(Nanowerk Spotlight) The use of minute particles as drug carriers
for targeted therapy has been studied
and discussed for more than 20 years. A
selective accumulation of active substances
in target tissues has been demonstrated for
certain so-called nanocarrier systems that
are administered bound to pharmaceutical
drugs. Great expectations are placed
on nanocarrier systems that can overcome
natural barriers such as the blood-brain
barrier (BBB) and transport the medication
directly to the desired tissue and thus heal
neurological diseases that were formerly
incurable. The BBB represents the border
between the circulating blood and the fluid
in the central nervous system. It functions
to protect the sensitive nerve cells from foreign
substances and infections from the
blood. Whether nanoparticles enter the
central nervous system unintentionally and
induce health problems is also being debated.
This dossier illustrates how the BBB
functions and the positive effects of the new
therapy possibilities, but also discusses the
negative impacts of nanoparticles that
enter the brain unintentionally.
The blood-brain barrier
The brain is permeated with a network of
fine blood vessels. These so-called capillaries
supply the brain with nutrients and
oxygen. Combined, the walls of these blood
vessels form the so-called blood-brain barrier.
In all mammals, as well as in humans,
it serves as a physiological barrier between
the blood circulation system and the brain.
Its task is to protect the brain from diseasecausing
agents, toxins and messenger
substances circulating in the blood. The
BBB therefore represents a highly selective
filter through which the nutrients needed
by the brain pass in one direction and the
resulting metabolic wastes in the other. This
supply and removal involves a series of
special transport processes.
Within the central nervous system, the
spaces between the neurons (nerve cells)
are almost entirely filled by glia or endothelial
cells and their processes (Figure 1).
Figure 1: The blood-brain barrier; above, cross section through the brain; center, schematic representation of the BBB; below, cellular structure. (Source: Ref. 11)
The metabolism of the nerve cells is via these
endothelial cells. These cells serve to insert,
isolate and supply the nerve cells and their
neurons. One type of glia cells are the astrocytes
(Figure 2). They bear numerous processes
with which they attach themselves to
the walls of the capillaries and form a nearly
uninterrupted coating surrounding the
capillaries. One feature distinguishes the vessel
walls of the capillaries that form the
blood-brain barrier from other blood vessels
in the body: there is a solid connection
between the adjoining vessel wall cells (socalled
capillary endothelial cells).
Figure 2: Schematic illustration of the capillaries in the brain, a) capillaries with astrocytes on the surface, b) cross section through a capillary. (Source: Ref. 12)
They are
formed by special protein complexes known
as tight junctions. Tight junctions (Figure 3)
are slender bands consisting of membrane
proteins that entirely wound around the epithelial
cells and are in close contact with the
bands of the neighboring cells. This enables
the tight junctions to seal the cell interspaces
and form a so-called diffusion barrier that
controls the flow of molecules across the epithelium.
Tight junctions therefore have three key functions:
i) a barrier function by closing up the
intercellular spaces, ii) the mechanical stabilization
of the epithelial cell aggregates and
iii) maintaining the polarity of the epithelial
cells by preventing the free floating of membrane
components along the cell membranes.
Substances that need to enter the
brain from the blood or move from the brain
into the blood cannot circumvent these
cells, but must be channeled directly through
the vessel wall cells by special transport systems
(Figure 4). This controlled process enables
a selective exchange of substances between
nerve cells and blood, and protects
the nerve cells from penetration by harmful
substances. Those substances that are necessary
for supplying the brain can pass unhindered,
namely oxygen and carbon dioxide.
At the same time, specific transport systems
transfer D-glucose, D-hexose, several
L-amino acids and certain lipid-soluble
substances through the BBB. This is accompanied
by a release of degradation products
into the blood. The terminal processes
of the astrocytes represent a barrier for numerous
substances such as certain hormones,
non-lipid-soluble, water-soluble and chemical
substances, along with proteins, which
helps maintain a constant milieu for the neurons
of the nervous system.
Figure 3: Schematic illustration of tight junctions. (Source: Ref. 13)
The permeability of the blood-brain barrier
is also affected by fluctuations of physiological
conditions. Thus, normal life processes
can trigger temporary fluctuations in permeability.
