Review Article Applications of Anti/Prooxidant Fullerenes in … · 2019. 7. 31. · on applications of fullerene C 60 and its derivatives in nanomedicine, as well as the in uence

Review ArticleApplications of AntiProoxidant Fullerenes in Nanomedicinealong with Fullerenes Influence on the Immune System

Danijela Petrovic1 Mariana Seke2 Branislava Srdjenovic3 and Aleksandar Djordjevic4

1Department of Natural Sciences and Mathematics Faculty of Education Sombor University of Novi Sad 25 000 Novi Sad Serbia2lnstitute of Nuclear Sciences ldquoVincardquo University of Belgrade 11 000 Belgrade Serbia3Department of Pharmacy Faculty of Medicine University of Novi Sad 21 000 Novi Sad Serbia4Department of Chemistry Biochemistry and Environmental Protection Faculty of Sciences University of Novi Sad21 000 Novi Sad Serbia

Correspondence should be addressed to Danijela Petrovic petrovidtcdie

Received 16 April 2015 Accepted 21 July 2015

Academic Editor Subhrajit Saha

Copyright copy 2015 Danijela Petrovic et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Fullerenes are molecules that due to their unique structure have very specific chemical properties which offer them very widearray of applications in nanomedicine The most prominent are protection from radiation-induced injury neuroprotection drugand gene delivery anticancer therapy adjuvant within different treatments photosensitizing sonosensitizing bone reparationand biosensing However it is of crucial importance to be elucidated how fullerenes immunomodulate human system of defenseIn addition the most current research merging immunology and nanomedicine results in development of nanovaccines whichmay represent the milestone of future treatment of diseases

1 Introduction

The aim of this review is to report the most recent progresson applications of fullerene C

60and its derivatives in

nanomedicine as well as the influence of fullerene nanopar-ticles on immune system Being novel substances fullerenesgenerate considerable interest particularly in terms of theirtoxicity biokinetics biodegradation and possible immuneresponsesThis paper emphasizes the fullerenersquos antioxidativeproperties but also its prooxidative features as well as theimpact of fullerenes on the cells of innate and adaptiveimmunity

The fullerene C60

due to its physicochemical propertieshas the ability to both scavenge and generate reactive oxygenspecies Antioxidant capacity of C

60is based on highly delo-

calized 120587 double bond system functioning as a ldquofree radicalspongerdquo and quenching different free radical species moreefficiently than conventional antioxidants [1 2] Fullerenesmay also induce prooxidant effects and this is likely to bedictated by the fullerene in question the cell type being

investigated and the experimental setup [3ndash6]The solubilityof C60

in polar solutions is very low which greatly limitsits potential applications in medicine However due to thepresence of double bonds C

60can be easily modified with

chemical groups that allow its better water solubility In thatway water-soluble C

60derivatives expand their opportunities

for various medical applications such as protection fromradiation-induced injury neuroprotection drug and genedelivery therapy against many diseases and processes photo-sensitizing sonosensitizing bone reparation and biosensing

2 Protection from Radiation-Induced InjuryIonizing Radiation and UVA

The main event during exposure of living organisms toionizing radiation is DNA damage and formation of DNAdouble-strand breaks Two mechanisms are involved directdamage of DNA by the radiation energy or indirect damagemediated through reactive oxygen species such as radicals

Hindawi Publishing CorporationJournal of NanomaterialsVolume 2015 Article ID 565638 11 pageshttpdxdoiorg1011552015565638

2 Journal of Nanomaterials

peroxides and superoxides produced during the waterradiolysis In the case of gamma radiation and X-rayswhere low linear energetic transfer is present a predominantproportion of the radiation damage results from the indirectmechanism Fullerenol C

60(OH)24

has been proven to bepromising protector against ionizing radiation Stankov et alhave shown better cell survival in fullerenol-pretreatedirradiated leukemic cells and significant overexpression ofantiapoptotic Bcl-2 and Bcl-xL genes as well as antioxidativecytoprotective genes such as GSTA4 MnSOD NOS CATand HO-1 [7] Unlike ionizing radiation UVA radiationhas far less energy but it also affects cells in an oxygen-dependent manner Cellular targets are various includingDNA proteins and membranes 8-Oxo-78-dihydroguaninehas been identified in several cell types as the major DNAoxidation product of UVA radiation [8] This ubiquitousDNA oxidation product can be produced by hydroxyl rad-ical (∙OH) singlet oxygen (1O

