Journal of APPLIED BIOMEDICINE
ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)
Volume 10 (2012), No 1, p 1-8
DOI 10.2478/v10136-012-0002-2
Fullerene nanoparticles and their anti-oxidative effects: a comparison to other radioprotective agents
Jirina Vavrova, Martina Rezacova, Jaroslav Pejchal
Address: Jirina Vavrova, Department of Radiobiology, University of Defence, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
vavrova@pmfhk.cz
Received 17th August 2011.
Revised 31st October 2011.
Published online 2nd November 2011.
Full text article (pdf)
Summary
Key words
Introduction
Mechanism of radioprotection
Radioprotective agents
Conclusion
Acknowledgement
References
SUMMARY
Radiation therapy occupies an important position in the treatment of malignant diseases in spite of the existence of radiation side effects on normal tissues. Thus, substances are being developed which are designed to reduce both the acute and long term radiation effects on healthy tissues. Currently a sulphur-containing compound amifostine (WR2721, ethyol) is used in clinical practice as a radioprotectant. However, it itself has considerable side effects including hypotension (found in 62% of patients), hypocalcaemia, diarrhoea, nausea, and vomiting. Carbon nanospheres, known as fullerenes, and their water soluble derivatives (e.g. C60(OH)24, dendrofullerene DF-1) exert anti-oxidative properties and reduce damage to the DNA in irradiated cells. Water soluble fullerenes are low-toxic substances and thus, are attractive in terms of their use as radioprotectants.
KEY WORDS
ionizing radiation; fullerenes; antioxidant; radioprotection; nanoparticles
INTRODUCTION
Radiotherapy is one of the major treatment modalities
in the management of human cancer. However, it can
lead to a number of side effects in the human body as
a consequence of a series of events over different
time periods varying from less than 10-12 s to many
weeks. The energy transfer from a photon and/or a
particle to atoms and molecules results in a direct
change, i.e. a chemical conversion of a macro-molecule, which could be of importance for the
biological function. The critical event is damage to
the DNA in the nucleus and formation of DNA
double-strand breaks (DSB). This initial event can be
caused by two mechanisms: either by direct damage
to the DNA by the radiation energy or indirect
damage mediated through radicals, peroxides and
superoxides produced during the water radiolysis. In
the case of radiation with low LET (Linear Energetic
Transfer) including gamma radiation and X-rays, a
prevalent proportion of the radiation damage results
from the indirect mechanism. In this review the effect
of classical radioprotectants is compared to the effect
of water-soluble C60 fullerenes.
MECHANISM OF RADIOPROTECTION
The radioprotection of living organisms by
pharmacological substances particularly depends on
their ability to reduce intracellular concentrations of
free radicals and peroxides produced over the first
milliseconds after irradiation. Substances, which
could be used in the protection of healthy tissues from
ionizing radiation effects in radiation therapy, should
adhere to the following two basic conditions: 1) they
must selectively protect normal tissues (without
affecting tumour cells) and 2) they must exert
minimum toxicity.
Radioprotection due to hypoxia
The degree of radiation damage to tissues directly
correlates with their oxygenation. Substances able to
reduce oxygenation can therefore have protective
effects. A reduction of oxygen levels to 3-10% in the
air inhaled during the course of irradiation can exert
protective effects in mice and rats comparable to
those achieved with traditional radioprotectants
(Vacek et al. 1971). Radioprotectants taking
advantage of hypoxia as the main mechanism of the
effect include indolylalkylamines (serotonin and
mexamine). The mechanism of their protective effect
is explained by the post-vasoconstriction hypoxia
(Zherebchenko and Suvorov 1963). However, given
their side effects, such as a decrease in arterial blood
pressure, a decrease in body temperature, and the
teratogenic effect or degenerative changes in testicles
(Kuna 1985), these substances did not find any use in
clinical practice.
Inactivation of oxidative radicals in water
Strongly reactive oxygen radicals produced during
irradiation by water radiolysis have harmful effects on
the cell. Radical scavenging is the basic mechanism
of many chemical substances and enzymes protecting
biological targets against ionising radiation. It is
essentially a competition for a radical between the
protective substance and the biological molecule. In
aqueous solutions, protective substances and enzymes
react with free radicals and peroxides, produce stable
non-toxic products and thus reduce the amounts of
these species. Many of these radioprotectants are very
good extinguishers of oxygen radicals. Compounds
containing sulphur are well known radioprotectants
exerting the highest protective effects, but they are
also very toxic. In contrast, antioxidants of natural
origin can be characterized by a relatively low
toxicity, but also lower radioprotective properties.
