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Cited by 95Cerebrospinal fluid and hydrocephalusBarrier Structure and Function StudiesAdvanced Drug Delivery Systems

Harnessing cerebrospinal fluid circulation for drug delivery to brain tissues

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Naseri Kouzehgarani, Ghazal, Feldsien, Thomas, Engelhard, Herbert H., Mirakhur, Kuldip K., Phipps, Colin, Nimmrich, Volker, Clausznitzer, Diana, Lefebvre, Didier R.·2021·Advanced Drug Delivery Reviews
DOI 10.1016/j.addr.2021.03.002
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Abstract

Initially thought to be useful only to reach tissues in the immediate vicinity of the CSF circulatory system, CSF circulation is now increasingly viewed as a viable pathway to deliver certain therapeutics deeper into brain tissues. There is emerging evidence that this goal is achievable in the case of large therapeutic proteins, provided conditions are met that are described herein. We show how fluid dynamic modeling helps predict infusion rate and duration to overcome high CSF turnover. We posit that despite model limitations and controversies, fluid dynamic models, pharmacokinetic models, preclinical testing, and a qualitative understanding of the glymphatic system circulation can be used to estimate drug penetration in brain tissues. Lastly, in addition to highlighting landmark scientific and medical literature, we provide practical advice on formulation development, device selection, and pharmacokinetic modeling. Our review of clinical studies suggests a growing interest for intra-CSF delivery, particularly for targeted proteins.

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Authors
Naseri Kouzehgarani, G., Feldsien, T., Engelhard, H. H., Mirakhur, K. K., Phipps, C., Nimmrich, V., Clausznitzer, D., & Lefebvre, D. R.
Affiliations
  • AbbVie (United States) (US)
  • University of Illinois Chicago (US)
  • AbbVie (Germany) (DE)
Corresponding author
Lefebvre, Didier R.
ORCID
Venue
Advanced Drug Delivery Reviews
Publisher
Elsevier BV
Published
2021-06
Volume
173
Pages
20-59
ISSN
0169-409X (ISSN-L)
DOI
10.1016/j.addr.2021.03.002
OpenAlex
W3134967225
Cited by
95
References
32
Citations by year
2026: 15 · 2025: 29 · 2024: 15 · 2023: 14 · 2022: 18 · 2021: 4
FWCI
1.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Advanced Drug Delivery Reviews (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
AbbVie Inc
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
cerebrospinal fluid flow, brain drug delivery, glymphatic system, hydrodynamic modeling, pharmacokinetic modeling, formulation development, infusion devices
MeSH terms
Brain, Cerebrospinal Fluid, Pharmaceutical Preparations, Humans, Drug Delivery Systems

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