Epileptologia • 2010 • 18 • 81–85 81

Perspectives of nanotechnology in epilepsy treatment

Władysław Lasoń Received June 25, 2010

Accepted for publication on-line July 29, 2010

Department of Experimental Neuroendocrinology,

Polish Academy of Sciences, Kraków and
Department of Drug Management, Institute of Public Health,
Jagiellonian University Medical College, Kraków, Poland

Correspondence
Władysław Lasoń
Institute of Pharmacology, Polish Academy of Sciences
12 Smętna str.
31-343 Kraków, Poland
lason@if-pan.krakow.pl

Summary
Introduction. Nanotechnology, based on discovery of scanning tunneling microscope, allows the study of
structures and devices on the atomic scale, where the size limit is 100 nanometers. Nanoparticles such as den-
drimers, fullerenes and nanotubes possess unique physicochemical properties whereby they easily penetrate
biological membranes and thus may serve as effective drug transport systems. On the other hand, nanode-
vices can help in localization of the epileptic focus.
Aim. The aim of the present article is to discuss the perspectives of nanotechnology in improvement of bio-
pharmaceutical, pharmacokinetic and pharmacodynamic properties of antiepileptic drugs. Furthermore, a po-
tential role of some nanoparticles in neuronal damage, diagnosis and patomechanism of epilepsy will also be
highlighted.
Discussion. Drugs encapsulated in polymeric nanoparticles show good bioavailability, are resistant to enzy-
matic degradation, and are released in a time-dependent controlled manner. For example, the water insoluble
antiepileptic drug carbamazepine in the form of nanoemulsion shows desired pharmacokinetic parameters
and can be administered intravenously. Another study demonstrated that the oxidative metabolism of primi-
done entrapped in nanocapsules was reduced. Also, the pharmacodynamic activity of antiepileptic drugs de-
livered in nanosystems may be significantly enhanced. To this end, phenytoin-loaded liposomes administered
locally inhibited cAMP/EDTA-induced seizures in rats. Furthermore, intravenous administration of the NMDA re-
ceptor antagonist MRZ 2/576 incorporated into nanoparticles prolonged its anticonvulsant activity more than
10 times compared to the free compound. It was also found that the intranasal delivery of TRH-PLA (thyrotro-
pin-releasing hormone-polylactide) nanoparticles retarded experimental epileptogenesis and reduced clonic
seizure intensity in mice. Regarding a potential application of nanotechnology in epilepsy diagnosis, it has been
Review paper

