Review Article | Published:

From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery

Nature Reviews Drug Discovery volume 15, pages 275292 (2016) | Download Citation

Abstract

One of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders is achieving sufficient blood–brain barrier (BBB) penetration. Research in the past few decades has revealed that the BBB is not only a substantial barrier for drug delivery to the CNS but also a complex, dynamic interface that adapts to the needs of the CNS, responds to physiological changes, and is affected by and can even promote disease. This complexity confounds simple strategies for drug delivery to the CNS, but provides a wealth of opportunities and approaches for drug development. Here, I review some of the most important areas that have recently redefined the BBB and discuss how they can be applied to the development of CNS therapeutics.

Key points

  • The blood–brain barriers (BBBs) are dynamic, adaptable, interactive monolayers of cells, including endothelial, ependymal and tanycytic cells, that participate in central nervous system (CNS) protection, are responsible for CNS nutrition and homeostasis, and facilitate serum-based brain–body communications.

  • The cells forming the BBB are in communication with other cells of the CNS, thus forming the neurovascular unit. This communication informs the BBB of the needs of the CNS, allowing it to adapt to the needs of the CNS.

  • The BBB also communicates with circulating immune cells and via blood-borne signals with the peripheral tissues. Through transport, secretion and other mechanisms, the BBB relays information between the periphery and the CNS.

  • The complexity of the BBB complicates CNS drug delivery, but also provides many unique opportunities for drug delivery. Manipulation of transporters, secretory functions, the extracellular pathways, and adsorptive transcytosis are examples of promising approaches to drug development.

  • The complexity of the BBB predisposes it to dysfunctions that can result in or promote disease. Such dysfunctions include BBB disruption as well as dysfunctions related to BBB transporters, neurovascular unit communication and secretion. Thus, the BBB itself can be a therapeutic target.

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Acknowledgements

The author is supported by the US Department of Veterans Affairs and a grant from the US National Institute on Aging (grant R01 AG046619).

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  1. Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center and Department of Medicine, University of Washington School of Medicine, Division of Gerontology and Geriatric Medicine, 1660 South Columbian Way, Seattle, Washington 98108, USA.

    • William A. Banks

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Glossary

Blood–brain barrier

(BBB). The modified capillary bed of the brain; can be conceptualized as those processes that, taken together, control the exchange of substances between the blood and the fluids (cerebrospinal fluid and brain interstitial fluid) of the central nervous system (CNS).

Neurovascular unit

(NVU). For the purposes of this Review, this refers to the concept that the cells forming the BBB are in communication with other cells of the central nervous system (CNS) and, by extension, with the circulating immune cells, and with the peripheral tissues via blood-borne secretions.

Transporters

Proteins that provide a mechanism by which substances can be carried from one side of the blood–brain barrier (BBB) to the other, thus greatly increasing (for blood-to-brain transporters) or greatly decreasing (for brain-to-blood transporters) the central nervous system (CNS) uptake of a substance in comparison with that predicted based on its physicochemical characteristics.

Polarization

A characteristic of the blood–brain barrier (BBB), arising from different characteristics of its abluminal and luminal surfaces, including differing levels of enzymes, glycoproteins, lipid composition and transporters.

Active transport

Transport by an energy-requiring transporter that can move its ligand against a concentration gradient.

Facilitated diffusion

Transport by a non-energy-requiring transporter that moves it ligand down a concentration gradient.

Adsorptive transcytosis

A mechanism by which glycoproteins or highly chargedmolecules bind to brain endothelial cell (BEC) glycoproteins, inducing vesicles that are routed to the opposite membrane.

Passive diffusion

The mechanism by which a substance crosses the blood–brain barrier (BBB) by non-saturable means, with the degree of passage depending on the physicochemical characteristics of the substance.

Extracellular pathways

Areas such as the pial surface and subarachnoid space that are deficient in a blood–brain barrier (BBB) and thus allow small amounts of blood-borne substances, including albumin and immunoglobulins, to access the brain primarily through the Virchow–Robin spaces.

Neurovascular hypothesis

The hypothesis that the impaired ability of the blood–brain barrier (BBB) to remove amyloid-β peptide from the central nervous system (CNS) contributes to amyloid-β accumulation and the progression of Alzheimer disease.

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DOI

https://doi.org/10.1038/nrd.2015.21

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