2) one-electron oxidants or

peroxynitrite [9] In the research of Eropkin and coworkersdifferent forms of fullerenols demonstrated dual activityFullerenols C

60(OH)18ndash24 and C

60(OH)30ndash38 showed a pro-

tective effect against UVA-induced phototoxicity as well asbroad spectrum of antiviral activity in vitro against actualstrains of human influenza virus A(H1N1) and A(H3N2)avian influenza A(H5N1) human herpes simplex virusadenovirus and respiratory-syncytial virus Fullerenols didnot show toxic effects toward human and animal cells ofvarious tissue origins [10] Kato et al have used fullerene-C60liposome complex as UVA protector The complex of

250ndash500 ppm restored HaCaT keratinocytes viability afterthe UVA-irradiation of 10 Jcm2 According to fluorescentimmunostaining C

60was mainly located around the outside

of nuclearmembranewithout impairment of cellmorphology[11] Further the complex was administered on the surfaceof three-dimensional human skin tissue model rinsed outbefore each UVA-irradiation at 4 Jcm2 and thereafter addedagain followed by 19-cycle repetition for 4 days (sum76 Jcm2) Skin damage involved breakdown of collagen typeIIV DNA strand cleavage and pycnosiskaryorrhexis andwas significantly reduced by the complex [12]

3 Neuroprotection

Oxidative stress on nervous tissue can produce damageby several interacting mechanisms including increases inintracellular free Ca2+ and release of excitatory amino acids aswell as excessive production of reactive oxygen species in thepresence of ldquocatalyticrdquo iron or copper ions Free radical reac-tions are also involved in the neurotoxicity of aluminum andin damage to the substantia nigra in patients with Parkinsonrsquosdisease [13] Oxidative stress generated in this regard causesphysical damage to neurons by demyelination mitochon-drial dysfunction microtubular damage and apoptosis [14]Ameliorating properties of fullerene derivatives on acetyl-cholinesterase (AChE) inhibition induced by organophos-phates have been investigated by Ehrich and coworkers [15]Organophosphorus compounds (OP) are widely used as

insecticides and their primary mechanism of action is inhi-bition of AChE which is followed by cholinergic poisoningRapid AChE inhibition occurring after OP exposure hasbeen reported to result in oxidative stress as indicated byreduction in glutathione increases in reactive oxygen speciesand production of stress proteins [16] Ehrich et al used henbrain and human neuroblastoma SH-SY5Y cells as modelsystems Cells were incubated with eight different derivatizedfullerene compounds before challenge with paraoxon ordiisopropylphosphorofluoridate (DFP) Activities of brainand SH-SY5Y AChE with OP compounds alone ranged from55 to 83 lower than nontreated controls after paraoxon andfrom 60 to 92 lower than nontreated controls after DFPMost of the incubations containing 1 and 10 120583M fullerenederivatives brought AChE activity closer to untreated con-trols with improvements in AChE activity The fullerenederivatives demonstrated significant antioxidant capabilityin neuroblastoma cells at 1 120583M concentrations No fullerenederivative at 1 120583M significantly affected neuroblastoma cellviability [15] The other group has generated nanocomplexof fullerene C

60formulated with poly(N-vinyl pyrrolidine)

(PVP) or poly(2-alkyl-2-oxazoline)s (POx) homopolymerand random copolymer Tracking of the selected formula-tions during cellular uptake and their intracellular distribu-tion were performed in catecholaminergic neurons C

60-POx

and C60-PVP complexes exhibited similar physicochemical

properties and antioxidant activities C60-POx complex but

not C60-PVP complex was efficiently taken up by neurons

and attenuated the increase of intraneuronal superoxideinduced by angiotensin II stimulation [17]

Bearing in mind that free radical injury has been specif-ically implicated in the pathogenesis of different neurode-generative disorders Vorobyov and coworkers have usedamyloid-120573 (A120573) rat model of Alzheimerrsquos disease (AD) tostudy the effects of hydrated fullerene C

60(C60HyFn) Inter-

relations between EEG frequency spectra from the frontalcortex and the dorsal hippocampus (CA1) were consideredInfusion of A1205731ndash42 protein into the CA1 region two weeksbefore EEG testing decreased hippocampal theta predomi-nance and eliminated cortical beta predominance observedin baseline EEG of rats infused with saline or with C