observed that non-radioactive alpha methyl tryptophan bound to magnetonanoparticles, readily crosses the
blood-brain barrier, accumulates in the epileptic focus and can be detected by MRI. However, it should be em-
phasized that the majority of available data are still preliminary. Furthermore there may be a downside in that
some nanoparticles may generate free radicals and damage neuronal tissue.
Conclusions. Nanotechnology may have a substantial impact on the treatment and diagnosis of epilepsy.
Drug delivery nanosystems may help to maintain the therapeutic concentration of antiepileptic drugs in the
brain tissue, whereas some nanodevices can be used in detecting of epileptic foci. However, the high reactivity
of nanoparticles raises safety concerns and emphasizes the need for further preclinical studies.
Key words: epilepsy, antiepileptic drugs, pharmacokinetics, nanotechnology
82
Introduction
Nanotechnology, also known as molecular engineering,
focuses on the construction of structures and devices on
the atomic scale. Their dimension ranges from 1 to 100
nanometers (1 nanometer = 0.000 001 mm). When a sub-
stance is so dispersed, it may acquire new physical features
resulting from a tremendously high surface-to-volume
ratio (Kaliszan, 2007). Development of nanotechnology
was greatly assisted by the construction of the scanning
tunnel microscope (STM) by H. Rohrera and I. Binnin-
ga, Nobel Prize winners in 1986 and 1996, respective-
ly. STM utilizes the phenomenon of electron tunneling
which enables observation of transfer and location of in-
dividual atoms, the spectacular example of which was the
arrangement of 35 xenon atoms to form the IBM logo.
Currently, nanotechnology belongs to the most dynami-
cally progressing fields in highly developed countries and
finds increasingly wide applications in industry, for in-
stance, in electronics, chemical engineering, food process-
ing, cosmetics, defense industry, and even cosmos explo-
ration (Jędrzejczyk, 2006; Kaliszan, 2007). Nanomateri-
als based on oxides of titanium, silver, zinc, platinum or
gold have been applied in the cosmetic (sun care prod-
ucts) and chemical (new anticorrosive coatings, stain-re-
sistant fabrics, aseptic soaps) industries.
Nanotechnology is particularly important in medicine
mostly because of increasing costs of healthcare and the
demand for less invasive and more efficient medical pro-
cedures. According to the US National Science Founda-
tion estimates, published in Med Tech Market Reports,
2008, the global market for nanotechnology-related prod-
ucts and services will reach one trillion-dollar value by
2015, therefore, nanotechnology will soon be a great-
er economic force than combined telecommunications
and information technology at their boom. The unique
physicochemical properties of nanoparticles find practi-
cal application in many disciplines of medicine (Bogu-
nia-Kubik, Sugisaka, 2002; Kubik et al., 2005). Most of
all, dispersion of active substances on the nano scale will
facilitate their penetration through biological membranes
and enhance their pharmacodynamic activity. Macrolide
antibiotics and perfluorinated carbohydrates used as he-
moglobin-replacing oxygen carriers are the examples. The
best known nanomaterials include fullerenes, spherical
structures constructed from single carbon atoms possess-
ing different shape-dependent electrical, thermal and me-
chanical properties, carbon nanotubes and branched den-
drimers. Since these structures are hollow, they can carry
within them antiseptics, antibiotics, chemotherapeutics
Władysław Lasoń
and other drugs while specific antibodies bound to their
surface will provide for their transport to targets bearing
respective antigens, i.e. cancer cells or infection foci. In
this way, targets for these drugs will be strictly defined
thus limiting undesired systemic reactions (Jędrzejczyk,
2006). Interestingly, carbon nanotubules could be help-
ful to neuroregeneration or drug transport to the nervous
tissue damaged by ischemia, status epilepticus or chron-
ic neurodegenerative diseases. Nanotechnology of deox-
yribonucleic acids incites huge interest among special-
ists since DNA shows the ability to spontaneously form
spatially complex structures if nucleotide sequences are
planned so that the DNA strands bind in a strictly de-
fined way (Liu et al., 2009). Such self-organizing nano-
tubes will be useful for coating implants, thereby improv-
ing their adhesion to tissue surface and decreasing the risk
of rejection reaction. Recently, the term systemic medi-
cine has been proposed. This discipline of medicine views
the organism as a system of interacting molecular net-
works and predicts that the application of nanotechnol-
ogy to precisely manipulate their components will serve
to enhance the study, the diagnostics and the treatment
of a majority of diseases (Heath et al., 2009).
Aim
The aim of the present article is to discuss the perspec-
tives of nanotechnology in improvement of biopharma-
