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

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 cerebro-spinal 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.

A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II

“…8 Third, idursulfase-IT is given as a bolus injection, followed by a flush of preservative-free saline, a procedure that may help drive the drug cephalad toward the brain. 9 Fourth, MPS II patients often have dilated Virchov-Robin spaces, which may result in enhanced drug delivery to the brain parenchyma. 9 In the pharmacokinetic analysis, we found a mean systemic bioavailability of 22-47% for idursulfase-IT at different doses, although limited information exists at the 1-mg dose.…”

“…9 Fourth, MPS II patients often have dilated Virchov-Robin spaces, which may result in enhanced drug delivery to the brain parenchyma. 9 In the pharmacokinetic analysis, we found a mean systemic bioavailability of 22-47% for idursulfase-IT at different doses, although limited information exists at the 1-mg dose. This was not unexpected, given the known clearance mechanisms for CSF.…”

“…This was not unexpected, given the known clearance mechanisms for CSF. 9 However, idursulfase-IT is not expected to supplant the need for weekly i.v. idursulfase to address certain somatic features of MPS II, particularly as idursulfase-IT therapy is administered monthly, not weekly, and is not dosed based on weight.…”

“…This novel approach is supported by existing knowledge of the leptomeningeal space and molecule transfer from CSF into the brain parenchyma. 8,9 …”

Interaction of SiO2 nanoparticles with neuronal cells: Ionic mechanisms involved in the perturbation of calcium homeostasis

“…This is of particular relevance for the nervous system (NS): nanoneuromedicine is rapidly gaining momentum (Gendelman et al, 2014),and silica NPs are good candidates for applications in this field, ranging from drug delivery (Rosenholmet al, 2011) to cell tracking and subcellular imaging (Montalti et al, 2014). They can pass the blood brain barrier (Kim et al, 2006); moreover, protocols for direct access of NPs to the cerebrospinal fluid have been proposed (Papisov et al, 2013). On the other hand, neurons are particularly delicate and sensitive cells, and even small functional perturbations that can be noninfluential in other cell types may have severe outcomes in the nervous tissue.…”