RNAi Therapeutic Delivery by Exosomes - RNA Interference from Biology to Therapeutics - page 184

unit consists of endothelial cells, basement membrane, pericytes, astrocytes, and
microglial cells [ 11 ]. The brain endothelial cells are the central cells in the BBB,
and these are tightly interconnected through complexes of tight and adherence
junctions that form an impermeable barrier for almost all substances, even small
hydrophilic molecules. Furthermore, these cells display remarkably low levels of
transcytosis, the process of vesicular trafficking of macromolecules across cells, yet
express specific receptors for transport of vital nutrients for the brain parenchyma
[ 12 ]. In addition, endothelial cells of the BBB express high levels of drug efflux
proteins that protect the brain from toxic substances [ 13 ]. Pericytes, which line the
entire surface of the BBB, were thought to only provide structural support to the
vasculature but have recently also been identified as key regulators of vesicular
trafficking in neighboring endothelial cells [ 14, 15 ]. The two glial cell types have
distinct functions in the BBB; astrocytes display extensions, called end feet, which
cover the entire cerebral vasculature and are thought to control endothelial junctions
as well as regulate water homeostasis at the BBB [ 16 ], whereas microglial cells are
the resident immune cells of the CNS [ 17 ]. Finally, the basement membrane is the
extracellular matrix that connects the above-mentioned cells and provides structural
support. In conclusion, the BBB is a tightly regulated biological barrier that protects
the brain from potentially harmful substances while allowing highly regulated
uptake of vital nutrients. In light of this, it is not surprising that only few drugs are
active in the brain following systemic delivery, and it has actually been estimated
that 98% of all small molecules do not cross the BBB.

9.2.2 Drug Delivery to Brain

As aforementioned, there is no paracellular pathway of solute exchange between
blood and brain, and there is minimal endocytosis, and consequently no significant
transcellular pathway for free solute exchange. Basically, there are only two known
mechanisms by which molecules in the blood can get access to brain interstitial
fluid (1) lipid-mediated transport of lipophilic substances below 400 Da and (2)
catalyzed transport, which includes carrier-mediated transport for small molecules
such as glucose and amino acids and receptor-mediated transport (RMT) for large
molecules such as insulin and transferrin [ 11 ] .
Several approaches have been attempted for the delivery of macromolecular
drugs across the BBB. These include local invasive delivery by direct injection or
infusion (e.g., nerve growth factor) [ 18 ], the olfactory route (e.g., insulin) [ 19 ] , and
nonselective osmotic or biochemical opening of the BBB [ 20, 21 ] . These routes of
delivery have all been hindered by several setbacks, including low efficacy of trans-
port across the BBB and serious limiting safety issues associated with neurosurgical
intervention or with nonselective permeation of the BBB.
Only a few successful systems have been reported for noninvasive systemic
delivery to brain. All of these utilize the RMT system for targeted delivery. Exploiting
RMT for brain delivery of macromolecules has been extensively studied by the
group of Pardridge [ 22, 23 ]. This has been accomplished by utilizing chimeric