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Cited by 97Cerebrospinal fluid and hydrocephalusBarrier Structure and Function StudiesNanoparticle-Based Drug Delivery

Physiology of the Intrathecal Bolus: The Leptomeningeal Route for Macromolecule and Particle Delivery to CNS

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Papisov, Mikhail I., Belov, Vasily V., Gannon, Kimberley S.·2013·Molecular Pharmaceutics
DOI 10.1021/mp300474mPMC PMC3646927
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Abstract

Presently, there are no effective treatments for several diseases involving the CNS, which is protected by the blood-brain, blood-CSF, and blood-arachnoid barriers. Traversing any of these barriers is difficult, especially for macromolecular drugs and particulates. However, there is significant experimental evidence that large molecules can be delivered to the CNS through the cerebrospinal fluid (CSF). The flux of the interstitial fluid in the CNS parenchyma, as well as the macro flux of CSF in the leptomeningeal space, are believed to be generally opposite to the desirable direction of CNS-targeted drug delivery. On the other hand, the available data suggest that the layer of pia mater lining the CNS surface is not continuous, and the continuity of the leptomeningeal space (LMS) with the perivascular spaces penetrating into the parenchyma provides an unexplored avenue for drug transport deep into the brain via CSF. The published data generally do not support the view that macromolecule transport from the LMS to CNS is hindered by the interstitial and CSF fluxes. The data strongly suggest that leptomeningeal transport depends on the location and volume of the administered bolus and consists of four processes: (i) pulsation-assisted convectional transport of the solutes with CSF, (ii) active "pumping" of CSF into the periarterial spaces, (iii) solute transport from the latter to and within the parenchyma, and (iv) neuronal uptake and axonal transport. The final outcome will depend on the drug molecule behavior in each of these processes, which have not been studied systematically. The data available to date suggest that many macromolecules and nanoparticles can be delivered to CNS in biologically significant amounts (>1% of the administered dose); mechanistic investigation of macromolecule and particle behavior in CSF may result in a significantly more efficient leptomeningeal drug delivery than previously thought.

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  • Widespread penetration of substances from CSF into brain parenchyma along perivascular spaces of arteries is well supported by animal studies with a similar experimental setup.

    “Widespread penetration of substances from CSF into brain parenchyma along perivascular spaces of arteries is, however, well supported by animal studies with a similar experimental setup to ours (1, 47-49).”

    From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [48]

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Authors
Papisov, M. I., Belov, V. V., & Gannon, K. S.
Affiliations
  • Harvard University (US)
  • NeuroPhage Pharmaceuticals, Inc., 222 Third Street, Suite 3120 Cambridge, Massachusetts 02142, United States
Corresponding author
Papisov, Mikhail I.
ORCID
Venue
Molecular Pharmaceutics
Publisher
American Chemical Society (ACS)
Published
2013-02-12
Volume
10
Issue
5
Pages
1522-1532
ISSN
  • 1543-8384 (ISSN-L)
  • 1543-8392
DOI
10.1021/mp300474m
PMC
PMC3646927
OpenAlex
W1974078894
Cited by
97
References
7
Citations by year
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FWCI
0.58
Type
journal article
Language
en
Open access
Locations
  • Molecular Pharmaceutics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R21CA152384)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
cerebrospinal fluid, macromolecule transport, nanoparticles, blood-CSF barrier, blood-brain barrier, pia mater, axonal transport, neuronal uptake, brain drug delivery
MeSH terms
Animals, Axonal Transport, Biological Transport, Active, Blood-Brain Barrier, Brain, Central Nervous System Agents, Central Nervous System Diseases, Humans, Injections, Spinal, Meninges, Drug Delivery Systems, Models, Animal, Macromolecular Substances

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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