Chronically altering the permeability
of the BBB or of the capillary walls can enable
the passage of substances and damage
the surrounding nerve cells. For example,
strong temperature increases promote
BBB permeability. Medical therapies can take
advantage of this phenomenon. At the same
time, this barrier hinders or prevents many
potential treatments of neurological diseases
because many active substances cannot pass
the BBB. Overcoming the BBB is therefore
an important field of current research that
seeks better treatments for diseases of the
central nervous system.
As noted above, the BBB – despite its function
as a protective barrier – must also enable
the transport of nutrients to the brain
and the corresponding removal of metabolic
products. Accordingly, water-soluble substances
and peptides overcome this barrier
via specific transporters or special canals in
the cell membrane (diffusion, paracellular
transport, specific transporter proteins, receptor-
mediated transport, adsorptive transport,
see Figure 4), while the other soluble
compounds pass this barrier via passive diffusion.
Nanoparticles and the blood-brain barrier: An opportunity for the treatment of diseases – are there associated risks?
Nanoparticles can be used as carrier systems
to overcome the BBB and deliver specific medications
to regions of the brain that would
normally be inaccessible. Their surfaces can
be coated with certain materials or manufactured
such that they can pass the BBB and
transport the pharmaceuticals to the sites
where they are needed. Thus, nanoparticle
carrier systems can distribute medications
spatially and temporally in the brain and
help cure diseases that were previously untreatable.
This enables a tissue-specific accumulation
of drugs, special depot effects
and overcomes the body's own barriers such
as the blood-brain barrier. This would allow
stronger concentrations of medications to be
applied with improved effects. This is a booming
research and development field and
shows ever greater promise in treating diseases
such as Alzheimer's, Parkinson's or
certain brain tumors. Currently, most applications
of nanoparticle carrier systems involve
drugs that are already in clinical use.
Research is being conducted on various scenarios
for the application of nanoparticle
carrier systems. For example, experiments
are being performed on rats to determine
whether the direct transport of genes (gene
therapy) is possible into specific regions of
the brain via nanocarriers in order to replace
damaged hereditary substances and therefore
treat Parkinson's disease, for example1.
Figure 4: Various transport pathways through the BBB. (Source: Ref. 14)
One currently used form of therapy, although
it does not overcome the BBB, is the so-called
hyperthermia therapy, which uses nano iron
particles to treat brain tumors such as glioblastoma.
Here, magnetized, iron-containing
nanoparticles are injected directly into
the brain tumor. These nanoparticles, also
known as "Trojan horses", are actively taken
up by the tumor cells because they are
coated with a layer of sugar molecules2. This
approach packs the cancer cells full of ironcontaining
particles, which can then be pinpointed
and heated by electromagnetic fields.
This overheating kills the tumor cells. What
remains unclear is the fate of the nanoparticles
remaining in the brain, what effect they
have there or whether they are eliminated3; 4.
An in-vitro study5 showed that TiO2-nanoparticles
can trigger oxidative stress6, especially
in certain brain cells, namely in the socalled
microglia cells (phagocyting immune
cells of the central nervous system). This effect
is only possible if the BBB is crossed. In
vivo studies have been unable to definitively
confirm this. In experiments on rats, injecting
TiO2-nanoparticles directly into the
blood stream did not lead to accumulation
of the particles in the brain7. A more recent
study, however, shows that relatively high
concentrations of TiO2-nanoparticles injected
into pregnant mice were detectable in the
brain of the offspring8. A further study by the
same research group revealed changes in
the DNA (gene expression) in the brain tissue
of the fetuses9. In this case, the BBB as
well as the barrier between the mother and
placenta may have been breached. Another
mechanisms beyond crossing physiological
barriers might be at play here because,
during the embryonic phase, the BBB is not
yet fully developed. The researchers point
out, however, that the determined effects are
not directly transferable to humans. In particular,
the biological relevance of the described
gene alterations is unclear. Unfortunately,
there are still too few results to draw
definitive conclusions on the permeability of
TiO2-nanoparticles through the blood-brain
barrier.
