The penetration of therapeutics across the blood-brain barrier: Classic case studies and clinical implications

Abstract

The blood-brain barrier (BBB) plays central roles in the maintenance and health of the brain. Its mechanisms to safeguard the brain against xenobiotics and endogenous toxins also make the BBB the primary obstacle to the development of drugs for the central nervous system (CNS). Here, we review classic examples of the intersection of clinical medicine, drug delivery, and the BBB. We highlight the role of lipid solubility (heroin), saturable brain-to-blood (efflux: opiates) and blood-to-brain (influx: nutrients, vitamins, and minerals) transport systems, and adsorptive transcytosis (viruses and incretin receptor agonists). We examine how the disruption of the BBB that occurs in certain diseases (tumors) can also be modulated (osmotic agents and microbubbles) and used to deliver treatments, and the role of extracellular pathways in gaining access to the CNS (albumin and antibodies). In summary, this review provides a historical perspective of the key role of the BBB in delivery of drugs to the brain in health and disease.

Graphical abstract

Figure 1

Mechanisms for therapeutic penetration across the BBB (A) A lipid-soluble substrate diffuses through the lipid bilayer of the cell membrane in a non-saturable manner. Acylation of substrates can enhance lipid solubility, allowing for increased BBB penetration (upper). However, substrates that are too lipid soluble are not able to exit the lipid bilayer, trapping them in the membrane. The physiochemical properties hydrogen bonding, charge, molecular weight, and protein binding inversely correlate with the ability to cross the BBB (lower). (B) Efflux systems modulate a substrate’s activity within the CNS. Some drugs exhibit peripheral effects, but with little or no CNS effects due to the affinity for efflux transporters. Aβ is a substrate for both LRP-1 and P-gp. (C) Some endogenous substrates have specific transporters that aid in delivery from blood to brain. These transporters can be saturable (LAT1) and mediated by receptor-ligand interactions (TfR). While not always selective, some transporters have been targeted by “Trojan horse”-mediated therapeutic delivery to the brain. (D) While lipid solubility is a good predictor of BBB penetration, charge can also play an important role. The glycocalyx and cell membrane play roles in substrate delivery due to interactions based on a substrate’s charge. CSF, brain parenchyma, and blood have slight variations in pH, impacting the charge interactions. Adsorptive transcytosis occurs when endocytosis is induced on the luminal surface, as occurs with wheat germ agglutinin (WGA). (E) BBB disruption is another technique used to enhance the delivery of therapeutics to the brain. Hypertonic solutions cause the brain endothelial cell to swell, disrupting the BBB, increasing paracellular transport. Focused ultrasound with microbubbles is another way to disrupt the BBB in a more targeted manner. Transcellular transcytosis through vesicular transport is also increased. However, these methods, though transient, can cause damage to healthy brain tissues. The figure was created with BioRender.