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Strategies for delivering therapeutics across the blood–brain barrier

Nature Reviews Drug Discovery volume 20, pages 362–383 (2021)Cite this article

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Abstract

Achieving sufficient delivery across the blood–brain barrier is a key challenge in the development of drugs to treat central nervous system (CNS) disorders. This is particularly the case for biopharmaceuticals such as monoclonal antibodies and enzyme replacement therapies, which are largely excluded from the brain following systemic administration. In recent years, increasing research efforts by pharmaceutical and biotechnology companies, academic institutions and public–private consortia have resulted in the evaluation of various technologies developed to deliver therapeutics to the CNS, some of which have entered clinical testing. Here we review recent developments and challenges related to selected blood–brain barrier-crossing strategies — with a focus on non-invasive approaches such as receptor-mediated transcytosis and the use of neurotropic viruses, nanoparticles and exosomes — and analyse their potential in the treatment of CNS disorders.

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Fig. 1: Anatomy of brain vasculature.
Fig. 2: Spectrum of brain delivery technologies.
Fig. 3: Biological transport mechanisms for crossing the blood–brain barrier.
Fig. 4: Viral entry into the CNS.
Fig. 5: Nanocarriers for non-invasive brain delivery.

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Authors and Affiliations

  1. Cambrian Biopharma, New York, NY, USA

    Georg C. Terstappen

  2. DMPK and Bioanalytical Research, AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany

    Axel H. Meyer

  3. Rare Disease Research Unit, Worldwide Research, Development and Medicine, Pfizer, Cambridge, MA, USA

    Robert D. Bell

  4. Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, ON, Canada

    Wandong Zhang

  5. Department of Cellular and Molecular Medicine, Faculty of Medicine, Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada

    Wandong Zhang

Authors
  1. Georg C. Terstappen
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  2. Axel H. Meyer
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  4. Wandong Zhang
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Contributions

G.C.T., A.H.M. and W.Z. contributed equally to all aspects of the article. R.D.B. contributed to the concept and execution of a revised version.

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Correspondence to Georg C. Terstappen.

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Competing interests

G.C.T. is a Cambrian Biopharma employee and owns Cambrian Biopharma stock options. A.H.M. is an AbbVie employee and owns AbbVie stock options. R.D.B. is a Pfizer employee and owns Pfizer stock options. W.Z. declares no competing interests.

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Glossary

Parenteral administration

Drug administration by injection, infusion and implantation.

Transcytosis

A type of transcellular transport by which various types of macromolecule are transported across the interior of a cell, such as a cell monolayer or a barrier composed of a cell layer.

BBB cells

Blood–brain barrier (BBB) cells comprise the cerebral microvascular and capillary endothelial cells.

Polymersomes

Synthetic vesicular structures, analogous to liposomes, that are formed in solution by self-assembly of amphiphilic copolymers.

Ependymal cells

A type of neuroglia forming an epithelial layer that lines the ventricles and the central canal of the spinal cord.

Immunoliposomes

A new class of drug delivery system generated by coupling of antibodies to the surface of liposomes, which combines antibody-mediated tumour recognition with liposomal delivery.

Morris water maze

A behavioural test of spatial learning for rodents that is based on cues to navigate from a start location in an open swimming area to a submerged platform.

Multivesicular body

A type of late endosome that is formed following the inward budding of the outer endosomal membrane and characterized by the accumulation of vesicles in the lumen.

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Terstappen, G.C., Meyer, A.H., Bell, R.D. et al. Strategies for delivering therapeutics across the blood–brain barrier. Nat Rev Drug Discov 20, 362–383 (2021). https://doi.org/10.1038/s41573-021-00139-y

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