Copyright 2010 American Scientic Publishers

All rights reserved

Printed in the United States of America

Journal of
Nanoscience and Nanotechnology
Vol. 10, 79197930, 2010

Biomechanisms of Nanoparticles (Toxicants,

Antioxidants and Therapeutics): Electron Transfer and
Reactive Oxygen Species
Peter Kovacic1
and Ratnasamy Somanathan2
2

1
Department of Chemistry, San Diego State University, San Diego CA 92182 USA
Centro de Graduados e Investigacin del Instituto Tecnolgico de Tijuana, Apdo postal 1166, Tijuana, B. C. Mexico

REVIEW

In recent years, nanoparticles have received increasing attention in research and technology, including a variety of practical applications. The bioactivity appears to be related to the small particle
size, in addition to inherent chemical activity as electron transfer (ET) agents, generators of reactive oxygen species (ROS) with subsequent oxidative stress (OS) and as antioxidants (AOs). The
mechanism of toxicity, therapeutic action and AO property is addressed based on the ET-ROS-OS
approach. There are several main classes of ET functionalities, namely, quinones (or phenolic precursors), metal compounds, aromatic nitro compounds (or reduction products) and imine or iminium
species. Most of the nanospecies fall within the metal category. Cell signaling is also discussed.
This review is apparently the rst to address the various bioactivities based on the ET-ROS-OS-AO
framework.

Delivered
by Publishing
Technology
to: Antioxidants,
Universidad Therapeutics,
Nacional Autonoma
MexicoReactive
(UNAM)
Keywords:
Nanoparticles,
Toxicants,
Electronde
Transfer,
IP: 132.248.116.122
On: Mon, 09 Mar 2015 15:59:25
Oxygen
Species, Mechanisms.
Copyright: American Scientific Publishers

CONTENTS
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Nanoparticle Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Unintentionally Produced Nanoparticles . . . . . . . . . . . . . .
2.2. Combustion-Derived Nanoparticles (CDNP) . . . . . . . . . .
2.3. Diesel Exhaust Particulate (DEP) . . . . . . . . . . . . . . . . . . .
2.4. Aggregated Carbon and Carbonaceous Nanoparticles . . .
2.5. Organic Nanoparticulates . . . . . . . . . . . . . . . . . . . . . . . . .
2.6. Welding Fumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7. Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8. Engineered Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . .
2.9. Fullerenes (C60 ) and Carbon Nanotubes . . . . . . . . . . . . . .
3. Metal Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Titanium Dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Silicon Dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Iron and Iron Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4. Cerium Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5. Copper Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6. Zinc Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7. Cobalt Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.8. Silver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.9. Quantum Dots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.10. Manganese . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.11. Aluminum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.12. Nickel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.13. Gold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Author to whom correspondence should be addressed.

J. Nanosci. Nanotechnol. 2010, Vol. 10, No. 12

7919
7921
7921
7921
7921
7921
7921
7922
7922
7922
7922
7923
7923
7924
7924
7925
7925
7925
7925
7925
7926
7926
7926
7926
7926

4. Nanoparticle Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Nanoparticle Theapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowlegment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7926
7927
7928
7928

1. INTRODUCTION
Nano has a longstanding use in science to mean one billionth (1 109
. The prex nano comes from the Greek
word meaning dwarf. Nanotechnology is the understanding
and control of matter on an atomic and molecular scale
at dimensions between 1 and 100 nanometers. Nanoparticles are chemically highly active, in part, because of
their large surface area proportional to their volume. This
causes formation of agglomerates in which particles are
held together by relatively weak forces, including van
der Waals forces, electrostatic forces and surface tension.
Nanoparticles may also form a group of strongly associated particles called aggregates. Nanoparticles less than
30 nm have markedly altered properties and are often
referred to as quantum dots because their size controls
the separation of energy levels within them, behaving like
a semiconductor. Nanoscale materials nd use in a variety of different areas, such as electronic, magnetic, optoelectronic, biomedical, pharmaceutical, cosmetic, energy,

1533-4880/2010/10/7919/012

doi:10.1166/jnn.2010.3028

7919

REVIEW

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

Kovacic and Somanathan

environmental, catalytic, and materials applications. Nanoalkyl peroxides, and diverse radicals (hydroxyl, alkoxyl,
technology is considered by many as the next step
hydroperoxyl, and superoxide [SO]). In some case, ET
in science, integrating engineering with biology, chemresults in interference with normal electrical effects (e.g.,
istry and physics. The potential of this technology has
in respiration or neurochemistry). Generally, active entitriggered a tremendous investment and investigation in
ties possessing ET groups display reduction potentials in
the academic and industrial worlds in recent years. The
the physiologically responsive range, (i.e., more positive
technology has moved from an exotic research pursuit to
than 0.5 V). ET, ROS, and OS have been increasingly
inclusion in hundreds of mainstream consumer products
implicated in the mode of action of drugs and toxins, e.g.,
with nanomaterial markets exceeding billions of dollars
antiinfective agents,9 anticancer drugs,10 carcinogens,11
annually. Many medical innovations, imaging, drug delivreproductive toxins,12 nephrotoxins,13 hepatotoxins,14 carery, nanotherapeutics and nanophase formulations, are in
diovascular toxins,15 nerve toxins,16 mitochondrial toxins,17
clinical trials. With this nanophase invasion of new materiabused drugs,18 ototoxins,19 immunotoxins,20 eye toxins,21
als and products into every aspect of life comes increasing
pulmonary toxins22 and various other categories.23
18
safety and exposure risk; several reviews have addressed
There is a plethora of experimental evidence supporting
this issue from an environmental and medical point of
the ET-ROS theoretical framework, including generation
view. It is recognized that nanoparticles produce reactive
of the common ROS, lipid peroxidation, degradation prodoxygen species (ROS) inside and outside the cell and is
ucts of oxidation, depletion of AOs, effect on exogethe key factor in toxicological effects.4 7
nous AOs, and DNA oxidation and cleavage products, as
Electron transfer (ET) is probably the most imporwell as electrochemical data. This comprehensive, unitant process in chemical transformations. Large impefying mechanism is in keeping with the frequent obsertus was provided to the area by Marcus theory. The
vations that many ET substances display a variety of
preponderance of bioactive substances or their metaboactivities (e.g., multiple-drug properties) as well as toxic
lites incorporate ET functionalities, which, we believe,
effects.
play an important role in physiological responses. The
This review provides a unifying mechanism for the
main groups include quinones (or phenolic precursors),
physiological action of nanoparticles, involving toxicity,
metal complexes (or complexors), aromatic nitro comantioxidant effects and therapeutic use. Apparently, this
Publishing Technology
Universidad
Nacional
Autonoma
deET-ROS-OS
Mexico (UNAM)
pounds (orDelivered
reduced by
hydroxylamine
and nitroso to:
derivaarticle
is the rst
based on
in the mode of
132.248.116.122
On: Mon,
09 Mar
2015 15:59:25
tives), and conjugated imines (orIP:iminium
species). In vivo
action.
However,
it is important to recognize that biologAmerican
Publishers
redox cycling with oxygen can occur, Copyright:
giving rise to
oxida- Scientific
ical action
is often complex entailing a variety of factors.
tive stress (OS) through generation of reactive oxygen
Literature references are mainly representative with origispecies (ROS), such as hydrogen peroxide, hydroperoxides,
nal ones present in prior reviews in some cases.

Peter Kovacic was born in Pennsylvania in 1921, graduated (BA) from Hanover College,
obtained Ph.D. from the University of Illinois, did postdoctoral work at MIT, was instructor
at Columbia University and research chemist at Du Pont. His academic carrier was spent at
Case Western Reserve University and the University of Wisconsin-Milwaukee. After being
a Visiting Professor at about a dozen universities, he is currently Adjunct Professor at San
Diego State University, working on fundamental mechanisms of physiological agents.

Ratnasamy Somanathan was born in Sri Lanka (Ceylon) in 1942, graduated (B.Sc.)
from University of Ceylon (Sri Lanka Peradeniya), obtained Ph.D. from the University of
Shefeld, England, did postdoctoral work at University of Liverpool, England and University of California Davis. Currently Professor at the Center for Graduate Studies, Institute of
Technology Tijuana, Mexico and Adjunct Professor at San Diego State University.

