Understanding the Blood-Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics

Abstract

This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of blood-brain barrier (BBB) transport and intra-CNS distribution in relation to CNS target site(s) exposure. To this end, we need to obtain and integrate quantitative and connected data on BBB using the Combinatory Mapping Approach that includes in vivo and ex vivo animal measurements, and the physiologically based comprehensive LEICNSPK3.0 mathematical model that can translate from animals to humans. For small molecules, slow diffusional BBB transport and active influx and efflux BBB transport determine the differences between plasma and CNS pharmacokinetics. Obviously, active efflux is important for limiting CNS drug delivery. Furthermore, liposomal formulations of small molecules may to a certain extent circumvent active influx and efflux at the BBB. Interestingly, for CNS pathologies, despite all reported disease associated BBB and CNS functional changes in animals and humans, integrative studies typically show a lack of changes on CNS drug delivery for the small molecules. In contrast, the understanding of the complex vesicle-based BBB transport modes that are important for CNS delivery of large molecules is in progress, and their BBB transport seems to be significantly affected by CNS diseases. In conclusion, today, CNS drug delivery of small drugs can be well assessed and understood by integrative approaches, although there is still quite a long way to go to understand CNS drug delivery of large molecules.

Figure 1

The Combinatory Mapping Approach. The combinatory Mapping Approach, providing partition coefficients of unbound drug (K_{p ,uu} values) between multiple CNS compartments: brain interstitial/extracellular fluid (brainECF = brainISF), brain intracellular fluid (brainICF), brain cell lysosomes, via measurements and/or calculations, also including compartment pH and pKa dependent neutral and charged drug molecules. The extent of transport between plasma and CSF is described by the blood‐cerebrospinal fluid barrier (BCSFB). BBB, blood‐brain barrier; CNS, central nervous system; CSF, cerebrospinal fluid.

Figure 2

The LEICNSPK3.0 model. (a) The LEICNSPK3.0 model structure, including peripheral, plasma, and multiple CNS compartments (brainECF, brainICF, brain cell lysosomes, and CSF in LV = lateral ventricle, TFV = third and fourth ventricle, CM = cisterna magna; and SAS = subarachnoid space), (brainECF bulk flow and CSF flow), pH and pKa dependent neural and charged drug molecules, and brain membrane (nonspecific) binding. (b) Model predictions overlayed actual data observed in rats. (c) Model prediction and actual data observed in humans.CNS, central nervous system; CSF, cerebrospinal fluid; ECF, extracellular fluid.

Figure 3

Schematic processes involved in the fate of the drug, using liposomal formulation for targeted brain drug delivery. Liposomal release of the drug in plasma, liposomal transport across the BBB, and liposomal release of the drug into brainECF should be considered as well as plasma PK, BBB transport, brain delivery, and intra‐brain distribution of the unbound drug itself. The drug can reach the target site via a liposome as a carrier (black dashed line) or as the released unbound drug (black full line). After intravenous administration of the liposome containing the drug, the following can happen: [1] The drug can be released from the liposome in the blood and reversibly bind to plasma proteins. It is only the unbound drug that can cross the BBB or BCSFB to reach the brainECF: [2] The liposome can fuse with the BBB cell membrane and release the drug into the cytosol of the BBB endothelial / BCSFB epithelial cells; [3] The liposome may undergo endocytosis in the BBB / BCSFB and release the drug into the intracellular fluid of the BBB endothelial / BCSFB epithelial cells; [4] The liposome can cross the BBB / BCSFB via transcytosis to reach the brainECF, followed by drug release into the brainECF / CSF. The unbound drug can exchange between brainECF and CSF, and between brainECF and brainICF; [5] The liposome may enter brainICF and can release the drug in the brainICF. Only the unbound drugs that reach the brainECF and/or brainICF (red dashed circles) are available for target site binding in these physiological compartments to induce their pharmacological effect. BBB, blood‐brain barrier; BCSFB, blood‐cerebrospinal fluid barrier; CSF, cerebrospinal fluid; ECF, extracellular fluid; PK, pharmacokinetic.