j.nanosci.nanotechnol.2010.10_7919-30

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Copyright 2010 American Scientic PublishersAll rights reservedPrinted in the United States of America

Journal ofNanoscience and Nanotechnology

Vol. 10, 79197930, 2010

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

Reactive Oxygen Species

Peter Kovacic1 and Ratnasamy Somanathan21Department of Chemistry, San Diego State University, San Diego CA 92182 USA

2Centro de Graduados e Investigacin del Instituto Tecnolgico de Tijuana, Apdo postal 1166, Tijuana, B. C. Mexico

In recent years, nanoparticles have received increasing attention in research and technology, includ-ing a variety of practical applications. The bioactivity appears to be related to the small particlesize, in addition to inherent chemical activity as electron transfer (ET) agents, generators of reac-tive oxygen species (ROS) with subsequent oxidative stress (OS) and as antioxidants (AOs). Themechanism of toxicity, therapeutic action and AO property is addressed based on the ET-ROS-OSapproach. There are several main classes of ET functionalities, namely, quinones (or phenolic pre-cursors), metal compounds, aromatic nitro compounds (or reduction products) and imine or iminiumspecies. 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-AOframework.

Keywords: Nanoparticles, Toxicants, Antioxidants, Therapeutics, Electron Transfer, ReactiveOxygen Species, Mechanisms.

CONTENTS

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79192. Nanoparticle Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7921

2.1. Unintentionally Produced Nanoparticles . . . . . . . . . . . . . . 79212.2. Combustion-Derived Nanoparticles (CDNP) . . . . . . . . . . 79212.3. Diesel Exhaust Particulate (DEP) . . . . . . . . . . . . . . . . . . . 79212.4. Aggregated Carbon and Carbonaceous Nanoparticles . . . 79212.5. Organic Nanoparticulates . . . . . . . . . . . . . . . . . . . . . . . . . 79212.6. Welding Fumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79222.7. Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79222.8. Engineered Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . 79222.9. Fullerenes (C60) and Carbon Nanotubes . . . . . . . . . . . . . . 7922

3. Metal Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79233.1. Titanium Dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79233.2. Silicon Dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79243.3. Iron and Iron Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79243.4. Cerium Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79253.5. Copper Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79253.6. Zinc Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79253.7. Cobalt Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79253.8. Silver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79253.9. Quantum Dots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79263.10. Manganese . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79263.11. Aluminum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79263.12. Nickel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79263.13. Gold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7926

Author to whom correspondence should be addressed.

4. Nanoparticle Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79265. Nanoparticle Theapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7927

Acknowlegment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7928References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7928

1. INTRODUCTION

Nano has a longstanding use in science to mean one bil-lionth (1109. The prex nano comes from the Greekword meaning dwarf. Nanotechnology is the understandingand control of matter on an atomic and molecular scaleat dimensions between 1 and 100 nanometers. Nanopar-ticles are chemically highly active, in part, because oftheir large surface area proportional to their volume. Thiscauses formation of agglomerates in which particles areheld together by relatively weak forces, including vander Waals forces, electrostatic forces and surface tension.Nanoparticles may also form a group of strongly asso-ciated particles called aggregates. Nanoparticles less than30 nm have markedly altered properties and are oftenreferred to as quantum dots because their size controlsthe separation of energy levels within them, behaving likea semiconductor. Nanoscale materials nd use in a vari-ety of different areas, such as electronic, magnetic, opto-electronic, biomedical, pharmaceutical, cosmetic, energy,

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

environmental, catalytic, and materials applications. Nano-technology is considered by many as the next stepin science, integrating engineering with biology, chem-istry and physics. The potential of this technology hastriggered a tremendous investment and investigation inthe academic and industrial worlds in recent years. Thetechnology has moved from an exotic research pursuit toinclusion in hundreds of mainstream consumer productswith nanomaterial markets exceeding billions of dollarsannually. Many medical innovations, imaging, drug deliv-ery, nanotherapeutics and nanophase formulations, are inclinical trials. With this nanophase invasion of new materi-als and products into every aspect of life comes increasingsafety and exposure risk;18 several reviews have addressedthis issue from an environmental and medical point ofview. It is recognized that nanoparticles produce reactiveoxygen species (ROS) inside and outside the cell and isthe key factor in toxicological effects.47

Electron transfer (ET) is probably the most impor-tant process in chemical transformations. Large impe-tus was provided to the area by Marcus theory. Thepreponderance of bioactive substances or their metabo-lites incorporate ET functionalities, which, we believe,play an important role in physiological responses. Themain groups include quinones (or phenolic precursors),metal complexes (or complexors), aromatic nitro com-pounds (or reduced hydroxylamine and nitroso deriva-tives), and conjugated imines (or iminium species). In vivoredox cycling with oxygen can occur, giving rise to oxida-tive stress (OS) through generation of reactive oxygenspecies (ROS), such as hydrogen peroxide, hydroperoxides,