RADIOPROTECTIVE AGENTS
Sulphur containing compounds
Radioprotectants containing sulphur are chemical
analogues of cysteine (a thiol group containing amino
acid). Similar to cysteine, these substances have their
SH group separated by two to three carbon atoms
from the basic amino group. To provide effective
radioprotection, these substances must be present in
the organism prior to irradiation. The optimum
radioprotection is achieved in the case of an
intravenous administration 15-30 min before
irradiation. Sulphur containing compounds act
through the mediation of three main mechanisms: as
extinguishers of free radicals, as carriers of oxygen
and last, but not least, they act as substances inducing
hypoxic effects. The most well known
radioprotectants of this group are cysteamine,
cystamine AET and WR2721 (Bacq 1954, Dostal
1967, Kuna 1985).
The Walter Reed Military Institute in the USA has
produced and tested 4000 compounds. In 1969, they
synthesized a substance marked WR-2721 (Piper et
al. 1969) (amifostine, ethyol) which is an organic
thiophosphate prodrug (2-(3-aminopropyla-mino)ethylsulphanyl phosphonic acid) hydrolysed in
vivo by alkaline phosphatase to the active
cytoprotective thiol metabolite, WR-1065
(2-((aminopropyl)amino)ethanethiol). The selective
protection of non-malignant tissues is believed to be
related to higher alkaline phosphatase activity, higher
pH, and vascular permeation in normal tissues. The
combination of hypovascularity, low pH, and reduced
enzyme levels results in a low accumulation of the
active drug in tumour tissues (Kouvaris et al. 2007).
Mean lethal doses were established for accurate
determination of the radioprotective effects. These
doses are typically related to the 30th day after
irradiation. LD50/30 is a lethal dose after which 50%
of animals survive up to the 30th day after irradiation.
The DRF (Dose Reducing Factor) is a ratio of the
mean lethal dose in protected animals to that in
non-protected animals. Table 1 presents DRF values
of different radioprotectants used in mice. In the case
of whole-body gamma-ray irradiation, WR-2721
administered at a dose of 300 mg/kg is obviously the
most effective radioprotectant (Kuna et al. 1983,
Kuna 1985). No radioprotective effect of WR-2721
was found when it was administered at a dose of
160 mg/kg (intravenously or intramuscularly) to rats
15-20 min before their whole-body exposure to
fission neutrons (Kuna et al. 2004). This is probably
due to the fact that neutrons primarily damage
biological molecules directly. WR-2721 also considerably reduces the toxicity of chemotherapeutic
agents, particularly of cisplatin (Yuhas 1980).
Table 1. Comparison of the radioprotective effect of DF-1 dendrofullerene with other known radioprotectants.
| Drug |
Dose |
Irradiation |
Animals |
DRF* |
Author | | WR-2721 |
300 mg/kg i.m.
15-20 min before irrad. |
gamma |
mice |
2.39 |
Kuna 1985 | | WR-2721 |
100 mg/kg i.m.
15-20 min before irrad. |
gamma |
mice |
1.3 |
Kuna 1985 | | Cystamine |
175 mg/kg i.m.
5-15 min before irrad. |
gamma |
mice |
1.83 |
Kuna 1985 | | Superoxide-dismutase |
i.v. 2 h before irrad. (200 mg/kg)
and 1 h after irrad. (35 mg/kg) |
X-rays |
mice |
1.56 |
Petkau 1978 | | Hypoxia - 8% O2 |
in the course of irrad. |
gamma |
mice |
1.5 |
Vacek et al.
1971 | | DF-1 dendrofullerene
nanoparticle |
300 mg/kg
15 min before irrad. |
X-rays |
mice |
1.22 |
Brown 2010 |
* The DRF (the Dose Reducing Factor) is a ratio of the mean lethal dose (LD50/30) in protected animals to that in non-protected
ones.
The undesirable side effects of WR-2721 are
related to the application of high doses. The LD50/48
value for mouse strain H after an intra peritoneal (i.p.)
administration was 764-1054 mg/kg. The best
radioprotective effect was achieved by an i.p.
application of 300 mg/kg, when DRF was 2.11-2.39.