ceutical, pharmacokinetic and pharmacodynamic prop-
erties of antiepileptic drugs. Furthermore, a potential role
of some nanoparticles in neuronal damage, diagnosis and
patomechanism of epilepsy will also be highlighted.
Disscussion
Nanotechnology in epilepsy pharmacotherapy
Compared to the already rich literature on the use of
nanotechnology in the diagnosis and treatment of can-
cer, cardiovascular diseases and in transplantology, only
sparse reports can be found on epilepsy. Preclinical biop-
harmaceutical and pharmacodynamic research are very
much needed in this regard. The generally accepted view
is that insufficient antiepileptic drug concentrations in
blood and in particular in the central nervous system,
can significantly hinder optimal epilepsy management.
Factors that regulate achieving and maintaining of ther-
apeutic antiepileptic drug concentration in the brain in-
clude: blood-brain barrier (permeable for lipophilic com-
pounds with molecular weight < 1000 Da), active remov-
nanotechnology in epilepsy
al of antiepileptic drugs from the brain to the vascular lu-
men by multidrug resistance-associated proteins (MRP),
systemic toxicity of drugs and drug phagocytosis by mac-
rophages in the reticulo-endothelial system. Therefore, it
could be purposeful to develop new strategies that will
aid in achieving and maintaining of therapeutic antiepi-
leptic drug concentration in the brain. Among such strat-
egies, it is worth highlighting the attempts to use pro-
drugs, inhibition of MRP proteins, hyperosmolar opening
of the blood-brain barrier or bypassing the blood-brain
barrier by direct drug application to the brain ventricles
of the cerebral cortex (Bialer et al., 2001). On the other
hand, increasing evidence suggests that nanotechnolo-
gy can provide a breakthrough in facilitating antiepilep-
tic drug transport into the brain (Bennewitz and Saltz-
man, 2009). Among nanocolloidal drug carriers, poly-
meric nanoparticles encapsulating an active substance
or forming a drug-polymer complex, liposomes entrap-
ping hydrophilic drugs in the aqueous core or binding
hydrophobic or aminophilic drugs to the lipid layer and
so-called stealth polymers bearing phagocytosis-hinder-
ing polymeric chains on the surface should be noted. In
terms of chemical structure, polymeric nanoparticles are
polyesters, e.g. polylactides, biodegradable polyalkylcy-
anoacrylates, polyglycolic acid, polycaprolactone and their
co-polymers and polysaccharides. PLGA poly (lactic-co-
glycolic acid), the most frequently used and approved by
FDA polymer is considered to be safe and biocompati-
ble. These nanoparticles have beneficial biopharmaceu-
tical features. Liposomes protect drugs from biodegrada-
tion and lower their toxicity while polymeric nanoparti-
cles exhibit a better stability in biological fluids and dur-
ing storage and enable control of the active substance re-
lease. Recent reports from preclinical studies seem to
confirm a potential usefulness of nanosystems in epilep-
sy pharmacotherapy. Local application of liposome-en-
trapped phenytoin was demonstrated to inhibit the ac-
tivity of the epileptic focus in the rat amygdala (Mori et
al., 1995). It was also shown that the intranasal delivery
of polymeric nanoparticles (D,L-polylactide) linked with
TRH, a neuropeptide endowed with antiseizure activi-
ty, at the dose of 20 microg/day for 7 days significant-
ly retarded the propagation of kindled seizures in rats
and lowered the intensity of clonic attacks (Kubek et al.,
2009). Other researchers have proposed a combination
of N-trimethyl-chitosan nanoparticles with ANEP (an-
ti-neuroexcitation peptide), that inhibits neuronal exci-
tation, in order to facilitate its transport into the brain
(Wang et al., 2010). It has also been reported that intra-
83
venous administration of the NMDA glutamate recep-
tor antagonist MRZ 2/576 incorporated into polymer-
ic nanoparticles (polybutylcyanoacrylate combined with
polysorbate 80) prolonged the time of its antiseizure ac-
tivity more than 10-fold (Friese et al., 2000).
Carbamazepine is an effective and widely used antie-
pileptic drug, but it is only slightly soluble in water and
cannot be used in the parenteral form. Advantageous
pharmacokinetic characteristics of carbamazepine ad-
ministered intravenously to mice in the form of nanoe-
mulsion has been recently described (Madhusudhan et
al., 2007; Kelmann et al., 2007). New technologies also
allow for influencing drug biotransformation, e.g. prim-
idone-loaded nanocapsules limited its oxidative metabo-
lism, i.e. the so-called phenobarbiturate path in rats (Fer-
ranti et al., 2001). The significance of nanoparticles in
antiepileptic drug transport into the brain has been ex-
tensively discussed in a recent article by Bennewitz and
Saltzman (2009).
Nanodevices in diagnosis and prevention of
epileptic attacks
Nanotechnology may be able to play a significant role in
diagnostics of epilepsy. Among new methods of locali-
zation of the epileptic focus, it has been proposed to use