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 instructorat Columbia University and research chemist at Du Pont. His academic carrier was spent atCase Western Reserve University and the University of Wisconsin-Milwaukee. After beinga Visiting Professor at about a dozen universities, he is currently Adjunct Professor at SanDiego 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 ofShefeld, England, did postdoctoral work at University of Liverpool, England and Univer-sity of California Davis. Currently Professor at the Center for Graduate Studies, Institute ofTechnology Tijuana, Mexico and Adjunct Professor at San Diego State University.

alkyl peroxides, and diverse radicals (hydroxyl, alkoxyl,hydroperoxyl, and superoxide [SO]). In some case, ETresults in interference with normal electrical effects (e.g.,in respiration or neurochemistry). Generally, active enti-ties possessing ET groups display reduction potentials inthe physiologically responsive range, (i.e., more positivethan 0.5 V). ET, ROS, and OS have been increasinglyimplicated in the mode of action of drugs and toxins, e.g.,antiinfective agents,9 anticancer drugs,10 carcinogens,11

reproductive toxins,12 nephrotoxins,13 hepatotoxins,14 car-diovascular toxins,15 nerve toxins,16 mitochondrial toxins,17

abused drugs,18 ototoxins,19 immunotoxins,20 eye toxins,21

pulmonary toxins22 and various other categories.23

There is a plethora of experimental evidence supportingthe ET-ROS theoretical framework, including generationof the common ROS, lipid peroxidation, degradation prod-ucts of oxidation, depletion of AOs, effect on exoge-nous AOs, and DNA oxidation and cleavage products, aswell as electrochemical data. This comprehensive, uni-fying mechanism is in keeping with the frequent obser-vations that many ET substances display a variety ofactivities (e.g., multiple-drug properties) as well as toxiceffects.This review provides a unifying mechanism for the

physiological action of nanoparticles, involving toxicity,antioxidant effects and therapeutic use. Apparently, thisarticle is the rst based on ET-ROS-OS in the mode ofaction. However, it is important to recognize that biolog-ical action is often complex entailing a variety of factors.Literature references are mainly representative with origi-nal ones present in prior reviews in some cases.

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

2. NANOPARTICLE TOXICITY

2.1. Unintentionally Produced Nanoparticles

There is relevant discussion in prior Refs. [1, 2]. Researchhas focused on the role of ultrane particles in air pollutionin relation to induction of OS leading to inammation andexacerbation of preexisting respiratory and cardiovasculardisease.24 There is a positive correlation between the levelof particulate air pollution and increased morbidity andmortality in the population. Studies conrm that ultraneparticles are more toxic than ne particles, and nanoparti-cles generate ROS to a greater extent than larger particles.Inhalation is the most signicant exposure route for

these unintentionally generated particulates. Primary par-ticles are emitted directly from sources or process, whichmight be natural, such as volcanoes, sea spray, res, auto-mobiles, diesel powered vehicles, coal combustion indus-try and incinerators. Secondary particles are formed inthe atmosphere by gas-to-particle conversions. Immedi-ately following nucleation, the secondary particles are verysmall (110 nm), and growing by coagulation or con-dense onto existing submicrometer particles.1 Nucleationevents may arise out of photochemical processes, and thesenanoparticles are important to cloud formation and canbe transported in the atmosphere over large distances andeventually result in human exposure via inhalation routes.1

2.2. Combustion-Derived Nanoparticles (CDNP)

There is relevant discussion in prior Refs. [3, 8]. Nanopar-ticles are dened as primary particles with at least onedimension



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human lung, culminating in cell toxicity. The data suggestROS production may be the rst event caused by exposureto tire organic debris. Hsp 70 expression is involved in thecascade of toxic effects produced on the alveolar A549 cellline.44 It is reported that 9,10-phenanthraquinone, foundin the diesel exhaust particles, produces superoxide. Thequinone is toxic to human pulmonary epithelial A549 cellsat micromolar concentrations. The mechanism involvestwo electron reduction to 9,10-dihydroxyphenanthrene,which is associated with propagation of ROS.45 A recentstudy showed wood dust was associated with various res-piratory symptoms, impaired lung function, and asthma inexposed workers. The data suggest that wood dust is cyto-toxic, and increased ROS production plays a major rolein apoptotic response in human broncho-epithelial cellsin vitro.46 Cigarette smoke has long been recognized to bea primary source for particulate matter indoors, and it isa contributor to ultrane particles. Cigarette smoke and itsrole in oxidative stress has been reviewed.22

2.6. Welding Fumes

There is relevant discussion in a prior Ref. [3]. Weldingis an industrial technique that involves joining of metalpieces using ller metal. The ller metal is produced froman electrode wire during the welding fusion process. Hightemperatures are involved, generating a welding fume aswell as radiation. The vaporized metal fumes contain metaloxide, such as from aluminum, cadmium, chromium andcopper, many of which are water soluble. Welding fumeshave been studied in both animals and in cells in cul-ture, and in both they produce marked pro-inammatoryeffects, which are driven largely by transition metals whichundergo redox-cycling resulting in OS.104748