60HyFn

alone In contrast these A1205731ndash42 effects were eliminated inrats pretreated with C

60HyFn Further to clear up the role

of dopaminergic mediation in AD peripheral injection of adopamine agonist apomorphine was applied In rats infusedwith C

60HyFn or A1205731ndash42 alone APO attenuated the cor-

tical beta predominance while pretreatment with C60HyFn

decreased the apomorphine effect in the A1205731ndash42-treated ratsAltogether intrahippocampal injection of A1205731ndash42 dramati-cally disrupts cortical versus hippocampal EEG interrelationsand pretreatment with C

60HyFn eliminates this abnormality

[18] In another model against 120573-amyloid- (A120573)(25ndash35-)induced toxicity toward Neuro-2A cells scientists investi-gated C

60fullerene derivative incorporating poly(ethylene

glycol) (PEG-C(60)-3) and its pentoxifylline-bearing hybrid(PTX-C(60)-2) PEG-C(60)-3 and PTX-C(60)-2 significantlyreduced A120573(25ndash35-) induced cytotoxicity with comparableactivities in decreasing reactive oxygen species and main-taining the mitochondrial membrane potential A120573(25ndash35)

Journal of Nanomaterials 3

treatment caused adenosine monophosphate-activated pro-tein kinase-associated autophagy Cytoprotection by PEG-C(60)-3 and PTX-C(60)-2 was partially diminished by anautophagy inhibitor indicating that the caused autophagyand antioxidative activities protected cells from A120573 damage[19]

Glutamates are the carboxylate anions and salts of glu-tamic acid Glutamate is the most abundant excitatoryneurotransmitter which in higher concentration results inexcitotoxicity causing degeneration of neurons and theirdeath Glutamate binds to metabotropic glutamate receptors(mGluRs) and triggers a signaling cascade Detrimental roleof group II mGluRs during hypoxic conditions has beendescribed [20] Giust et al suggested that [60]fullerenehydrosoluble derivative through modulation of mGluRscould be protective against hypoxia They used human neu-roblastoma cells (SH-SY5Y) to evaluate the long time (24 48and 72 hours) effects of the trans-3 isomer of [60]fullerene(t3ss) Low oxygen concentration (5 O

2) caused cell death

which was avoided by t3ss exposure in a concentrationdependent manner [21]

Knowing that neural cells are terminally differentiatedand that damaged neurons are difficult to regenerate C

60

derivatives could be helpful in solving this problem Inthe study of Tsumoto and coworkers water-soluble C

60

derivatives are shown to have an enhancing effect on theneurite outgrowth They used rat pheochromocytoma PC12cells as a model of nerve cells PC12 cells were treated withneurite growth factor (NGF) resulting in the induction ofdifferentiation and the formation of neurites Firstly it wasexamined whether or not C

60derivatives have similar activity

to NGF However no effects as seen withNGFwere observedNext the effect of C

60derivatives on neurite outgrowth

in NGF-treated PC12 cells was examined PC12 cells thatwere treated with NGF plus 0ndash50 120583M C

60derivative formed

neurites and both neurite number and length of outgrowthincreased in a dose-dependent manner reaching amaximumat 25 120583M [22]

4 Drug Delivery

Designing multifunctionalized C60

systems able to be effi-ciently targeted to specific tissues cross cell membranes anddelivery active agents is still an attracting challenge whichinvolves multidisciplinary approach In the study of Zhangand coworkers was developed a new kind of active targetingHyaluronic acid (HA) was grafted onto C

60and then com-

bined with transferrin (Tf) to obtain a multifunctional drugdelivery system (HA-C

60-Tf) with significant tumour target-

ing efficacy as well as capacity for photodynamic therapyAfter this step artesunate (AS) was adsorbed on HA-C

60-Tf

MCF-7 cells and tumour-bearing murine model were used toevaluate antitumour efficacy AS-loaded HA-C60-Tf showedenhanced antitumour efficacy in comparison with free AS inboth cases Furthermore with laser irradiation in vivo therelative tumour volume (VV0) of HA-C

60-TfAS declined by

half [23]