7920

J. Nanosci. Nanotechnol. 10, 79197930, 2010

Kovacic and Somanathan

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

2. NANOPARTICLE TOXICITY
2.1. Unintentionally Produced Nanoparticles

give rise to CDNP,28 with diesel producing more particles per unit fuel than gasoline. Animal studies demonstrate that DEP and other nanoparticulate forms of carbon
are carcinogenic.29 Studies have also shown the adjuvant effects of diesel particles on the intensity of allergic
responses. These effects could also be mediated indirectly
through inammation and oxidative stress.30 31 It was
shown that diesel exhaust, as well as titanium dioxide particles can directly induce cardiac cell damage and affect
the function of the cells through ROS formation.32 In an
epidemiological study, inhalation of diesel exhaust induced
epithelial cells in the lung, generating cell-damaging intracellular ROS.33 Recent reviews implicate reactive oxygen
species in the mechanism of action related to particleinduced oxidative stress and oxidation of DNA3 34 and
CNS diseases.35

J. Nanosci. Nanotechnol. 10, 79197930, 2010

7921

REVIEW

There is relevant discussion in prior Refs. [1, 2]. Research

has focused on the role of ultrane particles in air pollution
in relation to induction of OS leading to inammation and
exacerbation of preexisting respiratory and cardiovascular
disease.24 There is a positive correlation between the level
of particulate air pollution and increased morbidity and
mortality in the population. Studies conrm that ultrane
particles are more toxic than ne particles, and nanoparticles generate ROS to a greater extent than larger particles.
Inhalation is the most signicant exposure route for
these unintentionally generated particulates. Primary particles are emitted directly from sources or process, which
might be natural, such as volcanoes, sea spray, res, automobiles, diesel powered vehicles, coal combustion indus2.4. Aggregated Carbon and Carbonaceous
try and incinerators. Secondary particles are formed in
Nanoparticles
the atmosphere by gas-to-particle conversions. Immediately following nucleation, the secondary particles are very
There is relevant discussion in a prior Ref. [3]. A study
small (110 nm), and growing by coagulation or coninvolving outdoor and indoor soots (candle, wood, diesel,
dense onto existing submicrometer particles.1 Nucleation
tire and natural gas) showed cytotoxicity. The effect on
events may arise out of photochemical processes, and these
lung toxicity by various sizes of carbon black (CB)
nanoparticles are important to cloud formation and can
nanoparticles was examined.36 The nanoparticles aggrabe transported in the atmosphere over large distances and
vate lung inammation related to bacterial endotoxin in
eventually result in human exposure via inhalation routes.1
mice,Nacional
which is Autonoma
more prominent
with smaller
particles. The
Delivered by Publishing Technology to: Universidad
de Mexico
(UNAM)
enhancement
may
be
mediated
via
increased
expression of
IP: 132.248.116.122
2.2. Combustion-Derived Nanoparticles
(CDNP) On: Mon, 09 Mar 2015 15:59:25
Copyright: American Scientific
Publishers
proinammatory
cytokines and via OS. Production of ROS
by CB nanoparticles was measured in various biological
There is relevant discussion in prior Refs. [3, 8]. Nanoparmedia.37 Nanoparticulate CB caused single-strand DNA
ticles are dened as primary particles with at least one
breaks, evidently due to ROS formation.38 The result mimdimension <100 nm, while ultrane particles are dened
ics irradiation-induced carcinogenesis pathways. Nanoparas particles <100 nm in all dimensions and are commonly
ticle preparations of CB and TiO2 produced much stronger
produced by combustion processes.8 Like other nanoparpro-inammatory responses than did ne particles.39 GSH
ticles, CDNP agglomerate readily and leave the surface
assays conrmed that OS was involved in the responses to
area unaffected. NP has the ability to cause inammation
all particles. In a similar investigation, the role of surface
and also, in the case of insoluble CDNP, have potential to
area was determined for OS and proinammatory effects
escape from the site of deposition in the lungs and transloof CB and TiO2 .40 Inammatory effects were dependent
cate to the blood and other target organs. Insoluble NP
on the surface area of the nanoparticles and were mediated
provide surface on which catalytic chemistry can occur
through OS as indicated by inhibition induced by catalase.
that favors the formation of free radicals. These radicals
It was shown the cytotoxicity was not related to the
are responsible for driving oxidative stress, the underlypolyaromatic hydrocarbon content in the soot, but rather
ing mechanism that promotes an inammatory response to
to ROS generation, suggesting that soot induces celluCDNP. Transition metals and organics can undergo comlar OS and that cell viability assays can be indicators of
plex cyclical chemical reactions in the milieu of the lungs
ROS production.41 In a related study, carbon nanopartithat lead to the production of free radicals, such as super2527
cles induced OS in alveolar epithelial cells and alveolar
The exemplar CDNP disoxide or hydroxyl radical.
macrophages.42 Carbon black caused OS which translated
cussed here include diesel soot, fume and nanoparticulate
into activation of NF-k and Il-8 gene expression in
carbon black, fullerenes, and coal y-ash; all of these are
epithelial cells in vitro.43
environmental and occupational hazards. Some of these
are treated in greater detail in subsequent sections.
2.5. Organic Nanoparticulates
2.3. Diesel Exhaust Particulate (DEP)
Debris produced from the friction of motor vehicle tires
with asphalt constitutes 57% of the atmospheric particuThere is relevant discussion in a prior Ref. [3]. Both gasolate matter. Debris particles are small enough to enter the
line and diesel fuels undergo combustion in engines, and

REVIEW

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

human lung, culminating in cell toxicity. The data suggest

ROS production may be the rst event caused by exposure
to tire organic debris. Hsp 70 expression is involved in the
cascade of toxic effects produced on the alveolar A549 cell
line.44 It is reported that 9,10-phenanthraquinone, found
in the diesel exhaust particles, produces superoxide. The
quinone is toxic to human pulmonary epithelial A549 cells
at micromolar concentrations. The mechanism involves
two electron reduction to 9,10-dihydroxyphenanthrene,
which is associated with propagation of ROS.45 A recent
study showed wood dust was associated with various respiratory symptoms, impaired lung function, and asthma in
exposed workers. The data suggest that wood dust is cytotoxic, and increased ROS production plays a major role
in apoptotic response in human broncho-epithelial cells
in vitro.46 Cigarette smoke has long been recognized to be
a primary source for particulate matter indoors, and it is
a contributor to ultrane particles. Cigarette smoke and its
role in oxidative stress has been reviewed.22

Kovacic and Somanathan

iron in asbestos acts as a redox catalyst. Synergism of a

similar character has been reported involving tobacco and
asbestos. Investigations carried out on the relative reactivities of bers, including many different types of asbestos,
demonstrate that the content of iron is directly related to
the bers ability to create ROS. Moreover, redox cycling
of the surface iron seems to be occurring. Copper in
asbestos may be playing a similar role. The formation of
8-OH dG has also been noted. Asbestos-induced formation
of ROS also causes lipid peroxidation and the destruction
of enzymes which may also play roles in the carcinogenicity. Genetic factors were also examined involving DNA
double strand breaks, especially in certain repair decient
cells. Cells with genotype for speedy GSH restoration were
nearly immune to the toxic effects.
2.8. Engineered Nanoparticles

There is relevant discussion in a prior Ref. [1]. Engineered

nanoparticles are increasingly incorporated into consumer
products, such as pigments, resins and cosmetics, but the
2.6. Welding Fumes
potential for toxicity and lack of knowledge have brought
toxicology and the mechanism of action to the forefront.
There is relevant discussion in a prior Ref. [3]. Welding
There is increasing concern that exposure may lead to
is an industrial technique that involves joining of metal
adverse health effects. In a review toxicity of engineered
pieces using ller metal. The ller metal is produced from
nanoparticles and their adverse effects through the generan electrode wire during the welding fusion process. High
ationNacional
of oxidative
stress and
impact
of oxidant injury
temperatures
are
involved,
generating
a
welding
fume
as
Delivered by Publishing Technology to: Universidad
Autonoma
dethe
Mexico
(UNAM)
49
in
the
respiratory
tract
were
discussed.
well as radiation. The vaporizedIP:
metal
fumes
contain
metal
132.248.116.122 On: Mon, 09 Mar 2015 15:59:25
Copyright:
American
oxide, such as from aluminum, cadmium,
chromium
and Scientific Publishers
copper, many of which are water soluble. Welding fumes
2.9. Fullerenes (C60 ) and Carbon Nanotubes
have been studied in both animals and in cells in culFullerene (C60
, a third carbon allotrope, is a clasture, and in both they produce marked pro-inammatory
sical engineered material with potential application in
effects, which are driven largely by transition metals which
biomedicine. One of the biologically most relevant feaundergo redox-cycling resulting in OS.10 47 48
tures of C60 is the ability to quench various free radicals,
behaving
as a free radical sponge. Conversely, photosen2.7. Asbestos
sitization of C60 leads to its transition to a long-lived triplet
excited state and the subsequent energy or electron transfer
Asbestos is the name given to a group of minerals that
to molecular oxygen yields highly reactive singlet oxygen
occurs naturally in the environment as bundles of bers
or superoxide, respectively. These ROS react with a wide
that can be separated into thin, durable threads. These
range of biological targets and are known to be involved
bers are resistant to heat and chemicals and do not conin both cellular signaling and cell damage.50 Water-soluble
duct electricity. For these reasons, asbestos has been used
widely in many industries. Chemically, asbestos minerals
fullerene (nC60
has been shown to induce lipid peroxiare silicate compounds. Asbestos minerals are divided into
dation in brain of juvenile largemouth bass (Micropterus
two major groups: serpentine and amphibole. Like coal
salmoides).51 A related study showed C60 nanoparticles
and silica, asbestos dust with varying particle size, espeinduced lipid peroxidation in Cyprinus crpio brains.52
cially as nanoparticles, can be of serious health hazard.
Because of the ability to induce cell death in certain condiThere have been numerous case studies correlating cantions, fullerenes are potential anticancer and toxic agents.
cer, especially that of lung, with exposure to mineral bers,
In a study using mathematical modeling and nC60 susparticularly asbestos.11 After earlier puzzlement concernpensions prepared in various solvents, their capacity to
generate ROS, mitochondrial depolarization and necrotic
ing the mode of action, evidence now strongly supports a
cell death was investigated. The model indicated oxygenrole for OS. An in vitro study found that asbestos or peroxquenching power THF/C60 < EtOH/C60 < aqu/C60 .53 In a
ides alone cause moderate DNA damage. However, when
the two were used simultaneously, DNA strand cleavage
related study, fullerol (a polyhydroxylated, water soluble
increased several fold. Such synergism is strong evidence
form of the fullerene C60
was shown to produce ROS
that the Haber-Weiss reaction is occurring, wherein the
from both UV and polychromatic light sources.54
7922