2.7. Asbestos

Asbestos is the name given to a group of minerals thatoccurs naturally in the environment as bundles of bersthat can be separated into thin, durable threads. Thesebers are resistant to heat and chemicals and do not con-duct electricity. For these reasons, asbestos has been usedwidely in many industries. Chemically, asbestos mineralsare silicate compounds. Asbestos minerals are divided intotwo major groups: serpentine and amphibole. Like coaland silica, asbestos dust with varying particle size, espe-cially as nanoparticles, can be of serious health hazard.There have been numerous case studies correlating can-

cer, especially that of lung, with exposure to mineral bers,particularly asbestos.11 After earlier puzzlement concern-ing the mode of action, evidence now strongly supports arole for OS. An in vitro study found that asbestos or perox-ides alone cause moderate DNA damage. However, whenthe two were used simultaneously, DNA strand cleavageincreased several fold. Such synergism is strong evidencethat the Haber-Weiss reaction is occurring, wherein the

iron in asbestos acts as a redox catalyst. Synergism of asimilar character has been reported involving tobacco andasbestos. Investigations carried out on the relative reactiv-ities of bers, including many different types of asbestos,demonstrate that the content of iron is directly related tothe bers ability to create ROS. Moreover, redox cyclingof the surface iron seems to be occurring. Copper inasbestos may be playing a similar role. The formation of8-OH dG has also been noted. Asbestos-induced formationof ROS also causes lipid peroxidation and the destructionof enzymes which may also play roles in the carcinogenic-ity. Genetic factors were also examined involving DNAdouble strand breaks, especially in certain repair decientcells. Cells with genotype for speedy GSH restoration werenearly immune to the toxic effects.

2.8. Engineered Nanoparticles

There is relevant discussion in a prior Ref. [1]. Engineerednanoparticles are increasingly incorporated into consumerproducts, such as pigments, resins and cosmetics, but thepotential for toxicity and lack of knowledge have broughttoxicology and the mechanism of action to the forefront.There is increasing concern that exposure may lead toadverse health effects. In a review toxicity of engineerednanoparticles and their adverse effects through the gener-ation of oxidative stress and the impact of oxidant injuryin the respiratory tract were discussed.49

2.9. Fullerenes (C60) and Carbon Nanotubes

Fullerene (C60, a third carbon allotrope, is a clas-sical engineered material with potential application inbiomedicine. One of the biologically most relevant fea-tures of C60 is the ability to quench various free radicals,behaving as a free radical sponge. Conversely, photosen-sitization of C60 leads to its transition to a long-lived tripletexcited state and the subsequent energy or electron transferto molecular oxygen yields highly reactive singlet oxygenor superoxide, respectively. These ROS react with a widerange of biological targets and are known to be involvedin both cellular signaling and cell damage.50 Water-solublefullerene (nC60 has been shown to induce lipid peroxi-dation in brain of juvenile largemouth bass (Micropterussalmoides).51 A related study showed C60 nanoparticlesinduced lipid peroxidation in Cyprinus crpio brains.52

Because of the ability to induce cell death in certain condi-tions, fullerenes are potential anticancer and toxic agents.In a study using mathematical modeling and nC60 sus-pensions prepared in various solvents, their capacity togenerate ROS, mitochondrial depolarization and necroticcell death was investigated. The model indicated oxygen-quenching power THF/C60 < EtOH/C60 < aqu/C60.

53 In arelated study, fullerol (a polyhydroxylated, water solubleform of the fullerene C60 was shown to produce ROSfrom both UV and polychromatic light sources.54




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In a study of anticancer activity, multiple mechanismsappear to underly fullerene action.55 At the high dosesof C60, the antiglionia action was due to ROS-mediatednecrotic cell damage that was partly dependent onOS-induced activation of signal-regulated kinase. At lowconcentrations, C60 did not induce either necrotic or apop-totic cell death, but caused OS resulting in cell cycle blockand inhibition of tumor cell proliferation. Exposure of shto fullerene aggregates induced the AO enzymes SOD andcatalase, whereas GSH decreased.56 At certain levels ofC60, lipid peroxidation was enhanced, accompanied by anincrease in OS. The main mechanism of toxicity appears toentail OS. A study showed that C60 affects the OS responsein a marine species and that increased AO defenses pro-vide some tolerance.57 Aggregated nano-C60 was 34 timesmore toxic to dermal, lung and astrocyte cells as com-pared to the fullerol derivatives.58 In contrast, in vivo stud-ies with rats showed little or no difference between thetwo materials. Comparitive photoactivity and antibacterialproperties of C60 fullerene and TiO2 nanoparticles weredetermined.59 In photoactive studies, fullerol produced sin-glet oxygen and superoxide in microbial growth medium.C60 was more efcient than fullerol in generating the twoROS. The antibacterial activity of fullerene was linked toROS, in line with a prior review9 on mechanism of antibac-terial agents. Nano TiO2 primarily produced hydroxyl radi-cals in irradiated water and superoxide in microbial growthmedium. The TiO2 may be more efcient for water treat-ment involving UV or solar energy to enhance contaminantoxidation and disinfection. The fullerenes may be usefulas waste treatment agents targeting pollutants or microor-ganisms that are sensitive to superoxide or singlet oxygen.A report revealed protection of cells by fullerene nanopar-ticles from NO-mediated apoptotic death.60 The protectiveaction was not exerted by direct interaction with NO, butthrough neutralization of superoxide from mitochondria.Also, the C60 partially protected cells from the cytotoxiceffects of NO-releasing compounds. In a similar study,mitochondria-targeted AOs and protectors, such as C60nanoparticles and melatonin, effectively prevent ROS gen-eration, resulting in protection from mitochondrial OS.61