5 Therapeutic Agents

51 Antioxidant Fullerenol (C60(OH)24nanoparticles FNP)

is a symmetrical derivative of C60with good water solubility

In aqueous solutions it is in the form of poly anionicnanoparticles whose size distribution is in range between20 nm and 200 nm with the largest number of measurementsbetween 30 nm and 100 nm [24] Srdjenovic et al havedetermined its size distribution and 120577-potential in cell cultureRPMI 1640 medium supplemented with 10 fetal bovineserum (FBS) According to their results the size distributionof FNP nanoparticles was not affected by FBS andor cellmedium and formation of large particles was not inducedbut caused reduction in 120577-potential of nanoparticles (fromminus58mV to minus79mV) The researchers also investigated theinfluence of FNP on Chinese hamster ovary cells (CHO-K1)survival as well as antioxidant capacity of FNP in mitomycinC-treated cell line It has been shown that activity of antiox-idative enzymes was increased in dose-dependent mannerFurther results confirmed that FNP did not induce genotoxiceffects on the contrary antigenotoxic effects of FNP wereconfirmed in the experiment done onMMC-damaged CHO-K1 cells in concentrations of 11ndash2216120583M [25] Fullerenolwith its antioxidant activity can also mediate oxidative stress-induced senescence Retinal pigment epithelium (RPE) cellsand ARPE-19 cells were exposed to pulsed H

2O2stress for

5 days Fullerenol protected the RPE cells as it reduced thenumber of senescence positive cells alleviated the depletionof cellular antioxidants and reduced genomic DNA damage[26]

The results of Bal et alrsquos study provide preliminary indi-cation that hydrated nanoparticles of pristine C

60display the

superior antioxidant activity necessary to effectively alleviatediabetic complications by elimination of testicular apoptosisand consequent histopathological abnormalities thus result-ing in elevation of testosterone level and increase of spermcontent andmotility [27] In a quite different study Baati et alwanted to find out whether the lifespan can be prolongedThey administered C

60dissolved in olive oil (08mgmL)

orally at reiterated doses (17mgkg of body weight) to ratsand demonstrated that it did not entail chronic toxicity butit almost doubled their lifespan The effects of C

60olive oil

solutions in an experimentalmodel ofCCl4intoxication in rat

strongly suggested that the effect on lifespan is mainly due tothe attenuation of age-associated increase in oxidative stress[28] Antioxidant properties of fullerene derivatives havealso been examined in studies of hair loss Patients sufferingdifferent conditions such as alopecia chemotherapy andreactions to various chemicals could benefit from thesefindings Zhou et al [29] reported that fullerene derivativesaccelerated the hair growth in mice and human skin In addi-tion thesemolecules significantly increase the number of hairfollicles Finally the most recent paper on the treatment ofliver injury with C

60derivative tells us that interest in

fullerene application is still high [30]

52 Antitumour and Antimetastatic Agent Modulation ofoxidative stress in tumour tissues inhibition of the formationof angiogenesis factors and subsequent reduction in tumour


vessel density and the nutrient supply to tumour cells could beimportantmechanisms bywhich fullerenol C

60(OH)20aggre-

gates inhibit tumour growth and suppress carcinoma metas-tasis in vivo [31] In the case against KSHV-associated primaryeffusion lymphoma (PEL) seven water-soluble fullerenederivatives were investigated as potential drug candidatesIt was discovered that pyrrolidinium fullerene derivative111101584011015840-tetramethyl [60]fullerenodipyrrolidinium diiodideinduced apoptosis of PEL cells Pyrrolidinium fullerene treat-ment significantly reduced the viability of PEL cells comparedwith KSHV-uninfected lymphoma cells and induced theapoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage [32] The results of Hu et al suggested that folacinC60

derivative has the potential to prevent oxidative stress-induced cell death without evident toxicity The folacin C

60

derivative self-assembled to form spherical aggregates inwater Because the compoundwas amphiphilic it could pene-trate the cell membrane and protect PC12 cells against hydro-gen peroxide-induced cytotoxicity [33 34]Methanofullerenederivative [60] bearing four carboxylic groups whose sodiumand potassium salts are water soluble is compound that hasbeen confirmed to possess antiviral and anticancer activityas well as pronounced antioxidant properties in combinationwith a low toxicity The anticancer activity was assessed onmurine leukemia P388 tumour-bearing mice Antiviralactivity of 1-Na was investigated against HIV-1 and HIV-2and showed comparable activity against both virus strains[35]