J. Nanosci. Nanotechnol. 10, 79197930, 2010

Kovacic and Somanathan

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

J. Nanosci. Nanotechnol. 10, 79197930, 2010

7923

REVIEW

In a study of anticancer activity, multiple mechanisms

inammation can be stimulated which is also associated
appear to underly fullerene action.55 At the high doses
with ROS. A lower dose of the nanotubes did not result
of C60 , the antiglionia action was due to ROS-mediated
in the toxic manifestations. Topical exposure of SKH-1
necrotic cell damage that was partly dependent on
mice to unpuried single walled carbon nanotubes caused
OS-induced activation of signal-regulated kinase. At low
oxidative stress, depletion of glutathione, oxidation of proconcentrations, C60 did not induce either necrotic or apoptein thiols and carbonyls, elevated myeloperoxidase activtotic cell death, but caused OS resulting in cell cycle block
ity, increase of dermal cell numbers, and skin thickening
and inhibition of tumor cell proliferation. Exposure of sh
resulting from the accumulation of polymorphonuclear
to fullerene aggregates induced the AO enzymes SOD and
leukocytes and mast cells.66
56
catalase, whereas GSH decreased. At certain levels of
There is exploration of the interrelationship among parC60 , lipid peroxidation was enhanced, accompanied by an
ticle size, shape, chemical composition and toxicological
increase in OS. The main mechanism of toxicity appears to
effects of several nanomaterials, including ZnO and carentail OS. A study showed that C60 affects the OS response
bon nanotubes.67 ZnO induced much greater cytotoxicity
in a marine species and that increased AO defenses prothan non-metal nanoparticles, in accord with OS levels
vide some tolerance.57 Aggregated nano-C60 was 34 times
measured by GSH depletion, SOD inhibition, malondialdemore toxic to dermal, lung and astrocyte cells as comhyde production and ROS generation. Compared with ZnO
pared to the fullerol derivatives.58 In contrast, in vivo studnanoparticles, nanotubes were moderately cytotoxic, but
ies with rats showed little or no difference between the
induced more DNA damage.
two materials. Comparitive photoactivity and antibacterial
properties of C60 fullerene and TiO2 nanoparticles were
3. METAL COMPOUNDS
determined.59 In photoactive studies, fullerol produced singlet oxygen and superoxide in microbial growth medium.
This class is known for toxicity. The theme of ET-ROS-OS
C60 was more efcient than fullerol in generating the two
has enjoyed widespread mechanistic support.16 With
ROS. The antibacterial activity of fullerene was linked to
regard to electrochemistry, the reduction potentials of
ROS, in line with a prior review9 on mechanism of antibacheavier metals are generally quite amenable to ET in
terial agents. Nano TiO2 primarily produced hydroxyl radibiosystems. Divalent metal ions inuence a variety of
cals in irradiated
water
superoxide
in microbialto:
growth
Delivered
byand
Publishing
Technology
Universidad
Nacional
Autonoma
de Mexico
(UNAM)
membrane
signaling
processes
involving
ion channels.
for water treatmedium. The TiO2 may be more
IP:efcient
132.248.116.122
On: Mon, 09 Mar 2015 15:59:25
Relevant
studies
involving
cell
signaling
are
reported for
Copyright:
American Scientific Publishers
ment involving UV or solar energy to enhance
contaminant
68
Fe
and
Cu.
oxidation and disinfection. The fullerenes may be useful
Inorganic metals and their oxides play a vital role in the
as waste treatment agents targeting pollutants or microorengineering
of novel nanomaterials, exhibiting electrical,
ganisms that are sensitive to superoxide or singlet oxygen.
catalytic,
mechanical,
photonic, and thermal properties to
A report revealed protection of cells by fullerene nanopar60
aid
in
the
creation
of
unique
applications for commercial,
ticles from NO-mediated apoptotic death. The protective
medical
and
military
sectors.
action was not exerted by direct interaction with NO, but
through neutralization of superoxide from mitochondria.
Also, the C60 partially protected cells from the cytotoxic
3.1. Titanium Dioxide
effects of NO-releasing compounds. In a similar study,
Titanium dioxide has received much attention in matemitochondria-targeted AOs and protectors, such as C60
rials science and engineering due to its optoelctronic
nanoparticles and melatonin, effectively prevent ROS gen61
properties. For example, TiO2 has been utilized as phoeration, resulting in protection from mitochondrial OS.
tocatalysts for photochemical hydrogen production and is
As documented elsewhere in our review, fullerenes display
a main ingredient in many commercial sunscreens. Long
a variety of oxidative behavior. The apparent dichotomy
62
et al. showed Degussa P25, a commercially available
can be rationalized by a recent review dealing with the
TiO2 , stimulates ROS in brain cultures of immortalized
pro-oxidant action by AOs under certain conditions.63
mouse microglia and rapidly damages neurons at low conIn a study, reactive oxygen-induced genotoxicity and
centrations in complex brain cultures, plausibly through
cytotoxicity were compared using carbon nanotubes,
microglia generated ROS.69 Kang et al. showed nano-TiO2
fullerenes C60 and carbon black on mouse lung epithelial
induces ROS generation in lymphocytes, thereby activatcells. Results indicated fullerenes and carbon nanotubes
ing p-53-mediated DNA damage checkpoint signals.70 In
are less genotoxic than carbon black and diesel exhaust
64
a study, female mice were intranasally instilled with two
particles. When inhaled, carbon nanotubes become
types of well-characterized TiO2 nanoparticles (rutile and
imbedded in the lung tissue of mice.65 Attachment occurs
anatase). Results indicated TiO2 directly entered the brain
to the pleural tissue, similar to the action of toxic asbestos.
through the olfactory bulb and deposited in the hippocamSubsequent encapsulation by phagocytes occurs. These
pus region. Anatase-TiO2 showed the most oxidative damagents of the immune system are well-known generaage expressed as lipid peroxidation and impairment of the
tors of ROS which can then induce adverse effects. Also,