As documented elsewhere in our review, fullerenes displaya variety of oxidative behavior. The apparent dichotomycan be rationalized by a recent review62 dealing with thepro-oxidant action by AOs under certain conditions.63

In a study, reactive oxygen-induced genotoxicity andcytotoxicity were compared using carbon nanotubes,fullerenes C60 and carbon black on mouse lung epithelialcells. Results indicated fullerenes and carbon nanotubesare less genotoxic than carbon black and diesel exhaustparticles.64 When inhaled, carbon nanotubes becomeimbedded in the lung tissue of mice.65 Attachment occursto the pleural tissue, similar to the action of toxic asbestos.Subsequent encapsulation by phagocytes occurs. Theseagents of the immune system are well-known genera-tors of ROS which can then induce adverse effects. Also,

inammation can be stimulated which is also associatedwith ROS. A lower dose of the nanotubes did not resultin the toxic manifestations. Topical exposure of SKH-1mice to unpuried single walled carbon nanotubes causedoxidative stress, depletion of glutathione, oxidation of pro-tein thiols and carbonyls, elevated myeloperoxidase activ-ity, increase of dermal cell numbers, and skin thickeningresulting from the accumulation of polymorphonuclearleukocytes and mast cells.66

There is exploration of the interrelationship among par-ticle size, shape, chemical composition and toxicologicaleffects of several nanomaterials, including ZnO and car-bon nanotubes.67 ZnO induced much greater cytotoxicitythan non-metal nanoparticles, in accord with OS levelsmeasured by GSH depletion, SOD inhibition, malondialde-hyde production and ROS generation. Compared with ZnOnanoparticles, nanotubes were moderately cytotoxic, butinduced more DNA damage.

3. METAL COMPOUNDS

This class is known for toxicity. The theme of ET-ROS-OShas enjoyed widespread mechanistic support.16 Withregard to electrochemistry, the reduction potentials ofheavier metals are generally quite amenable to ET inbiosystems. Divalent metal ions inuence a variety ofmembrane signaling processes involving ion channels.Relevant studies involving cell signaling are reported forFe and Cu.68

Inorganic metals and their oxides play a vital role in theengineering of novel nanomaterials, exhibiting electrical,catalytic, mechanical, photonic, and thermal properties toaid in the creation of unique applications for commercial,medical and military sectors.

3.1. Titanium Dioxide

Titanium dioxide has received much attention in mate-rials science and engineering due to its optoelctronicproperties. For example, TiO2 has been utilized as pho-tocatalysts for photochemical hydrogen production and isa main ingredient in many commercial sunscreens. Longet al. showed Degussa P25, a commercially availableTiO2, stimulates ROS in brain cultures of immortalizedmouse microglia and rapidly damages neurons at low con-centrations in complex brain cultures, plausibly throughmicroglia generated ROS.69 Kang et al. showed nano-TiO2induces ROS generation in lymphocytes, thereby activat-ing p-53-mediated DNA damage checkpoint signals.70 Ina study, female mice were intranasally instilled with twotypes of well-characterized TiO2 nanoparticles (rutile andanatase). Results indicated TiO2 directly entered the brainthrough the olfactory bulb and deposited in the hippocam-pus region. Anatase-TiO2 showed the most oxidative dam-age expressed as lipid peroxidation and impairment of the

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central nervous system.71 Reeves et al. reported the poten-tial cytotoxic and genotoxic effects of TiO2 nanoparticleson gold sh skin. In the absence of UV light, the materialcaused elevated levels of Fpg-sensitive sites, indicating theoxidation of purine DNA (guanine) by TiO2. UV radiationof TiO2-treated cells caused further increase in DNA dam-age. Electron spin resonance (ESR) studies revealed thatthe observed toxic effects of nanoparticulate TiO2 weremost likely due to OH formation.72

Recently, nanomaterials, especially TiO2 coating, havegained much attention in orthopedic implants, such asbone, cartilage, joint, etc. The wear particles generatedfrom coating in living organism due to corrosion couldpose health risks. Wang et al. showed intraarticular injec-tion of anatase TiO2 nanoparticles had potential toxico-logical effects on major organs and knee joints of rats.In the TiO2-exposed synovium, the oxidative damage wasinduced because the glutathione peroxidase, reduced glu-tathione, and superoxide dismutase levels were high, inresponse to free radical generation. Further, lipid peroxi-dation was detected in the synovium through the expres-sion of proinammatory cytokines, such as tumor necrosisfactor alpha (TNF- and interleukin (IL-1.73 Cytotox-icities of titanium dioxide nanoparticles of different con-centrations were evaluated using human epithelial cell line,BEAS-2B. Exposure of the cultured cells to nanoparticlesled to cell death, with increase in ROS, reduced glutathioneand the induction of oxidative stress-related genes, such asheme oxygenase-1, thioredoxin, glutathione-5-transferase,catalase, and hypoxia inducible gene.74