53 Photosensitizers and Sonosensitizers Photodynamictherapy (PDT) is light-based therapy which is a nonsurgicalprocedure with minimally invasive approach that has beenused in the treatment of many solid cancers as well as otherdiseases [36] PDT requires the simultaneous presence of aphotosensitizer oxygen and light Fullerenes possesssome of the advantages in comparison to the other types ofphotosensitizers (1) they are comparativelymore photostableand demonstrate less photobleaching when compared withtetrapyrroles and synthetic dyes (2) fullerenes show bothkinds of photochemistry comprising free radicals and singletoxygen while tetrapyrroles demonstrate largely singletoxygen (3) fullerenes can be chemically modified for tuningthe drugrsquos partition coefficient and 119901119870a values for thevariation of in vivo lipophilicity and the prediction of theirdistribution in biological systems (4) to enhance the overallquantum yield and the ROS production and to extend theirabsorption spectrum further into the red wavelengths alight-harvesting antennae can be chemically attached toC60 (5) molecular self-assembly of fullerene cages into

vesicles allow improved drug delivery and can produceself-assembled nanoparticles that may have different tissue-targeting properties [37] Radical scavenging studies usingthe 111015840-diphenyl-2-picrylhydrazyl radical showed that C

60in

combination with human serum albumin (C60HSA) had an

increased antioxidant activity compared to HSA aloneFurther C

60HSA efficiently generated not only superoxide

anion radicals O2∙minus but also singlet oxygen 1O

2through

photoirradiation C60HSA showed A549 cell toxicity

characteristics after light irradiation but no toxicity wasobserved in the absence of irradiation In this way C

60HSA

not only has an excellent stability and antioxidant activitybut also has considerable phototoxicity properties [38] Ikedaet al have investigated the cationic C

60derivativesdot120574-CDx

complex and showed that it had higher photodynamic abilitythan pristine C

60because the complex possessed the ability to

generate high levels of 1O2and provided a higher level of

intracellular uptake The photodynamic activity of thiscomplex was also greater than photofrin which is the mostwidely used clinical photosensitizer [39] The other cationicderivative of C

60was examined in vivo by Lu et al They used

C60functionalized with three dimethylpyrrolidinium groups

(BF6) which had been shown as highly active broad-spectrum

antimicrobial photosensitizer in vitro when combined withwhite-light illumination In the in vivo study two mousemodels of infected wounds potentially lethal were usedAn excisional wound on the mouse back was contaminatedwith one of two stable bioluminescent Gram-negativespecies Proteus mirabilis and Pseudomonas aeruginosa Asolution of BF

6was placed into the wound followed by

delivery of up to 180 Jcm2 of broadband white light (400ndash700 nm) In both cases there was a light-dose-dependentreduction of bioluminescence from the wound notobserved in control groups (light alone or BF

6alone)

Fullerene-mediated photodynamic therapy of mice infectedwith P mirabilis led to 82 survival compared with 8survival without treatment Photodynamic therapy of miceinfected with highly virulent P aeruginosa did not lead tosurvival but when photodynamic therapy was combinedwith a suboptimal dose of the antibiotic tobramycin (6mgkgfor 1 day) there was a synergistic therapeutic effect with asurvival of 60 compared with a survival of 20 withtobramycin alone [40]

Nanomaterials with multifunctional characteristics suchas for cancer diagnosis PDT radiofrequency thermal ther-apy and magnetic targeting applications have become moreand more popular in nanomedicine One such hybrid isthe nanocomposite synthesized via decorating iron oxidenanoparticles (IONP) onto fullerene (C

60) and then function-

alized by polyethylene glycol (PEG2000) giving C60-IONP-

PEG excellent stability in physiological solutions Hemato-porphyrin monomethyl ether (HMME) a new photody-namic anticancer drug was conjugated to C

60-IONP-PEG

forming a C60-IONP-PEGHMME drug delivery system

which showed an excellent magnetic targeting ability incancer therapy Compared with free HMME remarkablyenhanced photodynamic cancer cell killing effect using C

60-

IONP-PEGHMMEwas realized not only in cultured B16-F10cells in vitro but also in an in vivomurine tumour model dueto 23-fold higher HMME uptake of tumour and strong pho-todynamic activity of C