REVIEW

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

Kovacic and Somanathan

TiO2 to ZnO. The presence of light was a signicant factor

central nervous system.71 Reeves et al. reported the potendue to its role in promoting generation of ROS.78 Exposure
tial cytotoxic and genotoxic effects of TiO2 nanoparticles
to SiO2 nanoparticles resulted in a dose-dependent cytoon gold sh skin. In the absence of UV light, the material
toxicity in cultured human embryonic kidney (HEK293)
caused elevated levels of Fpg-sensitive sites, indicating the
cells that was associated with increased oxidative stress.79
oxidation of purine DNA (guanine) by TiO2 . UV radiation
Lin et al. reported exposure of cultured human bronof TiO2 -treated cells caused further increase in DNA damchoalveolar carcinoma-derived cells to SiO2 nanoparticles
age. Electron spin resonance (ESR) studies revealed that
results in a dose dependent cytotoxicity with increased
the observed toxic effects of nanoparticulate TiO2 were
ROS levels and reduced glutathione levels.80 Park and
most likely due to OH formation.72
Park reported inammatory responses induced by silica
Recently, nanomaterials, especially TiO2 coating, have
nanoparticles in mice and RAW264.7 cell line. Results
gained much attention in orthopedic implants, such as
indicate ROS generation with decreased intracellular GSH,
bone, cartilage, joint, etc. The wear particles generated
which triggers the pro-inammatory responses both in vivo
from coating in living organism due to corrosion could
and in vitro.81 In a related study, exposure of bronchial
pose health risks. Wang et al. showed intraarticular injecepithelial cell Beas-2B to fumed or porous silicon dioxtion of anatase TiO2 nanoparticles had potential toxicoide nanoparticles exerted toxicity via oxidative stress, in
logical effects on major organs and knee joints of rats.
addition to the induction of heme oxygenase-1 via the NrfIn the TiO2 -exposed synovium, the oxidative damage was
2-ERK MAP kinase signaling pathway. Cells exposed to
induced because the glutathione peroxidase, reduced gluporous silica nanoparticles showed more sensitive response
tathione, and superoxide dismutase levels were high, in
than fumed silica.82
response to free radical generation. Further, lipid peroxidation was detected in the synovium through the expression of proinammatory cytokines, such as tumor necrosis
3.3. Iron and Iron Oxide
factor alpha (TNF-
and interleukin (IL-1
.73 Cytotoxicities of titanium dioxide nanoparticles of different conIron, one of the most abundant elements in the earths
centrations were evaluated using human epithelial cell line,
crust, plays an important role in physiological functions.
BEAS-2B. Exposure of the cultured cells to nanoparticles
The human body contains about four grams of iron
Delivered
Publishing
Technology
to: Universidad
de Mexico
(UNAM)
led to cell death,
with by
increase
in ROS,
reduced glutathione
that Nacional
is mainly Autonoma
present in oxygen
carrying
proteins called
IP: 132.248.116.122
09 Mar 2015 15:59:25
and the induction of oxidative stress-related
genes, suchOn:
as Mon,
hemoglobin
and
myoglobin,
as
well
as
in
siderphores.
Iron
Copyright: American Scientific Publishers
heme oxygenase-1, thioredoxin, glutathione-5-transferase,
can be found in cigarette smoke, human diet, and supcatalase, and hypoxia inducible gene.74
plemental vitamins. Overconsumption can cause toxicity
One of the active ingredients in commercial sunscreen
in the liver, pancreas, kidneys, heart, joints, and gonads.
is titanium dioxide, and it poses potential health hazards
Symptoms of overload include vomiting, gastrointestinal
in the presence of UV light. Brezov et al. showed conbleeding and severe shock.
tinuous in situ irradiation of titanium dioxide powder, recExcess iron elicits increased free-radical damage, one
ommended for cosmetic application, in different solvents
route being the Fenton reaction which produces ROS. The
(water, dimethyl sulfoxide, isopropyl alcohol) resulted in
hydroxyl radicals produced can then induce lipid peroxithe generation of oxygen-centered reactive species (superdation and DNA damage. Iron overload patients have eleoxide, hydroxyl and alkoxyl radicals).75 In a study, cells
vated levels of lipid peroxidation end-products in whose
incubated with titanium dioxide particles showed an eleformation haemosiderin may play a role. DNA damage
vated production of ROS, which was used as a model to
is a consequence of iron toxicity. Increasing amounts of
study lung cells at nanostructural level and to investigate
iron (II) in cultured cells raise levels of oxidative DNA
the toxic potential.76
damage.13
Bleomycin, a clinically useful drug, is a glycopeptide
produced
by a microorganism.10 It is a powerful chelator,
3.2. Silicon Dioxide
and the active form is the complex with Fe(II) which intercalates DNA by means of the bisthiazolyl entity. In the
In comparison to titanium dioxide, silica (SiO2
has been
presence of molecular oxygen, polymer chain degradation
studied more widely due to an occupational lung disoccurs. Of the various possible ROS, a ferric peroxide eviease called silicosis which is linked to crystalline phase
dently plays a key role, as well as the hydroxyl radical.
silica.77 Unlike TiO2 , however, research involving SiO2 in
Apoptosis can be induced.
the eld of nanotechnology deals mainly with amorphous
Iron oxide nanoparticles have extensive application in
phase silica. The potential eco-toxicity of nanosized titadiverse elds, ranging from biomedical drug delivery to
nium dioxide (TiO2
, silicon dioxide (SiO2
and zinc oxide
chemical catalysis. There are several phases of iron oxides
(ZnO) water suspension was studied using Gram-positive
which include Haematite (-Fe3 O4
, Magnetite (Fe3 O4
,
Bacillus subtilis and Gram-negative Escherichia coli as
Maghemite (, , -Fe2 O3
, and Wustite. Among them,
test organisms. Activity generally increased from SiO2 to
7924

J. Nanosci. Nanotechnol. 10, 79197930, 2010

Kovacic and Somanathan

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

Magnetite (Fe3 O4
nanoparticles have been the subject of

use for biomedical research. Alekseenko et al. reported
ferritin, a protein containing iron nanoparticle, induces
ROS formation and inhibits glutamate uptake in rat brain
synaptosomes, potentially leading to neurodegeneration.83
Iron oxide nanoparticles enhanced the cell permeability
through the production of ROS and the stabilization of
microtubules. Results also showed AKT/GSK-3beta signaling pathways are involved in iron nanoparticle-induced
cell permeability.84 Zhu et al. showed exposure to Fe2 O3
nanoparticles could induce OS in the lung.85 In a related
study it was shown nCFe was far more active biologically than nC in decomposing hydrogen peroxide to form
hydroxyl radicals.86
3.4. Cerium Oxide

reactions. Intracellular copper ions that preferentially bind

to GC-rich DNA residues lead to OS, resulting in 8-OHdG
production. Reaction with hydrogen peroxide generates
hydroxyl radicals via the Fenton reaction. Copper (I) participates in lipid peroxidation by decomposing hydroperoxides with generation of ROS.
3.6. Zinc Oxide

CeO2 nanoparticles when tested with human lung epithelial cells led to cell death, with increase in ROS, decrease
in GSH and the induction of oxidative stress-related
genes, such as heme oxygenase-1, catalase, glutathione
s-transferase, and thioredoxin reductase.87 In a related
study, CeO2 nanoparticles were shown to exert toxicity
through oxidative stress, as they cause signicant increase
in the cellular ROS concentrations, subsequently leading
to the strong induction of heme oxygenase-1 via the p383.7. Cobalt Oxide
88
Nrf-2 signaling
pathway.
Delivered
by Publishing Technology to: Universidad Nacional Autonoma de Mexico (UNAM)
Cobalt
oxide,
when
tested on a human cell line, enters the
IP: 132.248.116.122 On: Mon,
09 Mar
2015
15:59:25
cells
very
rapidly
and
causes a rapid induction of ROS if
Copyright:
American
Scientific
Publishers
3.5. Copper Oxide
supplied in the form of Co3 O4 nanoparticles, rather than
Metal oxide nanoparticles are often used as industrial cations.95
alysts, and elevated levels of these particles have been
clearly demonstrated at sites surrounding factories. To
3.8. Silver
date, limited toxicity data on these nanoparticles are availSilver namometal has been used in many consumer
able. Comparison was made of different metal oxide
applications, mostly because of its well-demonstrated
nanoparticles (Cu, Ti, Zn and Fe) in relation to toxicity,
89
and presumed safe use as an antimicrobial agent. Silver
DNA damage and oxidative lesions. Cu nanoparticles
nanoparticles in the sub-50 nm range exhibit increased
were the most potent regarding cytotoxicity, oxidative
efcacy in inhibiting a wide range of bacteria and fungi.
lesions and DNA damage. In a related study, epithelial
Although silver nanoparticles are already found widely
(HEp-2) cells were exposed to SiO2 , Fe2 O3 , and CuO
in multiple products, a concrete assessment of its effects
nanoparticles. CuO induced the greatest amount of cytoon human health and environmental implications remains
toxicity in a dose dependent manner. Although all metal
lacking.
oxide nanoparticles were able to generate ROS in HEp-2
Carlson et al. have shown size dependent toxicity
cells, CuO was better able to overwhelm antioxidant
of silver nanoparticles, largely mediated through oxidadefenses, e.g., catalase and glutathione.90 They were the
tive stress.96 The effect of Ag-25 nanoparticles on mice
only particle that caused a signicant increase in intrabrain was studied. RNA was isolated from the frontal
cellular ROS. It is important to distinguish effects of
cortex and hippocampus regions. Data suggest Ag-25
nanoparticles from dissolved metals.91 Nanocopper pronanoparticles may produce neurotoxicity by generating
duced different morphological effects and gene expression
free radical-induced OS and by altering gene exprespatterns than did soluble copper. Also, Cu nanoparticles
sion, producing apoptosis and neurotoxicity.97 A study
were toxic to plants.92 Since cupric ion released from
revealed the OS-dependent toxicity of silver nanopartiCu nanoparticles had neglible effects, the toxicity clearly
cles in human hepatoma cells. However, the toxicity and
resulted from the Cu nanoparticles. There is evidence that
DNA damage were prevented by use of the antioxidant
free radicals may contribute to toxicity by Cu.13 Wilsons
N -acetylcysteine.98 A systematic study on the in vitro
disease, a condition characterized by toxic levels of the
metal, seems to involve copper-stimulated free-radical
interactions of spherical silver nanoparticles with HT-1080
J. Nanosci. Nanotechnol. 10, 79197930, 2010

7925

REVIEW

In vitro, Zn compounds, at elevated levels, can be toxic

to cells leading to death. Accumulation of ROS was indirectly stimulated.17 In comparison with other metals, there
is substantially less literature on Zn in relation to ET-ROSOS. Release of Zn from glutamatergic synapses contributes
to the neuropathology of ischemia, traumatic brain injury
and stroke.93 Astrocytes at the site are vulnerable to the
metal toxicity which impairs the AO GSH system and
elevates ROS production. Results indicate that the toxicity is mainly associated with ROS generation, rather than
inhibition of the GSH system.
In a study, exposure of RAW 264.7 and BEAS-2B cell
lines to zinc oxide nanoparticles led to toxicity in both
cells, leading to the generation of ROS, oxidant injury,
excitation of inammation, and cell death.94