One of the active ingredients in commercial sunscreenis titanium dioxide, and it poses potential health hazardsin the presence of UV light. Brezov et al. showed con-tinuous in situ irradiation of titanium dioxide powder, rec-ommended for cosmetic application, in different solvents(water, dimethyl sulfoxide, isopropyl alcohol) resulted inthe generation of oxygen-centered reactive species (super-oxide, hydroxyl and alkoxyl radicals).75 In a study, cellsincubated with titanium dioxide particles showed an ele-vated production of ROS, which was used as a model tostudy lung cells at nanostructural level and to investigatethe toxic potential.76

3.2. Silicon Dioxide

In comparison to titanium dioxide, silica (SiO2 has beenstudied more widely due to an occupational lung dis-ease called silicosis which is linked to crystalline phasesilica.77 Unlike TiO2, however, research involving SiO2 inthe eld of nanotechnology deals mainly with amorphousphase silica. The potential eco-toxicity of nanosized tita-nium dioxide (TiO2, silicon dioxide (SiO2 and zinc oxide(ZnO) water suspension was studied using Gram-positiveBacillus subtilis and Gram-negative Escherichia coli astest organisms. Activity generally increased from SiO2 to

TiO2 to ZnO. The presence of light was a signicant factordue to its role in promoting generation of ROS.78 Exposureto SiO2 nanoparticles resulted in a dose-dependent cyto-toxicity in cultured human embryonic kidney (HEK293)cells that was associated with increased oxidative stress.79

Lin et al. reported exposure of cultured human bron-choalveolar carcinoma-derived cells to SiO2nanoparticlesresults in a dose dependent cytotoxicity with increasedROS levels and reduced glutathione levels.80 Park andPark reported inammatory responses induced by silicananoparticles in mice and RAW264.7 cell line. Resultsindicate ROS generation with decreased intracellular GSH,which triggers the pro-inammatory responses both in vivoand in vitro.81 In a related study, exposure of bronchialepithelial cell Beas-2B to fumed or porous silicon diox-ide nanoparticles exerted toxicity via oxidative stress, inaddition to the induction of heme oxygenase-1 via the Nrf-2-ERK MAP kinase signaling pathway. Cells exposed toporous silica nanoparticles showed more sensitive responsethan fumed silica.82

3.3. Iron and Iron Oxide

Iron, one of the most abundant elements in the earthscrust, plays an important role in physiological functions.The human body contains about four grams of ironthat is mainly present in oxygen carrying proteins calledhemoglobin and myoglobin, as well as in siderphores. Ironcan be found in cigarette smoke, human diet, and sup-plemental vitamins. Overconsumption can cause toxicityin the liver, pancreas, kidneys, heart, joints, and gonads.Symptoms of overload include vomiting, gastrointestinalbleeding and severe shock.Excess iron elicits increased free-radical damage, one

route being the Fenton reaction which produces ROS. Thehydroxyl radicals produced can then induce lipid peroxi-dation and DNA damage. Iron overload patients have ele-vated levels of lipid peroxidation end-products in whoseformation haemosiderin may play a role. DNA damageis a consequence of iron toxicity. Increasing amounts ofiron (II) in cultured cells raise levels of oxidative DNAdamage.13

Bleomycin, a clinically useful drug, is a glycopeptideproduced by a microorganism.10 It is a powerful chelator,and the active form is the complex with Fe(II) which inter-calates DNA by means of the bisthiazolyl entity. In thepresence of molecular oxygen, polymer chain degradationoccurs. Of the various possible ROS, a ferric peroxide evi-dently plays a key role, as well as the hydroxyl radical.Apoptosis can be induced.Iron oxide nanoparticles have extensive application in

diverse elds, ranging from biomedical drug delivery tochemical catalysis. There are several phases of iron oxideswhich include Haematite (-Fe3O4, Magnetite (Fe3O4,Maghemite (, , -Fe2O3, and Wustite. Among them,




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Magnetite (Fe3O4 nanoparticles have been the subject ofuse for biomedical research. Alekseenko et al. reportedferritin, a protein containing iron nanoparticle, inducesROS formation and inhibits glutamate uptake in rat brainsynaptosomes, potentially leading to neurodegeneration.83

Iron oxide nanoparticles enhanced the cell permeabilitythrough the production of ROS and the stabilization ofmicrotubules. Results also showed AKT/GSK-3beta sig-naling pathways are involved in iron nanoparticle-inducedcell permeability.84 Zhu et al. showed exposure to Fe2O3nanoparticles could induce OS in the lung.85 In a relatedstudy it was shown nCFe was far more active biologi-cally than nC in decomposing hydrogen peroxide to formhydroxyl radicals.86