60-IONP-PEG [41] In another study

by Shi and coworkers folic acid (FA) a widely used tumourtargeting molecule was linked to C

60-IONP-PEG in order

to obtain an active tumour targeting effect to MCF-7cells and malignant tumour in mice models C

60-IONP-

PEG-FA served not only as a powerful tumour diagnostic


magnetic resonance imaging contrast agent but also as astrong photosensitizer and powerful agent for photothermalablation of tumour Furthermore a remarkable synergisticenhancement of PDT combination with thermal therapy wasalso observed during the treatment both in vitro and invivo Moreover the multifunctional nanoplatform also couldselectively kill cancer cells in highly localized regions via theexcellent active tumour targeting andmagnetic target abilities[42]

On the other hand sonodynamic therapy is based onthe sonosensitizing agent (sonosensitizer) and its subsequentactivation by ultrasound irradiation Yumita et al have exam-ined polyhydroxy fullerene (PHF) and the participation oflipid peroxidation in the mechanism of the sonodynamicallyinduced antitumour effect Sarcoma 180 cells were exposed to2MHz ultrasound in the presence and the absence of PHFSignificant enhancement of the rates of both ultrasonicallyinduced cell damage and lipid peroxidation was observed inthe presence of PHF and was positively correlated with PHFThe enhancement of cell damage and lipid peroxidation withPHF was suppressed by reactive oxygen scavengers such ashistidine and tryptophan [43]

54 Biosensors A major problem for the application ofbiosensors is their reduction of performance caused by theinactivation of biomolecules In order to solve this problemantioxidant defense systems have been used to reduce theoxidative damage In the study of Guo et al polyhydroxy-lated fullerene derivatives (C

60(OH)119909) were introduced into

hemoglobin (Hb) electrochemical biosensors through layer-by-layer assembly Not only have C

60(OH)119909

provided afavorable microenvironment to realize the direct electro-chemistry and electrocatalysis of hemoglobin but they havebeen successfully used as protective compounds to reduce theoxidant damage caused by the attack of H

2O2as well [44]

55 Bone Repair Fracture healing involves complex pro-cesses of cell and tissue proliferation and differentiationMany players are involved including growth factors inflam-matory cytokines antioxidants bone breakdown (osteoclast)and bone building (osteoblast) cells hormones amino acidsand various other nutrients Traumatic injuries and patho-logical conditions such as osteoporosis osteonecrosis andbone tumours can lead to bone fractures that do not healthrough endogenous mechanisms Yang et al have appliedan innovative approach to solve the issue They used fullerolas a strong antioxidant to enhance osteogenic differentiationin adipose-derived stem cells When incubated together withosteogenicmedium fullerenol promoted osteogenic differen-tiation in a dose-dependent manner It was also proved thatfullerenol promoted expression of FoxO1 a major functionalisoform of forkhead box O transcription factors that defendagainst reactive oxygen species in bone [45] It was alsoshown that fullerenol can be potentially used for preventionand treatment of corticosteroid-induced osteonecrosis Liuet al evaluated the effect of fullerenol on adipogenic andosteogenic differentiation of a mouse bone marrow derived

multipotent cell line D1 Simultaneous treatment of dexam-ethasonewith antioxidant glutathione or fullerenol decreasedthe number of cells containing lipid vesicles Treatment withdexamethasone for 7 days resulted in a significant increase inadipogenic markers peroxisome proliferator-activated recep-tor gamma and adipocyte protein 2 gene expression Inaddition decrease in expression of osteogenic markers runt-related transcription factor 2 and osteocalcin and antiox-idative enzymes superoxide dismutase and catalase was alsoobserved While glutathione and fullerenol both were ableto antagonize the effects of dexamethasone fullerenol hada greater effect than glutathione Cellular reactive oxygenspecies increased after dexamethasone treatment and addi-tion of fullerenol attenuated this activity which indicatedthat fullerenol inhibited adipogenesis and simultaneouslyenhanced osteogenesis by marrow mesenchymal stem cells[46]

