it down their concentration gradient.
Facilitated Transport: Some small molecule drugs are transported across the BBB via carrier-mediated transport systems. These are specialized proteins embedded in the cell membrane that bind to the drug molecule and carry it across the cell membrane.
Larger Biologic Drugs
Transporting larger biologic drugs, such as proteins and antibodies, across the BBB is more challenging due to their size and polarity. However, several mechanisms exist:
Receptor-Mediated Transcytosis (RMT): This is the primary mechanism for transporting large molecules across the BBB. Specific receptors on the endothelial cells bind to the drug molecule, triggering endocytosis (the formation of a vesicle around the molecule). The vesicle is then transported across the cell and released on the other side, a process known as transcytosis.
Adsorptive-Mediated Transcytosis (AMT): This mechanism involves the nonspecific adsorption of positively charged molecules to the negatively charged cell surface, triggering endocytosis and subsequent transcytosis.
While the BBB serves an essential protective function for the brain, it also presents a significant hurdle for drug delivery. Understanding the mechanisms by which drugs can cross the BBB is crucial in the development of effective treatments for neurological conditions. Advances in research continue to provide innovative strategies to enhance the transport of both small molecule and biologic drugs across the BBB.