Harnessing cerebrospinal fluid circulation for drug delivery to brain tissues

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.