3.4. Cerium Oxide

CeO2 nanoparticles when tested with human lung epithe-lial cells led to cell death, with increase in ROS, decreasein GSH and the induction of oxidative stress-relatedgenes, such as heme oxygenase-1, catalase, glutathiones-transferase, and thioredoxin reductase.87 In a relatedstudy, CeO2 nanoparticles were shown to exert toxicitythrough oxidative stress, as they cause signicant increasein the cellular ROS concentrations, subsequently leadingto the strong induction of heme oxygenase-1 via the p38-Nrf-2 signaling pathway.88

3.5. Copper Oxide

Metal oxide nanoparticles are often used as industrial cat-alysts, and elevated levels of these particles have beenclearly demonstrated at sites surrounding factories. Todate, limited toxicity data on these nanoparticles are avail-able. Comparison was made of different metal oxidenanoparticles (Cu, Ti, Zn and Fe) in relation to toxicity,DNA damage and oxidative lesions.89 Cu nanoparticleswere the most potent regarding cytotoxicity, oxidativelesions and DNA damage. In a related study, epithelial(HEp-2) cells were exposed to SiO2, Fe2O3, and CuOnanoparticles. CuO induced the greatest amount of cyto-toxicity in a dose dependent manner. Although all metaloxide nanoparticles were able to generate ROS in HEp-2cells, CuO was better able to overwhelm antioxidantdefenses, e.g., catalase and glutathione.90 They were theonly particle that caused a signicant increase in intra-cellular ROS. It is important to distinguish effects ofnanoparticles from dissolved metals.91 Nanocopper pro-duced different morphological effects and gene expressionpatterns than did soluble copper. Also, Cu nanoparticleswere toxic to plants.92 Since cupric ion released fromCu nanoparticles had neglible effects, the toxicity clearlyresulted from the Cu nanoparticles. There is evidence thatfree radicals may contribute to toxicity by Cu.13 Wilsonsdisease, a condition characterized by toxic levels of themetal, seems to involve copper-stimulated free-radical

reactions. Intracellular copper ions that preferentially bindto GC-rich DNA residues lead to OS, resulting in 8-OHdGproduction. Reaction with hydrogen peroxide generateshydroxyl radicals via the Fenton reaction. Copper (I) par-ticipates in lipid peroxidation by decomposing hydroper-oxides with generation of ROS.

3.6. Zinc Oxide

In vitro, Zn compounds, at elevated levels, can be toxicto cells leading to death. Accumulation of ROS was indi-rectly stimulated.17 In comparison with other metals, thereis substantially less literature on Zn in relation to ET-ROS-OS. Release of Zn from glutamatergic synapses contributesto the neuropathology of ischemia, traumatic brain injuryand stroke.93 Astrocytes at the site are vulnerable to themetal toxicity which impairs the AO GSH system andelevates ROS production. Results indicate that the toxic-ity is mainly associated with ROS generation, rather thaninhibition 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 bothcells, leading to the generation of ROS, oxidant injury,excitation of inammation, and cell death.94

3.7. Cobalt Oxide

Cobalt oxide, when tested on a human cell line, enters thecells very rapidly and causes a rapid induction of ROS ifsupplied in the form of Co3O4 nanoparticles, rather thanions.95

3.8. Silver

Silver namometal has been used in many consumerapplications, mostly because of its well-demonstratedand presumed safe use as an antimicrobial agent. Silvernanoparticles in the sub-50 nm range exhibit increasedefcacy in inhibiting a wide range of bacteria and fungi.Although silver nanoparticles are already found widelyin multiple products, a concrete assessment of its effectson human health and environmental implications remainslacking.Carlson et al. have shown size dependent toxicity

of silver nanoparticles, largely mediated through oxida-tive stress.96 The effect of Ag-25 nanoparticles on micebrain was studied. RNA was isolated from the frontalcortex and hippocampus regions. Data suggest Ag-25nanoparticles may produce neurotoxicity by generatingfree radical-induced OS and by altering gene expres-sion, producing apoptosis and neurotoxicity.97 A studyrevealed the OS-dependent toxicity of silver nanoparti-cles in human hepatoma cells. However, the toxicity andDNA damage were prevented by use of the antioxidantN -acetylcysteine.98 A systematic study on the in vitrointeractions of spherical silver nanoparticles with HT-1080




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and A431 cells revealed decreased GSH, increased lipidperoxidation, DNA fragmentation and cell apoptosis.99

Hussain et al. reported the toxicity of silver nanoparticlein BRL 3A rat liver cells. The data showed signicantdepletion of GSH levels, reduced mitochondrial membranepotential and increase in ROS levels, suggesting that cyto-toxicity of silver in liver cells is likely to be mediatedthrough OS.100

In genetically susceptible humans, heavy metals, suchas Hg, Au, and Ag, induce adverse immunological reac-tions e.g., allergy and autoimmunity.101 Findings indicatethat Ag evokes the release of ROS and oxidation of thi-ols critical for the activation of certain Ca channels. Theseprocesses may well play a role in the adverse reactions.The antibacterial activity of Ag nanoparticles is

dependent on chemisorbed Ag+ particles and oxidizedsurface.102 Comparison was made of the antimicrobialeffect of Ag, Au and ZnO on S. mutans in dental caries.103