REVIEW

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

Kovacic and Somanathan

and A431 cells revealed decreased GSH, increased lipid

membrane, including that in the brain. Further, aluminum
peroxidation, DNA fragmentation and cell apoptosis.99
has been shown to inhibit SOD. However, Al itself did not
Hussain et al. reported the toxicity of silver nanoparticle
stimulate membrane lipid peroxidation. Evidence points to
in BRL 3A rat liver cells. The data showed signicant
an indirect effect entailing release of bound Fe into a form
depletion of GSH levels, reduced mitochondrial membrane
with Fenton activity, followed by marked potentiation of
potential and increase in ROS levels, suggesting that cytoFe-induced OS and neuronal death. There is the possibility
toxicity of silver in liver cells is likely to be mediated
that Al may aggravate NO/Ca2+ -dependent excitotoxicity
100
through OS.
damage of neurons, perhaps by increasing NO production
In genetically susceptible humans, heavy metals, such
and subsequent RNS. Alternatively, a recent review claims
as Hg, Au, and Ag, induce adverse immunological reacthat OS is due to formation of an Al-superoxide semiretions e.g., allergy and autoimmunity.101 Findings indicate
duced radical ion.
that Ag evokes the release of ROS and oxidation of thiols critical for the activation of certain Ca channels. These
3.12. Nickel
processes may well play a role in the adverse reactions.
The antibacterial activity of Ag nanoparticles is
Biological responses elicited by synthetic Ni nanopartidependent on chemisorbed Ag+ particles and oxidized
cles were investigated.111 Ni, a transition metal, can induce
102
surface.
Comparison was made of the antimicrobial
free radicals on cell surface. Toxicity depends on whether
effect of Ag, Au and ZnO on S. mutans in dental caries.103
Ni is internalized as the metal or an organic compound,
A higher antimicrobial effect was shown by Ag as comwhich inuences solubility.13 Nickel can be consumed by
pared to the other two materials, which would allow
the oral route, inhalation, and absorption through the skin.
achieving desired clinical effects with reduced toxicity.
The kidney, pituitary, skin, adrenal, and testes have been
A review documents evidence for an ET-ROS-OS mechfound as the primary targets. The metal induces carcinoanism with anti-infective agents.9 Su et al. used silver
genesis, in addition to toxicity in lungs, kidneys, liver,
nanoparticles 30 nm in diameter on clay surface to
and brain. Nickel affects enzymes involved in heme syninitiate bacterial cell death via ROS.104 A similar study
thesis and degradation, which may contribute to its toxic
also showed silver-ion-mediated reactive oxygen species
effects, similar to those of platinum. There is evidence
105
generationDelivered
affecting bactericidal
activity.
by Publishing
Technology
to: Universidad
Nacional
de nickel
Mexicoas(UNAM)
of OS
in rats Autonoma
injected with
observed by base
IP: 132.248.116.122 On: Mon,
09 Mar 2015
modications
in 15:59:25
DNA taken from kidney cells. ROS are
Copyright: American Scientific
Publishers
generated,
apparently via Fenton type reactions and redox
3.9. Quantum Dots
cycling. Lipid peroxidation and protein carbonyl formaQuantum dots are luminescent nanoparticles with unique
tion have also been documented. In the presence of peroxoptical properties that have been exploited for single-cell
ides, biomolecules can chelate with nickel (II) and alter its
and whole animal imaging. Cadmium telluride is in this
reduction potential, thus facilitating generation of hydroxyl
category which induces reactive oxygen species formation
radicals.
leading to multiple organelle damage and cell death.106 In
a related study involving cadmium telluride quantum dots,
3.13. Gold
the authors show Cd+ may play a role in generating ROS
107
which leads to cell death.
Cadmium sulde, another
Direct ET of Cu, Zn SOD is realized at Au nanostructures
quantum dot nanoparticle, induces intracellular ROS prowithout mediators or promoters.112 Thermodynamic and
duction, GSH depletion, and produces cadmium ions as
kinetic parameters of the ET vary with morphology of
a possible mechanism for CdS cytotoxicity.108 Cadmium
the Au nanostructures, suggesting morphology-dependent
selenide (CdSe) quantum dots were shown to damage calf
electrochemistry of SOD. Superoxide could be detected as
thymus DNA by free radicals and ROS induced by light.109
part of the ET process in the presence of oxygen.
3.10. Manganese
A study showed manganese nanoparticles depleted
dopamine and its metabolites, dihydroxyphenylacetic acid,
and homovanillic acid, possibly through the generation of
ROS.110
3.11. Aluminum
Various reports establish the occurrence of Al-mediated
OS.16 Myelin appears to be a preferential target of oxidative damage. Aluminum produces peroxidation of the lipid
7926

4. NANOPARTICLE ANTIOXIDANTS
The prior portion of this review provides extensive evidence for participation of nanoparticles in the generation
of ROS and OS. There is an apparent dichotomy since the
following section documents many reports of these entities
in the role of AOs. A rationale can be provided. In the case
of OS, the particles may be acting as ET agents by transferring electrons to oxygen with formation of superoxide,
a precursor of other ROS. With regard to AO action, it is
known that nanoparticles, e.g., the C60 type,113 can absorb
J. Nanosci. Nanotechnol. 10, 79197930, 2010

Kovacic and Somanathan

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

J. Nanosci. Nanotechnol. 10, 79197930, 2010

7927

REVIEW

and inactivate radicals. Such radicals could be involved in

AO action in protection of hepatic injury.127 Nanospheremediated delivery of vitamin E, which may be a useful
oxidative events, e.g., generation of ROS in catalytic chain
adjunct for AO therapy in Alzheimers disease, increases
reactions. The dual nature of nanoparticles was addressed
its efciency against OS.128 Additional AO reports may be
in an article which raised the question: Is C60 a powerful
114
found in other sections.
AO or a damaging agent? An analogous situation pertains in the pro-oxidant action under certain conditions of
well-known AOs, such as, vitamin E and thiols, which also
5. NANOPARTICLE THEAPEUTICS
has been rationalized.62
Often, the efcacy and commercial viability of a drug
Fullerenes have attracted appreciable AO attention. C60
depends upon its mode of delivery.129 A long-standing
and water-soluble fullerene derivative can function as AOs
113
issue for drug companies is to deliver the correct dose
against radical-initiated lipid peroxidation.
The result
of a particular therapeutic (small molecules, proteins or
refelects the high reactivity of C60 toward various organic
nucleic acids) to a specic disease site. Since this is genradicals. Numerous studies demonstrate that C60 derivaerally unachievable, therapeutics have to be administered
tives can protect cells from attack by ROS. Three differin excessively high doses, thereby increasing the odds of
ent types of water soluble fullerene can intercept all of
toxic side effects. The concept of site-specic delivery of
the major physiologically relevant ROS.115 Cells are proa therapeutic arises from this classic drawback of traditected against oxidative damage, the mitochondrial memtional therapeutics, e.g., 810% of an oral therapeutic is
brane potential is stabilized and ROS levels are lowered.
either denatured by the stomach environment or eliminated
These fullerene derivatives may be of use in cytoprotecvia liver metabolism. Nanoparticles have enormous potention in vivo and as therapeutic agents. A study revealed the
tial in addressing this failure of traditional therapeutics:
AO effects of C60 nanostructures on removal of hydroxyl
they offer specic targeting of therapeutics. Nanoparticles
radicals and in protecting DNA against oxidative damage
are also better suited than their microparticle counterparts
induced by ionnizing radiation.116 The protective action
for intravenous delivery. Nanoparticles can also be used
of C60 nanoparticles was not exerted via direct interacfor getting drugs into the brain. The blood-brain barrier
tion with NO, but through neutralization of mitochon(BBB) is a dynamic endothelial interface which has unique
drial product superoxide in NO-treated cells.117 Thus, C60
structure
due to
the presence
of tight(UNAM)
junctions. In fact,
Delivered
by Publishing
Technology
to: Universidad
Nacional
Autonoma
de Mexico
might prevent
NO-mediated
cell injury
in inammatory
98%
of
drugs
are
unable
to
transverse
the
BBB. However,
132.248.116.122
and autoimmune disorders. C60IP:
nanomaterials
inhibitOn:
the Mon, 09 Mar 2015 15:59:25
Copyright: American Scientific
Publishers
nanoparticles
drug delivery is particularly useful for disorallergic responses, evidently by interfering with signaling
ders of the central nervous system because some nanoparmolecules involved in generation of OS resulting from
ticles are able to cross the BBB. There are two types
ROS.118
of nanoparticle-based therapeutic formulations: (a) those
Reports document related studies with Pt nanoparticles,
in which the therapeutic molecules are the nanoparticles
which function as AOs in inhibition of pulmonary inam(therapeutic function as its own carrier); and (b) those
mation resulting from exposure to cigarette smoke.119 This
in which the therapeutic molecules are directly coupled
AO class acts to efciently quench ROS. It is well estab(functionalized, entrapped or coated) to a carrier. Nanoparlished that the smoke contains various components that
ticle therapeutics has been a burgeoning area in recent
give rise to ET-ROS-OS.120 The Pt nanoclass is a useyears. The following reports are illustrative.
ful scavenger of superoxide and hydrogen peroxide.11 It
Silver is an effective antimicrobial agent with low
may be a SOD/catalase mimetic which can function in
toxicity.130 Drugs releasing silver in ionic form are known
medical treatment of OS diseases. In a related study,
to be neutralized by biological uids and may be toxic. Ag
these nanoparticles reduced accumulation of ROS induced
nanoparticles have been the focus of increasing interest.
by paraquat.121 Worm lifespan was increased, pointing to
Gram-negative bacteria were killed more effectively than
potential anti-aging properties.
gram-positive ones. Good antifungal activity was exhibRare earth nanoparticles prevent retinal degeneration
ited, in addition to favorable anti-inammatory properties.
induced by ROS, such as, peroxides.122 Antioxidant funcEven though the particles elicit OS, cellular AO systems,
tion of Gd-fullerene nanoparticles was demonstrated.123
such as GSH, SOD and catalase, get triggered and preAdministration can restore the damaged liver and kidvent oxidative damage. Prior studies suggest that nanoparney of tumor-bearing mice, suggesting regulation of
ticle drug delivery might improve the therapeutic response
ROS production in vivo. Quercetin nanoparticles were
to anticancer drugs.131 Targeting methotrexate increased
effective in scavenging superoxide and preventing lipid
its anticancer activity and markedly decreased its toxicity,
peroxidation.124 Cerium oxide nanoparticles are cardioproallowing therapeutic responses not possible with the free
tective by attenuation of myocardial OS and inammadrug.
tory processes probably through their AO properties.125
Nanoparticles in the size range of 1100 nm are emergA related report deals with neuroprotection via modulaing as a class of therapeutics for cancer.132 These partion of OS.126 MelatoninSe nanoparticles inhibit OS via
ticles can show enhanced efcacy, while simultaneously