Another route by which nanoparticles can
enter the brain is via the olfactory nerve, circumventing
the blood-brain barrier. The olfactory
nerve (nervus olfactorius) has a direct
connection to the brain by way of its long
processes (axons). It is therefore conceivable
that inhaled nanoparticles enter the olfactory
nerve and are transported to the brain
along the axons. This phenomenon has been
observed in rats. After inhalation, individual
carbon-containing nanoparticles entered
the olfactory bulbs in the nose and were then
transported along the olfactory nerve to the
brain10. The extent to which this result is
transferable to humans remains unclear because
the brain anatomy of rats and humans
differs considerably. In this case as well, no
final conclusions can be drawn as to whether
the concentrations of nanoparticles transported
in this manner – which are probably
minimal – is biologically relevant and therefore
relevant from a health perspective.
Health effects would be expected only under
continuous exposure and exposure to
high concentrations of nanoparticles.
Conclusions
Artificially manufactured particles can be
applied to help overcome natural physiological
barriers such as the blood-brain
barrier. This phenomenon can be used to
intentionally transport drugs to parts of the
organism where they are needed, for example
the brain. Research is currently being
conducted to determine whether nanoparticles
are able to reach the brain by
other mechanisms such as along the olfactory
nerve. It also remains poorly known
whether nanoparticles unintentionally pass
the blood-brain barrier and cause potential
damage. The few available studies on
the risks of nanoparticles that have entered
the central nervous system are controversial.
This prevents drawing definitive conclusions
about the health effects of unintentional
exposure of the brain to nanoparticles.
Notes and References
1 Zhang, Y., Calon, F., Zhu, C., Boado, R. J. and
Pardridge, W. M., 2003, Intravenous nonviral
gene therapy causes normalization of striatal
tyrosine hydroxylase and reversal of motor impairment
in experimental parkinsonism, Hum
Gene Ther 14(1), 1-12
3 Jordan, A. and Maier-Hauff, K., 2007, Magnetic
nanoparticles for intracranial thermotherapy,
J Nanosci Nanotechnol 7(12), 4604-6
4 Jordan, A., Scholz, R., Maier-Hauff, K., van
Landeghem, F. K., Waldoefner, N., Teichgraeber,
U., Pinkernelle, J., Bruhn, H., Neumann,
F., Thiesen, B., von Deimling, A. and Felix, R.,
2006, The effect of thermotherapy using magnetic
nanoparticles on rat malignant glioma,
J Neurooncol 78(1), 7-14
5 Long, T. C., Saleh, N., Tilton, R. D., Lowry, G.
V. and Veronesi, B., 2006, Titanium dioxide
(P25) produces reactive oxygen species in immortalized
brain microglia (BV2): implications
for nanoparticle neurotoxicity, Environ Sci Technol
40(14), 4346-52
7 Fabian, E., Landsiedel, R., Ma-Hock, L., Wiench,
K., Wohlleben, W. and van Ravenzwaay, B.,
2008, Tissue distribution and toxicity of intravenously
administered titanium dioxide nanoparticles
in rats, Arch Toxicol 82(3), 151-7
8 Takeda, K., Suzuki, K., Ishihara, A., Kubo-Irie,
M., Fujimoto, R., Tabata, M., Oshio, S., Nihei,
Y., Ihara, T. and Sugamata, M., 2009, Nanoparticles
transferred from pregnant mice to
their offspring can damage the genital and cranial
nerve systems, J Health Sci 55, 95-102.
9 Shimizu, M., Tainaka, H., Oba, T., Mizuo, K.,
Umezawa, M. and Takeda, K., 2009, Maternal
exposure to nanoparticulate titanium dioxide
during the prenatal period alters gene expression
related to brain development in the
mouse, Part Fibre Toxicol 6, 20
10 Oberdorster, G., Sharp, Z., Atudorei, V., Elder,
A., Gelein, R., Kreyling, W. and Cox, C., 2004,
Translocation of inhaled ultrafine particles to
the brain, Inhal Toxicol 16(6-7), 437-45.
By NanoTrust, Austrian Academy of Sciences. NanoTrust Dossiers are published irregularly and contain the research
results of the Institute of Technology Assessment in the framework of its research project NanoTrust. The Dossiers are made available to the public exclusively on epub.oeaw.ac.at/ita/nanotrust-dossiers.
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