A higher antimicrobial effect was shown by Ag as com-pared to the other two materials, which would allowachieving desired clinical effects with reduced toxicity.A review documents evidence for an ET-ROS-OS mech-anism with anti-infective agents.9 Su et al. used silvernanoparticles 30 nm in diameter on clay surface toinitiate bacterial cell death via ROS.104 A similar studyalso showed silver-ion-mediated reactive oxygen speciesgeneration affecting bactericidal activity.105

3.9. Quantum Dots

Quantum dots are luminescent nanoparticles with uniqueoptical properties that have been exploited for single-celland whole animal imaging. Cadmium telluride is in thiscategory which induces reactive oxygen species formationleading to multiple organelle damage and cell death.106 Ina related study involving cadmium telluride quantum dots,the authors show Cd+ may play a role in generating ROSwhich leads to cell death.107 Cadmium sulde, anotherquantum dot nanoparticle, induces intracellular ROS pro-duction, GSH depletion, and produces cadmium ions asa possible mechanism for CdS cytotoxicity.108 Cadmiumselenide (CdSe) quantum dots were shown to damage calfthymus DNA by free radicals and ROS induced by light.109

3.10. Manganese

A study showed manganese nanoparticles depleteddopamine and its metabolites, dihydroxyphenylacetic acid,and homovanillic acid, possibly through the generation ofROS.110

3.11. Aluminum

Various reports establish the occurrence of Al-mediatedOS.16 Myelin appears to be a preferential target of oxida-tive damage. Aluminum produces peroxidation of the lipid

membrane, including that in the brain. Further, aluminumhas been shown to inhibit SOD. However, Al itself did notstimulate membrane lipid peroxidation. Evidence points toan indirect effect entailing release of bound Fe into a formwith Fenton activity, followed by marked potentiation ofFe-induced OS and neuronal death. There is the possibilitythat Al may aggravate NO/Ca2+-dependent excitotoxicitydamage of neurons, perhaps by increasing NO productionand subsequent RNS. Alternatively, a recent review claimsthat OS is due to formation of an Al-superoxide semire-duced radical ion.

3.12. Nickel

Biological responses elicited by synthetic Ni nanoparti-cles were investigated.111 Ni, a transition metal, can inducefree radicals on cell surface. Toxicity depends on whetherNi is internalized as the metal or an organic compound,which inuences solubility.13 Nickel can be consumed bythe oral route, inhalation, and absorption through the skin.The kidney, pituitary, skin, adrenal, and testes have beenfound as the primary targets. The metal induces carcino-genesis, in addition to toxicity in lungs, kidneys, liver,and brain. Nickel affects enzymes involved in heme syn-thesis and degradation, which may contribute to its toxiceffects, similar to those of platinum. There is evidenceof OS in rats injected with nickel as observed by basemodications in DNA taken from kidney cells. ROS aregenerated, apparently via Fenton type reactions and redoxcycling. Lipid peroxidation and protein carbonyl forma-tion have also been documented. In the presence of perox-ides, biomolecules can chelate with nickel (II) and alter itsreduction potential, thus facilitating generation of hydroxylradicals.

3.13. Gold

Direct ET of Cu, Zn SOD is realized at Au nanostructureswithout mediators or promoters.112 Thermodynamic andkinetic parameters of the ET vary with morphology ofthe Au nanostructures, suggesting morphology-dependentelectrochemistry of SOD. Superoxide could be detected aspart of the ET process in the presence of oxygen.

4. NANOPARTICLE ANTIOXIDANTS

The prior portion of this review provides extensive evi-dence for participation of nanoparticles in the generationof ROS and OS. There is an apparent dichotomy since thefollowing section documents many reports of these entitiesin the role of AOs. A rationale can be provided. In the caseof OS, the particles may be acting as ET agents by trans-ferring electrons to oxygen with formation of superoxide,a precursor of other ROS. With regard to AO action, it isknown that nanoparticles, e.g., the C60 type,

113 can absorb




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and inactivate radicals. Such radicals could be involved inoxidative events, e.g., generation of ROS in catalytic chainreactions. The dual nature of nanoparticles was addressedin an article which raised the question: Is C60 a powerfulAO or a damaging agent?114 An analogous situation per-tains in the pro-oxidant action under certain conditions ofwell-known AOs, such as, vitamin E and thiols, which alsohas been rationalized.62

Fullerenes have attracted appreciable AO attention. C60and water-soluble fullerene derivative can function as AOsagainst radical-initiated lipid peroxidation.113 The resultrefelects the high reactivity of C60 toward various organicradicals. Numerous studies demonstrate that C60 deriva-tives can protect cells from attack by ROS. Three differ-ent types of water soluble fullerene can intercept all ofthe major physiologically relevant ROS.115 Cells are pro-tected against oxidative damage, the mitochondrial mem-brane potential is stabilized and ROS levels are lowered.These fullerene derivatives may be of use in cytoprotec-tion in vivo and as therapeutic agents. A study revealed theAO effects of C60 nanostructures on removal of hydroxylradicals and in protecting DNA against oxidative damageinduced by ionnizing radiation.116 The protective actionof C60 nanoparticles was not exerted via direct interac-tion with NO, but through neutralization of mitochon-drial product superoxide in NO-treated cells.117 Thus, C60might prevent NO-mediated cell injury in inammatoryand autoimmune disorders. C60 nanomaterials inhibit theallergic responses, evidently by interfering with signalingmolecules involved in generation of OS resulting fromROS.118