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

Kovacic and Somanathan

REVIEW

reducing side effects. The review describes features that

distinguish them from prior anticancer therapy, such as
nanoparticle size. Nanoparticles are proposed for target
drug delivering to the inammation site in severe cases
of bowel inammation where standard delivery devices
fail.133 The technique allowed enhanced and selective drug
penetration into the inamed site. The use of drug-loaded
nanoparticles offers several advantages, such as higher
selectivity and enhanced drug penetration into inammation sites. There are other relevant articles.134 135 In some
cases nanomaterial may be acting simply as a carrier; in
other instances, they are involved in the therapeutic action.
Prior reviews document the participation of ET-ROS-OS
in the mechanism of anti-infective agents9 and anticancer
drugs.10

24. V. Stone, H. Johnston, and M. J. Clift, IEEE Trans Nanobioscience

6, 331 (2007).
25. S. Hirano, A. Furuyama, E. Koike, and T. Kobayashi, Toxicology
187, 119 (2003).
26. J. D. McNeily, M. R. Heal, I. J. Beverland, A. Howe, M. D. Gibson,
L. R. Hibbs, W. MacNee, and K. Donaldson, Toxicol. Appl.
Pharmacol. 196, 95 (2004).
27. L. C. Renwick, D. Brown, A. Clouter, and K. Donaldson, Occup.
Environ. Med. 61, 442 (2004).
28. L. Morawska and J. J. Zhang, Chemosphere 49,1045 (2002).
29. U. Heinrich, R. Fuhst, S. Rittinghausen, O. Creutzenberg,
B. Bellmann, W. Koch, and K. Levsen, Toxicology 7, 533 (1995).
30. J. C. Ball, A. M. Straccia, W. C. Young, and A. E. Aust, J. Air
Waste Manag. Assoc. 50, 1897 (2000).
31. M. Riedl and D. Az-Sanchez, J. Allergy Clin. Immunol. 115, 221
(2005).
32. M. Helfenstein, M. Miragoli, S. Rohr, L. Mller, P. Wick, M. Mohr,
P. Gehr, and B. Rothen-Rutishauser, Toxicology 253, 70 (2008).
33. C.-P. Chio, S.-C. Chen, K.-C. Chiang, W.-C. Chou, and C.-M. Liao,
Sci. Total Environ. 387, 113 (2007).
Acknowledgment: Editorial assistance by Thelma
34. P. Mller, J. K. Folkmann, L. Forchhammer, E. V. Bruner, P. H.
Chavez is acknowledged.
Danielsen, L. Risom, and S. Loft, Canc. Lett. 266, 84 (2008).
35. M. L. Block and L. Caldern-Garciduenas, Trends Neuroscience
32, 506 (2009).
References and Notes
36. K. Inoue, H. Takano, R. Yanagisawa, S. Hirano, M. Sakurai,
A. Shimada, and T. Yoshikawa, Environ. Health Perspect.
1. P. Biswas and C.-Y. Wu, Air Waste Mange. Assoc. 55, 708 (2005).
114, 1325 (2006).
2. P. J. A. Borm, D. Robbins, S. Haubold, T. Kuhlbusch, H. Fissan,
37. L. Foucaud, M. R. Wilson, D. M. Brown, and V. Stone, Toxicol.
K. Donaldson, R. Schins, V. Stone, W. Keyling, J. Lademann,
Lett. 174, 1 (2007).
D. Warheit, and E. Oberdoser, Particle Fibre Toxicol. 3, 11 (2006).
38. A. R. M. Mroz, R. P. Schins, H. Li, L. A. Jimenez, E. M. Drost,
3. K. Donaldson, L. Tran, L. A. Jimenez, R. Dufn, D. E. Newby,
A. Holowina, W. MacNee, and K. Donaldson, Eur. Respir. J.
N. Mills, W. MacNee, and V. Stone, Particle Fibre Toxicol. 2, 10
31, 241 (2008).
Nacional Autonoma de Mexico (UNAM)
(2005).Delivered by Publishing Technology to: Universidad
39. C. Monteiller, L. Tran, W. MacNee, S. Faux, A. Jones, B. Miller,
IP:Stucky,
132.248.116.122
On: Mon, 09and
Mar
2015 15:59:25
4. W. H. Suh, K. S. Suslick, G. D.
and Y.-H. Suh, Prog.
K. Donaldson, Occup. Environ. Med. 64, 609 (2007).
Copyright: American Scientific
Publishers
Neurobiol. 87, 133 (2009).
40. S. Hussain, S. Boland, A. Baeza-Squiban, R. Hamel, L. C. J.
5. J. M. Tsay and X. Michalet, Chem. Biol. 12, 1159 (2005).
Thomassen, J. A. Martens, M. A. Billon-Galland, J. Fleury-Feith,
6. D. W. Grainger, Adv. Drug Deliv. Rev. 61, 419 (2009).
F. Moisan, J. C. Pairon, and F. Marano F., Toxicology 260, 142
7. A. Nel, T. Xia, L. Madler, and N. Li, Science 311, 622 (2006).
(2009).
8. M. D. Avakian, B. Dellinger, H. Fiedler, B. Gullet, C. Koshland,
41. K. M. Garza, K. F. Soto, and L. E. Murr, Internat. J. Nanomedicine
S. Markland, G. Oberdoster, S. Safe, A. Sarom, K. R. Smith,
3, 83 (2008).
D. Schwartz, and W. A. Suk, Environ. Health Perspect. 110, 1155
42. E. Koike and T. Kobayashi, Chemosphere 65, 946 (2006).
(2002).
43. A. Shukla, C. Timblin, K. BeruBe, T. Gordon, W. McKinney,
9. P. Kovacic and L. E. Becvar, Curr. Pharm. Des. 6, 143 (2000).
K. Driscoll, P. Vacek, and B. T. Mossman, Am. J. Respir. Cell Mol.
10. P. Kovacic and J. A. Osuna, Curr. Pharm. Des. 6, 277 (2000).
Biol. 23, 182 (2000).
11. P. Kovacic and J. D. Jacintho, Curr. Med. Chem. 8, 773 (2001).
44. M. Gualtieri, P. Mantecca, F. Cetta, and M. Camatini, Environ. Int.
12. P. Kovacic and J. D. Jacintho, Curr. Med. Chem. 8, 863 (2001).
34, 437 (2008).
13. P. Kovacic, A. Sacman, and M. Wu-Weis, Curr. Med. Chem. 9, 823
45. K. Taguchi, M. Shimada, S. Fujii, D. Sumi, X. Pan, S. Yamano,
(2002).
T. Nishiyama, A. Hiratsuka, M. Yamamoto, A. K. Cho, J. R.
14. G. Poli, G. H. Cheeseman, M. U. Dianzani, and T. F. Slater,
Froines, and Y. Kumagai, Free Rad. Biol. Med. 44, 1645 (2008).
Free Radicals in the Pathogenesis of Liver Injury, Pergamon Press,
46. L. Pylkknen, H. Stockmann-Juvala, H. Alenius, K. HusgafvelOxford (1989), pp. 1330.
Pursianinen, and K. Savolainen, Toxicology 262, 265 (2009).
15. P. Kovacic and L. A. Thurn, Curr. Vasc. Pharmacol. 3, 107 (2005).
47. G. J. Li, L. L. Zhang, L. Lu, P. Wu, and W. Zheng, J. Occup.
16. P. Kovacic and R. Somanathan, Cur. Med. Chem-CNS Agents 5, 249
Environ. Med. 46, 241 (2004).
(2005).
48. M. D. Taylor, J. R. Roberts, S. S. Leonard, X. Shi, and J. M.
17. P. Kovacic, R. S. Pozos, R. Somanathan, N. Shangari, and P. G.
Antonini, Toxicol. Sci. 75, 181 (2003).
OBrien, Curr. Med. Chem. 5, 2601 (2005).
49. N. Li, T. Xia, and A. E. Nel, Free Rad. Biol. Med. 44, 1689 (2008).
18. P. Kovacic and A. L. Cooksy, Med. Hypotheses 64, 367 (2005).
50. Z. Markovic and V. Trajkovic, Biomaterials 29, 3561 (2008).
19. P. Kovacic and R. Somanathan, Med. Hypotheses 70, 914 (2008).
51. E. Oberdesster, Environ. Health Perspect. 112, 1058 (2004).
20. P. Kovacic and R. Somanathan, J. Recept. Signal Transduct. 28, 323
52. N. Shinohara, T. Matsumoto, M. Gamo, A. Miyauchi, S. Endo,
(2008).
Y. Yonezawa, and J. Nakanishi, Environ. Sci. Technol. 43, 948
21. P. Kovacic and R. Somanathan, Cell Membr. Free Rad. Res. 1, 56
(2009).
(2008).
53. Z. Markovic, B. Todorovic-Markovic, D. Kleut, N. Nikolic,
22. P. Kovacic and R. Somanathan, Reviews of Environmental ContamS. Vranjes-Djuric, M. Misirkic, L. Vucicevic, K. Janjeyovic,
ination and Toxicology, edited by W. P. Whitaere Springer, New
A. Isakovic, L. Harhaji, B. Babic-Stojic, M. Dramicanin, and
York (2009), Vol. 201, p. 41.
V. Trajkovic, Biomaterials 28, 5437 (2007).
23. B. Halliwell and J. M. C. Gutteridge, Free Radicals in Biology and
54. K. D. Pickering and M. R. Wiesner, Environ. Sci. Technol. 39, 1359
(2005).
Medicine, Oxford University Press, New York (1999), pp. 1936.