non-radioactive magnetonanoparticles (MNP) covalent-
ly bound with alpha-methyl-tryptophan capable of cross-
ing the blood-brain barrier and of accumulation in the
epileptic tissue in animal models of temporal lobe epi-
lepsy. This approach enables the precise detection of the
epileptic tissue by nuclear magnetic resonance (magnet-
ic resonance imaging, MRI) (Akhtari et al., 2008). On
the other hand, American researchers from the Universi-
ty of Oregon have suggested the application of superpar-
amagnetic iron oxide-based nanoparticles in diagnostics
and treatment of central nervous system diseases (par-
ticularly in neurooncology) (Weinstein et al., 2010). The
mentioned nanoparticles are useful as contrast agents in
MRI diagnostics of blood-brain barrier defects related to
tumors and neuroinflammatory pathologies, in determi-
nation of cerebral vasculature condition and in in vivo
detection of brain damage at the cellular level. Accord-
ing to Weinstein et al. (2010), nanotechnological strate-
gies should vitally improve the detection of the disease,
monitoring and evaluation of treatment efficacy in pa-
tients with brain tumors, ischemia, atherosclerosis, mul-
tiple sclerosis, mechanical brain damage and epilepsy.
Nano- and microdevices currently under development
can also be used for diagnostics and prevention of epilep-
84
tic attacks. It is worth highlighting that research present-
ly in progress aims to construct head-mounted subcuta-
neously implantable microsensors allowing for detection
of the pathological neuronal firing preceding epileptic at-
tack. Also plans are to hand to build a device capable of
quenching epileptic attacks, so-called “a convulsion stop
machine” (Yambe et al., 2010).
Potential implication of nanoparticles
in epileptogenesis
Apart from many indisputable benefits, nanotechnology
can also carry certain risks, including environmental haz-
ards. Notably, silver-based nanoparticles used for coating
of fabrics, due to bactericidal properties, can kill the use-
ful bacterial strains. It is also distressing that some types
of carbon nanotubes can be potentially hazardous, since,
like asbestos fibers, they can induce mesothelioma. It can-
not be excluded that some materials dispersed on the nano
scale can produce epileptogenic effect. Nanoparticles are
highly reactive and can generate free radicals which dam-
age nervous cells and participate in the mechanisms of
epileptogenesis (Majkowski, 1994). Some in vitro studies
showed that protective coatings made of zinc oxide nan-
oparticles induced neuronal cell apoptosis (Deng et al.,
2009). These studies, performed with the use of confocal
and electron microscopic methods and flow cytometry,
demonstrated that zinc oxide nanoparticles concentration-
dependently but size-independently lowered the viability
of the neuronal stem cells in mice. Moreover, it was dem-
onstrated that the toxicity of zinc oxide nanoparticles was
related to the presence of ions of this metal both in culture
medium and within the cytosol. The quality of nanoma-
terials for medical use is of critical importance. For exam-
ple, there are suggestions that the contamination of car-
bon nanoparticles with ytrium can inhibit neuronal cal-
cium channel function, while these channels are targets
for some antiepileptic drugs. In addition, as highlighted
above, nanoparticles can easily penetrate the blood-brain
barrier and can accumulate in the brain, and other tissues,
so as to achieve toxic level. It has been reported that the
inhalation of nanoparticles can cause their accumulation
in the lungs and in the brain tissue and this was accompa-
nied by an increase in biochemical stress and inflamma-
tory indicators (Muller et al., 2010). The two-year stud-
ies conducted by the School of Public Health UCLA re-
vealed that mice receiving titanium dioxide nanoparticles
showed DNA and chromosomal damage to the extent in-
dicative of significant cancer etiopathogenesis, of cardio-
vascular and neurological diseases and of aging.
Władysław Lasoń
Conclusions
Recent reports suggest that nanotechnology can have
a significant impact on the diagnosis and treatment of ep-
ilepsy. Drug administration in the form of nanoprepara-
tions should be conducive to maintaining of their thera-
peutic level in the brain tissue, while nanodevices can be
applied in the future for identification of epileptic foci.
However, it should be kept in mind, that the majority of
data on the possible use of nanotechnology in the phar-
macotherapy of epilepsy are still preliminary. Moreover,
the high physicochemical reactivity of nanoparticles in-
dicates that further preclinical studies on safety of these
preparations are necessary.
Acknowledgment
The author would like to express his gratitude to Ms. Inga
Bechyne, M.Sc. from the Department of Cell Biology,
Faculty of Biochemistry, Biophysics and Biotechnology,
Jagiellonian University in Kraków for valuable sugges-
tions and details on nanotechnology.
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