Reports document related studies with Pt nanoparticles,which function as AOs in inhibition of pulmonary inam-mation resulting from exposure to cigarette smoke.119 ThisAO class acts to efciently quench ROS. It is well estab-lished that the smoke contains various components thatgive rise to ET-ROS-OS.120 The Pt nanoclass is a use-ful scavenger of superoxide and hydrogen peroxide.11 Itmay be a SOD/catalase mimetic which can function inmedical treatment of OS diseases. In a related study,these nanoparticles reduced accumulation of ROS inducedby paraquat.121 Worm lifespan was increased, pointing topotential anti-aging properties.Rare earth nanoparticles prevent retinal degeneration

induced by ROS, such as, peroxides.122 Antioxidant func-tion of Gd-fullerene nanoparticles was demonstrated.123

Administration can restore the damaged liver and kid-ney of tumor-bearing mice, suggesting regulation ofROS production in vivo. Quercetin nanoparticles wereeffective in scavenging superoxide and preventing lipidperoxidation.124 Cerium oxide nanoparticles are cardiopro-tective by attenuation of myocardial OS and inamma-tory processes probably through their AO properties.125

A related report deals with neuroprotection via modula-tion of OS.126 MelatoninSe nanoparticles inhibit OS via

AO action in protection of hepatic injury.127 Nanosphere-mediated delivery of vitamin E, which may be a usefuladjunct for AO therapy in Alzheimers disease, increasesits efciency against OS.128 Additional AO reports may befound in other sections.

5. NANOPARTICLE THEAPEUTICS

Often, the efcacy and commercial viability of a drugdepends upon its mode of delivery.129 A long-standingissue for drug companies is to deliver the correct doseof a particular therapeutic (small molecules, proteins ornucleic acids) to a specic disease site. Since this is gen-erally unachievable, therapeutics have to be administeredin excessively high doses, thereby increasing the odds oftoxic side effects. The concept of site-specic delivery ofa therapeutic arises from this classic drawback of tradi-tional therapeutics, e.g., 810% of an oral therapeutic iseither denatured by the stomach environment or eliminatedvia liver metabolism. Nanoparticles have enormous poten-tial in addressing this failure of traditional therapeutics:they offer specic targeting of therapeutics. Nanoparticlesare also better suited than their microparticle counterpartsfor intravenous delivery. Nanoparticles can also be usedfor getting drugs into the brain. The blood-brain barrier(BBB) is a dynamic endothelial interface which has uniquestructure due to the presence of tight junctions. In fact,98% of drugs are unable to transverse the BBB. However,nanoparticles drug delivery is particularly useful for disor-ders of the central nervous system because some nanopar-ticles are able to cross the BBB. There are two typesof nanoparticle-based therapeutic formulations: (a) thosein which the therapeutic molecules are the nanoparticles(therapeutic function as its own carrier); and (b) thosein which the therapeutic molecules are directly coupled(functionalized, entrapped or coated) to a carrier. Nanopar-ticle therapeutics has been a burgeoning area in recentyears. The following reports are illustrative.Silver is an effective antimicrobial agent with low

toxicity.130 Drugs releasing silver in ionic form are knownto be neutralized by biological uids and may be toxic. Agnanoparticles have been the focus of increasing interest.Gram-negative bacteria were killed more effectively thangram-positive ones. Good antifungal activity was exhib-ited, in addition to favorable anti-inammatory properties.Even though the particles elicit OS, cellular AO systems,such as GSH, SOD and catalase, get triggered and pre-vent oxidative damage. Prior studies suggest that nanopar-ticle drug delivery might improve the therapeutic responseto anticancer drugs.131 Targeting methotrexate increasedits anticancer activity and markedly decreased its toxicity,allowing therapeutic responses not possible with the freedrug.Nanoparticles in the size range of 1100 nm are emerg-

ing as a class of therapeutics for cancer.132 These par-ticles can show enhanced efcacy, while simultaneously




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reducing side effects. The review describes features thatdistinguish them from prior anticancer therapy, such asnanoparticle size. Nanoparticles are proposed for targetdrug delivering to the inammation site in severe casesof bowel inammation where standard delivery devicesfail.133 The technique allowed enhanced and selective drugpenetration into the inamed site. The use of drug-loadednanoparticles offers several advantages, such as higherselectivity and enhanced drug penetration into inamma-tion sites. There are other relevant articles.134135 In somecases nanomaterial may be acting simply as a carrier; inother instances, they are involved in the therapeutic action.Prior reviews document the participation of ET-ROS-OSin the mechanism of anti-infective agents9 and anticancerdrugs.10

Acknowledgment: Editorial assistance by ThelmaChavez is acknowledged.

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


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