7928

J. Nanosci. Nanotechnol. 10, 79197930, 2010

Kovacic and Somanathan

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS

J. Nanosci. Nanotechnol. 10, 79197930, 2010

7929

REVIEW

55. L. Harhaji, A. Isakovic, N. Raicevic, Z. Markovic, B. Todorovic85. M.-T. Zhu, W.-Y. Feng, B. Wang, T.-C. Wang, Y.-Q. Gu, M. Wang,
Markovic, N. Nikolic, S. Vranjes-Djuric, I. Markovic, and
Y. Wang, H. Ouyang, Y.-L. Zhao, and Z.-F. Chai, Toxicology
V. Trajkovic, Eur J. Pharmacol. 568, 89 (2007).
247, 102 (2008).
56. X. Zhu, L. Zhu, and Y. Chen, Environ. Toxicol. Chem. 27, 1979
86. W. J. Waldman, R. Kristovich, D. A. Knight, and P. K. Dutta, Chem.
(2008).
Res. Toxicol. 20, 1149 (2007).
57. T. M. Bickley and P. McClellan-Green, Environ. Toxicol. Chem.
87. E. J. Park, J. Choi, Y.-K. Park, and K. Park, Toxicology 245, 90
27, 1964 (2008).
(2008).
58. C. M. Sayes, A. A. Marchione, K. L. Reed, and D. B. Warheit,
88. H.-J. Eom and J. Choi, Toxicol. Lett. 187, 77 (2009).
Nano Lett. 7, 2399 (2007).
89. H. L. Karlsson, P. Cronholm, J. Gustafsson, and L. Mller, Chem.
59. L. Brunet, D. Y. Lyon, E. M. Hotze, P. J. Alvarez, and M. R.
Res. Toxicol. 21, 1726 (2008).
Wiesner, Environ. Sci. Technol. 43, 4355 (2009).
90. B. Fahmy and S. A. Cormier, Toxicol. Vitro 23, 1365 (2009).
60. M. S. Misirkic, M. Todorovic-Markovic, L. M. Vucicevic, K. D.
91. R. J. Griftt, R. Weil, K. A. Hyndman, N. D. Denslow, K. Powers,
Janjetovic, V. R. Jokanovic, M. D. Dramicanin, Z. M. Markovic,
D. Taylor, and D. S. Barber, Environ. Sci. Technol. 41, 8178 (2007).
and V. S. Trajkovic, Biomaterials 30, 2319 (2009).
92. W. M. Lee, Y. J. An, H. Yoon, and H. S. Kweon, Environ. Toxicol.
61. M. J. Jou, Adv. Drug Deliv. Rev. 60, 13 (2008).
Chem. 27, 1915 (2008).
62. P. Kovacic and R. Somanathan, In Antioxidants: New Research,
93. G. M. Bishop, R. Dringen, and S. R. Robinson, Free Rad. Biol.
edited by H. V. Panglossi, Nova Science Publishers Inc., NY
Med. 42, 1222 (2007).
(2006), p. 1.
94. T. Xia, M. Kovochich, M. Liong, L. Mdler, B. Gilbert, H. Shi,
63. C. Blaise, F. Gagn, J. F. Frard, and P. Eullaffroy, Environ. Toxicol.
J. I. Yeh, J. I. Zink, and A. E. Nel, ACS Nano 2, 2121 (2008).
23, 591 (2008).
95. E. Papis, F. Rossi, M. Raspanti, I. Dalle-Donne, G. Colombo,
64. N. R. Jacobsen, G. Pojana, P. White, P. Mller, C. A. Cohn,
A Milzani, G. Bernardini, and R. Gornati, Toxicol. Lett. 189, 253
K. S. Korsholm, U. Vogel, A. Marcomini, S. Loft, and H. Wallin,
(2009).
Environ. Mol. Mutagen 49, 476 (2008).
96. C. Carlson, S. M. Hussain, A. M. Schrand, L. K. Braydich-Stolle,
65. J. P. Ryman-Rasmussen, M. F. Ceta, A. R. Brody, J. K. ShipleyK. L. Hess, R. L. Jone, and J. J. Schlager, J. Phys. Chem. B
Phillips, J. I. Everitt, E. W. Tewksbury, O. R. Moss, B. A. Wong,
112, 13608 (2008).
D. E. Dodd, M. E. Andersen, and J. C. Bonner, Nat. Nanotechnol.
97. M. F. Rahman, J. Wang, T. A. Patterson, U. T. Saini, B. L.
4, 747 (2009).
Robinson, G. D. Newport, R. C. Murdock, J. J. Schlager, S. M.
66. A. R. Murray, E. Kisi, S. S. Leonard, S. H. Young, C. Kommineni,
Hussain, and S. F. Ali, Toxicol. Lett. 187, 15 (2009).
V. E. Kagan, V. Castranova, and A. A. Shvedova, Toxicology
98. S. Kim, J. E. Choi, J. Choi, K.-H. Chung, K. Park, J. Yi, and D.-Y.
257, 161 (2009).
Rye, Toxicol. Vitro 23, 1076 (2009).
67. H. Yang, C. Liu, D. Yang, H. Zhang, and Z. Xi, J. Appl. Toxicol.
99. S. Arora, J. Jain, J. M. Rajwade, and K. M. Paknikar, Toxicol. Lett.
29, 69 Delivered
(2009).
by Publishing Technology to: Universidad Nacional
Autonoma de Mexico (UNAM)
179, 93 (2008).
68. P. Kovacic, Birth Defects Res. Part
78, 333 (2006).
IP:C 132.248.116.122
On: Mon,
09
Mar
2015
15:59:25
100. S. M. Hussain, K. L. Hess, J. M. Gearhart, K. T. Geiss, and J. J.
69. T. C. Long, J. Tajuba, P. Sama, N. Saleh,
C. Swartz,American
J. Parker, Scientific Publishers
Copyright:
Schlager, Toxicol. Vitro 19, 975 (2005).
S. Hester, G. V. Lowrt, and B. Veronesi, Environ. Health Perspect.
101. T. Yoshimaru, Y. Suzuki, T. Inoue, O. Niide, and C. Ra, Free Rad.
115, 1631 (2007).
Biol. Med. 40, 1949 (2006).
70. S. J. Kang, B. M. Kim, Y. J. Lee, and H. W. Chung, Environ. Mol.
102. C. N. Lok, C. M. Ho, R. Chen, Q. Y. He, W. Y. Yu, H. Sun, P. K.
Mutagen 49, 399 (2008).
Tam, J. F. Chiu, and C. M. Che, J. Biol. Inorg. Chem. 12, 527
71. J. Wang, Y. Liu, F. Jiao, F. Lao, W. Li, Y. Gu, Y. Li, C. Ge, G. Zhou,
(2007).
B. Li, Y. Zhao, Z. Chai, and C. Chen, Toxicology 254, 82 (2008).
103. J. F. Hernndez-Sierra, F. Ruiz, D. C. Pena, F. Martinez72. J. F. Reeves, S. J. Davies, N. J. F. Dodd, and A. N. Jha, Mutat.
Gutirrez, A. E. Martinez, J. Guilln Ade, and G. M. Tapia-Pnn,
Res. 640, 113 (2008).
Nanomedicine 4, 237 (2008).
73. J.-X. Wang, Y.-B. Fan, Y. Gao, Q.-H. Hu, and T.-C. Wang,
104. H.-L. Su, C.-C. Chou, D.-J. Hung, S.-H. Lin, J.-C. Pao, J.-H. Lin,
Biomaterials 30, 4590 (2009).
F.-L. Huang, R.-X. Dong, and J.-J. Lin, Biomaterials 30, 5979
74. E.-J. Park, J. Yi, K.-H. Chung, D.-Y. Ryu, J. Choi, and K. Park,
(2009).
Toxicol. Lett. 180, 222 (2008).
105. J. Kim, H.-J. Park, J.-H. Lee, J.-S. Hahn, M. B. Gu, and J. Yoon,
75. V. Brezov, S. Gabcov, D. Dvoranov, and A. Stako,
Water Res. 43, 5252 (2009).
J. Photochem. Photobiol. B: Biol. 79, 121 (2005).
106. J. Lovric, S. J. Cho, F. M. Winnik, and D. Maysinger, Chem. Biol.
76. B. Rothen-Rutishauser, L. Mueller, F. Blank, C. Brandenberger,
12, 1227 (2005).
C. Muehfeld, and P. Gehr, ALTEX 25, 191 (2008).
107. S. J. Cho, D. Maysinger, M. J. Jain, B. Rder, S. Hackbarth, and
77. T. J. Brunner, P. Wick, P. Manser, P. Spohn, R. N. Grass, L. K.
F. M. Winnik, Langmuir 23, 1974 (2007).
Limbach, A. Bruinink, and W. J. Stark, Environ. Sci. Tech. 40, 4374
108. K. G. Li, J. T. Chen, S. S. Bai, X. Wen, S. Y. Song, Q. Yu, J. Li,
(2006).
and Y. Q. Wang, Toxicol. Vitro 23, 1007 (2009).
78. L. K. Adams, D. Y. Lyon, and A. J. J. Alvarez, Water Res. 40, 3527
109. J. Liang, Z. He, S. Zhang, S. Huang, X. Ai, H. Yang, and H. Han,
(2006).
Talanta 71, 1675 (2007).
79. F. Wang, F. Gao, M. Lan, H. Yuan, Y. Huang, and J. Liu, Toxicol.
110. S. M. Hussain, A. K. Javorina, A. M. Schrand, H. M. Duhart, S. F.
Vitro 23, 808 (2009).
Ali, and J. J. Schlager, Toxicol. Sci. 92, 456 (2006).
80. W. Lin, Y.-W. Huang, X.-D. Zhou, and Y. Ma, Toxicol. Appl.
111. M. D. Cheng, J. Environ. Sci. Health A Tox. Hazard Subst. Environ.
Pharmacol. 217, 252 (2006).
Eng. 39, 2691 (2004).
81. E.-J. Park and K. Park, Toxicol. Lett. 184, 18 (2009).
112. H. Liu, Y. Tian, and P. Xia, Langmuir 24, 6359 (2008).
82. H.-J. Eom and J. Choi, Toxicol. Vitro 23, 1326 (2009).
113. C. Wang, L. A. Tai, D. D. Lee, P. P. Kanakamma, C. K.-F. Shen,
83. A. Alekseenko, Y. V. Waseem, and S. V. Fedorovich, Brain Res.
T.-Y. Luh, C. H. Cheng, and K. C. Hwang, J. Med. Chem. 42, 4614
1241, 193 (2008).
(1999).
84. P. L. Apopa, Y. Qian, R. Shao, N. L. Guo, D. Schwegler-Berry,
114. P. Spohn, C. Hirsch, F. Hasler, A. Bruinink, H. F. Krug, and
M. Pacurari, D. Porter, X. Shi, V. Vallyathan, V. Castranova, and
P. Wick, Environ. Pollution 157, 1134 (2009).
D. C. Flynn, Part Fibre Toxicol. 6, 1 (2009).