A decrease in the dose to 100 mg/kg caused a
significant decrease in the protective effect (DRF =
1.3) (Kuna 1985). The side effects of WR-2721
include hypotension, hypocalcaemia, diarrhoea and
nausea (France et al. 1986). Hwang et al. (2004)
applied WR-2721 to patients during myeloablative
conditioning therapy for allogenic bone marrow
transplantation. WR-2721 was administered at a dose
of 1000 mg/day of conditioning and was well
tolerated if attention was paid to the serum calcium
level, blood pressure and antiemetics.
Antioxidants of natural origin
There are a few substances of natural origin that are
able to protect cells from the negative effects of free
radicals and reactive oxygen species. These
substances can be divided into two groups: 1)
low-molecular substances acting as scavengers of
oxygen radicals and 2) enzymes detoxifying reactive
oxygen radicals and peroxides.
The low-molecular compounds acting as oxygen
radical scavengers include vitamins A and E, which
are lipophilic, and vitamin C, which is hydrophilic.
Several studies have established the radioprotective
values of vitamins A, C and E and carotenoids in
normal cells (Malick et al. 1978, Konopacka et al.
1998, Prasad et al. 2002). In these compounds, the
DRF values range between 1.1 and 1.2. Lipophilic
vitamins A and E administrated i.p. and hydrophilic
vitamin C administered i.m. to mice for 14 days
(3 days before immunoradiotherapy and 11 days after
immunoradiotherapy) reduced the body weight loss
and myelosupression associated with radio-
immunotherapy (Blumenthal et al. 2000).
The group of enzymes with antioxidant properties
includes superoxide-dismutase (SOD), catalase,
glutathione peroxidase and glutathione reductase
(Citrin et al. 2010) and these are described below.
Superoxide-dismutase (SOD)
Superoxide-dismutase is an enzyme important for the
detoxification of reactive oxygen radicals catalyzing
the superoxide radical conversion to hydrogen
peroxide (H2O2) and hydrogen. H2O2 is subsequently
removed by a reaction with the participation of two
enzymes (catalase and glutathione peroxidase). The
administration of superoxide-dismutase 2 h prior to
irradiation (200 mg/kg) and 1 h after irradiation
(35 mg/kg) provides a relatively high radioprotective
effect - DRF = 1.58 (Petkau 1978). In contrast to
radioprotectants containing sulphur, these enzymes
exert only a minimum toxicity.
In terms of radiation damage, not only DNA
impairment is important, but also the damage to
mitochondria mediated through the production of
superoxide and other reactive oxygen species (ROS)
derived from superoxide. An increased ROS
production can be observed in the irradiated tissues 6
months after the exposure (Epperly et al. 2008). The
damage to the mitochondria is manifested by
induction of apoptosis. Manganese superoxide
dismutase (MnSOD), which is an enzyme present in
human cells, is actually the first line of defense
against an increased superoxide production in the
mitochondria (Belikova et al. 2009). Thus,
antioxidant gene therapy studies have utilised
manganese superoxide dismutase-plasmid liposomes
(MnSOD-PL). Overexpression of the mitochondria
localized MnSOD gene product have been shown to
decrease the ionizing radiation-induced apoptosis of
cells in vitro (Epperly et al. 2002). In the case of
intravenous application of MnSOD-PL to mice before
their exposure to 9.5 Gy (antioxidant gene therapy -
the mice received intravenously 100 microl of liposomes
containing 100 microg of human MnSOD-transgene
plasmid 24 hours prior to irradiation), increased
animal survival was observed 30 days as well as
340 days after irradiation (Epperly et al. 2008).
Fullerene - derivatives
Compounds developed based on nanotechnology,
such as for example, carbon nanospheres named
fullerenes (C60, C70, C80-C200) also represent an
important group of antioxidants due to the possible
absorption of many oxygen radicals in a single
fullerene molecule (Bosi et al. 2003). The most
abundant form of fullerenes is buckminsterfullerene
C60 (Fig. 1) with 60 carbon atoms arranged in a
spherical structure (Markovic and Trajkovic 2008).
Fig. 1. Structure of fullerene C60.
