Drug Targeting Organ-Specific Strategies

Although there is no cellular barrier preventing diffusion from the ventricular surface into
brain tissue (there are no tight junctions between the ependymal cells lining the ventricular
surface), the low speed of diffusion severely restricts tissue uptake of even small molecular
weight drugs and practically prevents the penetration of large molecules such as peptides and
proteins into deep tissue layers. Possible enzymatic inactivation and binding or sequestration
by brain cells along the diffusion path may even lower the actual drug concentrations in brain
interstitial spaces to levels lower than predicted from the molecular size and diffusion coefficients
[61]. Figure 2.7a shows an example of a large molecule, the 26-kDa nerve growth factor
(NGF), that could not penetrate into rat brain deeper than 1–2 mm from the infused ventricle.
This might be expected, as even small drugs show very steep concentration gradients
over a distance of only 2–3 mm from the ventricular surface (Figure 2.7b). Exceptions are
found in areas to which retrograde transport occurs, e.g. into the neurons of the basal cholinergic
nuclei in the case of NGF (Figure 2.7a).
After i.c.v. injection, the rate of elimination from the CNS compartment is dominated by
cerebrospinal fluid dynamics. The CSF, which is secreted by the choroid plexus epithelium
across the apical membrane, circulates along the surface and convexities of the brain in a rostral
to caudal direction. It is reabsorbed by bulk flow into the peripheral bloodstream at the
arachnoid villi within both cranial and spinal arachnoid spaces [62]. Of note is that the
turnover rate of total CSF volume is species dependent and varies between approximately
1 h in rats and 5 h in humans. In adult human brain, the total CSF volume amounts to
100–140 ml and the production rate is 21 ml h –1 [63]. Accordingly, the entire cerebrospinal
volume is exchanged regularly 4–5 times per day. This rapid drainage of CSF into peripheral
blood leads to relatively high drug concentrations in the peripheral circulation. For instance,
the concentration of methotrexate in peripheral blood reaches 1% of the ventricular CSF
concentration following intrathecal administration of the drug [64]. In Rhesus monkeys,
parenchymal concentrations of methotrexate of 1% of the intraventricular concentration
have been measured at a distance of 2 mm from the ependymal surface [65]. Therefore, the
concentration of methotrexate in the blood is actually higher than at tissue regions beyond
2 mm from the ependymal surface following intrathecal application.
2.4.2.2 Intraparenchymal Route
2.4 Drug Delivery Strategies 37
Restricted diffusion also limits tissue distribution after intraparenchymal drug administration,
as shown in Figure 2.7c and d. Distribution has been measured in the rat brain after implantation
of polymer discs containing NGF [66]. Drug concentrations decreased to less than
10% of the values measured on the disc surface within a distance of 2–3 mm, even after prolonged
periods of several days. Therefore, applying this approach in the larger human brain
would require the stereotaxic placement of multiple intraparenchymal depots, as has been
evaluated in rat brain [67], on a repetitive schedule.
The same pharmacokinetic limitation is true in principle for the implantation of encapsulated
genetically engineered cells, which synthesize and release neurotrophic factors [68].