REVIEW

Biomechanisms of Nanoparticles (Toxicants, Antioxidants and Therapeutics): Electron Transfer and ROS
115. J.-J. Yin, F. Lao, P. P. Fu, W. G. Wamer, Y. Zhao, P. C. Wang,
Y. Qjiu, B. Sun, G. Xing, J. Dong, X.-J. Liang, and C. Chen,
Biomaterials 30, 611 (2009).
116. G. V. Andrievsky, V. I. Bruskov, A. A. Tykhomyrov, and S. V.
Gudov, Free Rad. Biol. Med. 47, 786 (2009).
117. M. S. Misirkic, B. M. Todoroviv-Markovic, L. M. Vucicevic, K. D. Janjetovic, V. R. Jokanovic, M. D. Dramicanin,
Z. M. Markovic, and V. S. Trajkovic, Biomaterials 30, 2319
(2009).
118. J. J. Ryan, H. R. Bateman, A. Stover, G. Gomez, S. K. Norton,
W. Zhao, L. B. Schwartz, R. Lenk, and C. L. Kepley, J. Immunol.
179, 665 (2007).
119. S. Onizawa, K. Aoshiba, M. Kajita, Y. Miyamoto, and A. Nagai,
Pulmonary Pharmacol. Therapeut. 22, 340 (2009).
120. M. Kajita, K. Hikosaka, M. Iitsuka, A. Kanayama, N. Toshima, and
Y. Miyamoto, Free Radic. Res. 41, 615 (2007).
121. L. Kim, M. Takahashi, T. Shimizu, T. Shirasawa, M. Kajita,
A. Kanayama, and Y. Miyamoto, Mech. Ageing Develop. 129, 322
(2008).
122. J. Chen, S. Patil, S. Seal, and J. F. McGinnis, Nat. Nanotechnol.
1, 142 (2006).
123. J. Wang, C. Chen, B. Li, H. Yu, Y. Zhao, J. Sun, Y. Li, G. Xing,
H. Yuan, J. Tang, Z. Chen, H. Meng, Y. Gao, C. Ye, Z. Chai,
C. Zhu, B. Ma, X. Fang, and L. Wan, Biochem. Pharmacol. 71, 872
(2006).

Kovacic and Somanathan

124. T.-H. Wu, F.-L. Yen, L.-T. Lin, T.-R. Tsai, C.-C. Lin, and T.-M.
Cham, Int. J. Pharmaceutics 346, 160 (2008).
125. J. Niu, A. Azfer, L. M. Rogers, X. Wang, and P. E. Kolattukudy,
Cardiovascular Res. 73, 549 (2007).
126. D. Schubert, R. Darusch, J. Raitano, and S.-W. Chan, Biochem.
Biophys. Res. Commun. 342, 86 (2006).
127. H. Wang, W. Wei, S.-Y. Sheng, Y.-X. Shen, Y. Li, N.-P. Wang, and
S.-Y. Xu, J. Pineal Res. 39, 156 (2005).
128. T. B. Shea, D. Ortiz, R. J. Nicolosi, R. Kumar, and A. C. Watterson,
J. Alzheimers Dis. 7, 297 (2005).
129. R. Bawa, Nanotechnol. Law Business 5, 135 (2008).
130. J. Jain, S. Arora, J. Rajwade, S. Khandelwal, and K. M. Pakniker,
Mol. Pharm. 6, 1388 (2009).
131. J. F. Kukowska-Latalo, K. A. Candido, Z. Cao, S. S. Nigavekar,
I. J. Majoros, T. P. Thomas, L. P. Balogh, and M. K. Khan, Cancer
Res. 65, 5317 (2005).
132. M. E. Davis, Z. Chen, and D. M. Shin, Nature Rev. Drug Discov.
7, 771 (2008).
133. A. Lamprechet, H. Yamamoto, H. Takeuchi, and Y. Kawashima,
J. Pharmacol. Exper. Therapeut. 315, 196 (2005).
134. A. Z. Wang, F. Gu, L. Zhang, J. M. Chan, A. Radovic-Moreno,
M. R. Shaikh, and O. C. Farokhzad, Expert Opin. Biol. Ther.
8, 1063 (2008).
135. Y.-Y. Yang, Y. Wang, R. Powell, and P. Chen, Clin. Exp.
Pharmacol. Physiol. 33, 557 (2006).

Received: 18 November 2009. Revised/Accepted: 24 February 2010.

Delivered by Publishing Technology to: Universidad Nacional Autonoma de Mexico (UNAM)

IP: 132.248.116.122 On: Mon, 09 Mar 2015 15:59:25
Copyright: American Scientific Publishers

7930

J. Nanosci. Nanotechnol. 10, 79197930, 2010