C60 is soluble in aromatic solvents and carbon
disulfide but essentially insoluble in water and
alcohol (Jensen et al. 1996). For their use in biology,
it is necessary to obtain fullerene derivatives, which
are soluble in polar solvents. Chemical modification
of the fullerene carbon cage by the attachment of
various functional groups (e.g.-OH, NH2, -COOH)
enables the fullerene molecule to establish bonds with
water via hydrophilic functional adducts (Markovic
and Trajkovic 2008). Johnston et al. (2010) reviewed
analyses of the toxicity of fullerenes in detail.
Manipulating fullerene water solubility has included
the use of surface modifications, solvents, extended
stirring, and mechanical processes. However, the
ability of these processes to have an impact on
fullerene toxicity requires further assessment,
especially when considering the use of solvents,
which particularly enhance the toxicity of fullerene
derivates (Johnston et al. (2010).
Inhibition of HIV replication
These substances were also shown to possess
considerable antiviral effects. In 1993, the
water-soluble derivative of C60 [bis(monosuccini-mide) derivative of bis(2-aminoethyl)diphenyl-C60]
was found to be a substance inhibiting HIV-1
protease (Schinazi et al. 1993). A derivative of
tris-hydroxymethyl methano-fullerene was later
discovered to exert an even higher antiviral activity
(Jensen et al. 1996). The antiviral activity seems to be
characteristic for many non-toxic derivatives of the
C60 fullerene (Friedmann et al. 1998, Cheng et al.
2010).
Photodynamic therapy of tumours
Mroz et al. (2007) showed that the C60 molecule
mono-substituted with a single pyrollidinium group is
a remarkably efficient photosensibilizer and can
mediate the killing of a panel of mouse cancer after
exposure to white light. Following intravenous
injection of C60-PEG (polyethylene glycol - PEG
conjugated with C60) to tumour-bearing mice, coupled
with exposure of the tumour site to visible light, the
volume increase of tumour mass was suppressed and
C60-PEG conjugate exhibited a stronger suppressive
effect than Photofrin (Tabata et al. 1997, Liu et al.
2007). These data demonstrate the potential use of
these compounds as photo-sensibilizers for
photodynamic therapy of tumours.
Antioxidant activity
Oxidative stress and associated oxidative damage are
mediators of cellular injury in many pathological
conditions, including autoimmunity, atherosclerosis,
diabetes, and neurodegenerative disorders (Markovic
and Trajkovic 2008). In many studies, it has been
shown that water-soluble fullerene derivates can act
as antioxidant substances scavenging oxygen radicals
(including ROS generated by ionising radiation) and protecting cells and/or tissues against ROS damage.
The known antioxidant activity of water soluble C60
derivatives is summarized in Table 2.
Table 2. Water soluble C60 derivates and their antioxidative effects.
| Fullerene type |
Biological effects |
Author | | C60(OH)24 |
radioprotection
protection from doxorubicin toxicity |
Trajkovic et al. 2007, Cai et al. 2010
Injac et al. 2008 | | C60(OH)22 |
protection from H2O2 induced
oxidative injury |
Yin et al. 2008 | | Malonic acid C60 derivates
carboxyfullerenes |
neuroprotection |
Dugan et al. 1996, 2001,
Ali et al. 2008 | | C60 dendrofullerene |
radioprotection |
Brown et al. 2010, Theriot et al. 2010 | | Polyvinylpyrrolidone wrapped C60 |
reduces synovitis |
Yudoh et al. 2009 |
For instance, polyhydroxylated fullerenes -
C60(OH)x, also referred to as fullerenols, were studied
by Trajkovic et al. (2007) and Cai et al. (2010).
Trajkovic et al. (2007) demonstrated the radioprotective effect of fullerenol (C60(OH)24)
administered to rats intraperitoneally in a dose of
100 mg/kg 30 min prior to 8 Gy irradiation. The
fullerenol protected the rats' haemopoietic and
lymphoid tissues. Cai et al. (2010) studied the
radioprotective effects of repeated fullerenol
administrations (for a period of 14 days) at a dose of
40 mg/kg on the mouse immune system. It was found
that 2-week C60(OH)24 pretreatment effectively
reduced whole body irradiation-induced mortality
without apparent toxicity. C60(OH)24 pretreatment also
showed significant protective effects against ionizing-
radiation-induced decreases in immune and
mitochondrial function and antioxidant defense in the
liver and spleen. This suggests that the
polyhydroxylated fullerene derivative C60(OH)24
protects against ionizing-radiation-induced mortality,
possibly by enhancing the immune function,
decreasing oxidative damage and improving the
mitochondrial function.
