Drug delivery system for active brain targeting - Artificial Cells, Cell Engineering and Therapy - page 407

period of a few hours, and so allow the delivery of antineoplastic agents to the
human brain. In contrast to osmotic disruption methods, a biochemical opening
approach uses bradykinin receptor stimulation as a means to transiently increase
BBB permeability. Although from a quantitative point of view these approaches
look attractive, the risk of this barrier function loss may allow uncontrolled
access of solutes into the brain.
An intravenous (injectable) drug delivery technology for CNS-active bio-
pharmaceutical drugs will enhance treatment of many more brain disorders.
Currently, there are, however, no such brain drug delivery technologies on the
market for clinical use. One reason for this might be that these technologies still
involve potential safety hazards, such as the obstruction of brain entry of
essential compounds (like insulin or iron), or potentially dangerous interactions
with endogenous substrates.
Moreover, two routes have been proposed for the direct passage of drugs
from the nose to the brain: an intraneuronal and an extraneuronal pathway. This
suggests that even large molecules such as peptides (such as nerve growth
factor) could be transported from the nasal cavity to the CNS by nasal spray, and
will help to treat brain problems and other CNS disorders. The main advantage
of intranasal administration is the minimal invasiveness. It also offers several
other advantages. For example, in imaging technologies, it can allow the rapid
diagnosis and assessment of acute brain injury in stroke and trauma.
Although these modes of delivery are traditional, the risks of infection and
neuropathological changes due to disruption of the BBB emphasize the need to
develop new noninvasive delivery strategies.
17.2.2 Pharmaceutical strategies
Pharmacologic-based strategies include small molecules, lipidization strategies,
liposomes and nanoparticles. Small molecules are delivered to the brain in
proportion to the lipid solubility of the compound, providing there is no
significant plasma protein binding of the drug. However, what is not generally
appreciated is that there is a molecular mass threshold of lipid soluble small
molecule transport through the BBB and this threshold has been estimated at
400±600 Da. Indeed, essentially all small molecule drugs that are currently in
neuropathological practice fulfill the dual criteria of lipid-solubility and a
molecular mass less than a threshold of 500 Da. Lipidization also increases its
penetration in other tissues in the body and decreases systemic exposure.
Another possibility to increase the passive diffusion of drugs through the BBB is
the encapsulation of the compound into small liposomes or nanoparticles.
Liposomes, even small unilamellar vesicles of 50 nm in diameter, are too large
to undergo transport through the BBB. Although the mechanism is not fully
understood, nanoparticle delivery to the brain may be a promisingly strategy for
the treatment of brain tumors.