56 Anti-Inflammatory Agents Inflammation is a compleximmunovascular response which involves immune cellsblood vessels and molecular mediators with the purpose toeliminate the initial cause of cell injury to clear out necroticcells and tissues and to initiate their reparation Symptomsof inflammation are unpleasant and can include rednessswollen joint joint pain joint stiffness and loss of joint func-tion In chronic inflammation or in autoimmune responsesthe bodyrsquos normally protective immune system causes dam-age to its own tissues and can lead to various diseases such asdifferent types of arthritis fibromyalgia muscular low backpain muscular neck pain lupus erythematosus and cancerLiu et al have investigated the anti-inflammatory effects offullerol on mouse dorsal root ganglia (DRG) under TNF-120572induction Their results undoubtedly suggested that fulleroltreatment suppresses the inflammatory responses of DRGand neurons as well as cellular apoptosis by decreasingthe level of ROS and enhancing antioxidative enzyme geneexpression [47] In the study of Dragojevic-Simic et al theyhave compared anti-inflammatory effects of FNP in regard toamifostine (AMI) and indomethacin (IND) FNP and INDdissolved in dimethylsulfoxide and AMI dissolved in salinewere intraperitoneally injected to rats in a dose range of125ndash75mgkg 3ndash10mgkg and 50ndash300mgkg respectivelyThe carrageenan-induced rat footpad edema test was usedfor anti-inflammatory evaluation The drugs were given30min before carrageenan injection Footpad swelling wasmeasured 3 hours after carrageenan application FNP dosedependently and significantly reduced the extent of footpadedema comparable to that of IND and significantly betterthan AMI Histopathological examination confirmed theseresults [48]

Dexamethasone (DEX) is a well-known anti-inflam-matory drug whose widespread clinical use is restrictedby its serious side effects By conjugation of DEX withC60 Zhang and coworkers have found that DEX retained the

anti-inflammatory activity while side effects were reducedIn mouse thymocytes the cytotoxicity of DEX-C

60was

significantly lower than that of free DEX and much less


apoptotic thymocytes were noticed Interestingly such reduc-tion of cytotoxicity and apoptosis were not observed whenequal moles of free C

60and free DEX were coincubated

with thymocytes suggesting that the conjugation alters thesignal pathway of DEX Researchers have also found thatthe binding of DEX-C

60onto glucocorticoid receptor (GR)

was partially blocked in the thymocytes which resulted indownregulation of several apoptosis-related genes [49]

Tuftsin (Thr-Lys-Pro-Arg) is a naturally occurringtetrapeptide which possesses a wide range of biologicalactivities including stimulation of phagocytosismotility andchemotaxis of phagocytes for example neutrophils mono-cytes and macrophages However the degradation of thepeptide in serum especially caused by leucine aminopep-tidase greatly limits its clinical use [50] To solve thisproblem Xu et al have come up with the idea toconjugate fullerene C

60to tuftsin by covalently linking with

the carboxyl terminal and the amino terminal respectivelyThe two compounds NH

2-etuftsineC

60and C

60etuftsine-

COOH were synthesized The C60etuftsin conjugates

showed complete resistance to the leucine aminopeptidasedegradation At the same time both of the conjugates showedmore potent stimulation activities than the free tuftsinin the phagocytosis and chemotaxis of murine peritonealmacrophages Moreover they could upregulate significantlythe MHC II molecule expression on the surface ofmacrophages whereas the free tuftsin shows no such effectFinally both conjugates show no toxicity to macrophages[51]

Ischemic stroke can be the cause of brain inflammationThe brainrsquos kinds of tissue become swollen and the patientcould suffer headache and a fever as well as more severesymptoms in some cases Glucosamine (GlcN) which atten-uates cerebral inflammation after stroke was combined withfullerenol into conjugates (GlcN-F) and their protectiveeffects regarding stroke-induced cerebral inflammation andcellular damagewere examined Fullerene derivatives or vehi-cle was administered intravenously in normotensive Wistar-Kyoto (WKY) rats and in spontaneously hypertensive rats(SHR) immediately after transient middle cerebral arteryocclusion Treated rats showed an amelioration of neurolog-ical symptoms as both fullerenol and GlcN-F prevented neu-ronal loss in the perilesional area Cerebral immunoreactivitywas reduced in treated WKY and SHR Expression of IL-1120573 and TLR-4 was attenuated in fullerenol-treated WKY rats[52]