The antioxidant and protective properties of
carboxy-fullerenes have been described by Dugan et
al. (1996) and Ali et al. (2008). Both studies showed
that carboxy-fullerenes are able to protect neurons
against the oxidative stress associated with
Parkinson's disease and ischaemic brain injury.
Moreover, Ali et al. (2008) compared the structure of
6 carboxy-fullerenes and found the best antioxidative
effect in the tris-adduct malonic acid derivate of
fullerene - C60(C(COOH)2)3. Ali et al. (2008)
described carboxy-fullerenes as three-dimensional
carbon carriers with the antioxidative properties
depending not only on the number of bound
carboxylic groups but also on their distribution on the
fullerene ball.
The ability of fullerenes to modulate cytokine
production and cellular damage was shown in
bis-adduct malonic acid derivate and water-soluble
C60 fullerene (polyvinylpyrrolidone wrapped C60).
Bis-adduct malonic acid derivate inhibited the
TNF-alpha initiated apoptosis in HeLa cells (Li et al.
2011). On the other hand, findings by Yudoh et al.
(2009) indicate that polyvinylpyrrolidone wrapped
C60 reduces pro-inflammatory cytokine production
from synovial inflammation-related cells and
mitigates the resultant synovitis in vitro. Intra-
articular treatment with this compound significantly
attenuates synovitis and joint destruction in the rat
model of arthritis.
Another promising fullerene derivate is dendro
(60) fullerene-1 (DF-1). The derivate is characterised
by a single branched dendromer architecture
containing 18 terminal carboxylic groups attached to
the fullerene ball. DF-1 is readily soluble in water, is
non-toxic and has radioprotective effects (Brown et
al. 2010, Theriot et al. 2010). Theriot et al. (2010) has
shown that DF-1 protects lymphocytes as well as cells
in the intestinal crypts from radiation-induced cell
death. In this study, human lymphocytes and rat
intestinal crypt cells (IEC-6) were incubated with
100 microM DF-1 one hour prior to irradiation, rinsed and
immediately exposed to a single dose of 4 Gy in the
fresh medium. The study shows that 1-hour
incubation with DF-1 reduces the number of
micronuclei (an indicator of DNA damage) in both
types of cells compared to the irradiated
non-protected groups. Brown et al. (2010) evaluated
the DF-1 DNA protective effects via the expression of
phosphorylated histone H2AX (gamma-H2AX). Gamma-H2AX
serves as an indicator of DNA double strand brakes.
In the DU145 cell culture, a 30-min pre-treatment
with 100 microM DF-1 resulted in a significant decrease
in the number of gamma- H2AX foci 1 and 6 h after 4 Gy
irradiation. Both studies demonstrate that there is a
reduction in DNA damage after DF-1 incubation and
that DF-1 acts not only against the oxidative stress
but also against the DNA damage generated by
ionizing radiation.
CONCLUSION
Polyamino- and polyhydroxy-fullerenes show that
water-solubility increases with the number of groups
introduced into the molecule. It is possible to state
conclusively that water-soluble fullerene derivatives
exert considerable protective effects against the
oxidative stress as scavengers of free radicals in vitro
as well as in vivo (Dugan et al. 2001, Ali et al. 2004,
Bakry et al. 2007, Injac et al. 2008). The radioprotective effects were demonstrated in fullerenols,
carboxy-fullerenes, polyvinylpyrrolidone wrapped
fullerene, and DF-1. Table 1 summarizes a
comparison of the DRFs after a single water-soluble
dendrofullerene DF-1 application 30 min before
irradiation (DRF = 1.22) with the effects of other
radioprotectants. Given the fact that these substances
(fullerenol, DF-1) have no or only slight side effects,
they offer a great potential to become radioprotectants
with the possibility of repeated administration, which
is necessary in standard fractionated radiotherapy.
ACKNOWLEDGEMENTS
The authors would like to thank the Ministry of
Defence of Czech Republic (project
MO0FVZ0000501 and project OVUOFVZ200806)
for financial support.
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