6 Fullerenes Misconception or Milestoneof Medicine

It is well established that fullerenes have wide spectrum ofpotential and promising applications in medicine Howeverthere are many debates about the health and safety issues thatfullerenes may have in biological systems Existing studiesreport inconclusive and conflicting results regarding thetoxicity of fullerene nanoparticles [53] The first study thatreported oxidative damage in brain and gills of largemouthbass [54] later on was proven to be unfounded since it did not

include adequate control and could not exclude the effects ofimpurities However the recent study has demonstrated thatfullerenes may create risk to benthic organisms particularlysmall agglomerates of fullerene [55] Nakagawa et al haverevealed that C

60(OH)24

induced DNA fragmentation in rathepatocytes which could be prevented with special pretreat-ment [56] Furthermore study that investigated cytotoxiceffects of fullerenol in different cell types concluded that cyto-toxicity was cell type specific and that cell cycle was arrestedin G1 phase [57] Saathoff et al have observed decrease inviability of human epidermal keratinocytes onlywhen treatedwith the highest concentration of C

60(OH)32(used range was

0000544ndash425 120583gmL used fullerenols were C60(OH)20

C60(OH)24 and C

60(OH)32) [58] Surface chemistry and

concentration of fullerene nanoparticles as well as the celltype are the major factors involved in fullerene toxicityDevelopment of high-throughput analysis particularly high-content screening will enable the generation of toxicologicaldata contributing to the safety assessment of fullerene andits derivatives in biological systems This will contribute to abetter understanding of potentially hazardous effects inhumans and the environment [59]

7 Fullerenes and Immunity

One of the main focal points is undoubtedly fullerenesrsquomodulation of possible immune responses However a largebody of evidence on their influence on immune system is stillmissing Previous study by Chen et al revealed that C

60

fullerene derivative conjugated to bovine thyroglobulininduced production of fullerene-specific IgG antibodies inimmunized mice [60] demonstrating an ability of adap-tive arm of immune system to recognize novel chemicalspecies that were encountered Similar observation was madeby Braden et al who reported IgG antibodies specific tofullerene when it was conjugated to the carrier protein rabbitserum albumin (RSA) (Figure 1) [61] The humoral immuneresponse protects the extracellular space and during initialinfection the adaptive immune system is slow to start butrapidly excludes the invader when the organism is rechal-lenged with the same pathogen However it remains unclearwhether it is generation of specific antibodies response ofimmune system to the fullerene nanoparticle itself or it isresponse to the conjugate with the carrier proteins In the caseof the latter it is possibly due to the increase in size ofnanoparticle [62]

The first study to investigate interaction between C60

carboxyfullerene and cells of immune system revealed thatC60was able to protect human peripheral bloodmononuclear

cells (PBMCs) from apoptosis due to a mechanism thatimplicated mitochondrial membrane potential integrity [63]Recent study by Bunz et al has demonstrated that nei-ther polyhydroxy-C

60(poly-C

60) nor N-ethyl-polyamino-

C60

(nepo-C60) nanoparticles were able to alert adaptive

immunity since they have had no influence on T cell reactiv-ity (no T cell proliferation was observed as well as no increasein T cell cytokine production was noticed) when PBMCswere treated with these nanoparticles However significant


NK

IP-10

Chemoattractants

Cell proliferation

Antiviral activity

Antigen presentationDC

TNF IL-12 Macrophage

IL-1 IL-6

Inflammation

Proliferation

Proliferation

IL-2

clonal expansion

clonal expansion

IL-21

B cell

Antibodies

IL-12IL-12

IL-21

IL-10IL-2

IL-18

TNF-120572

IFN-120574

MIP-1120572

TGF-120573

C60

CD8+ T cell

CD8+ T cell

CD4+ T cell

CD4+ T cell

IL-2 IFN-120574

and IFN120574

Figure 1 Response of the cells of innate and adaptive immune system to fullerene The cells of the innate immune system are the firstto respond When they encounter the intruder they become activated and start producing different cytokines which have direct antiviralactivity (IFN-120574 TNF-120572) deliver stimulatory signals to other cells of the innate system (IL-12 IL-18) initiate inflammation (IL-1120572120573 IL-6)or act as chemoattractants that recruit inflammatory cells to the site of infection (MIP-1120572 IP-10) During this cascade of events the antigensare presented to T cells mainly by DC which are the professional antigen presenting cells that link the innate and adaptive immune systemWhen primed T cells secrete IL-2 which induces their clonal proliferation and development of effector functions Differentiated effectorcells particularly CD8+ T cells tackle infection and eliminate the virus B cells can be activated by cells of innate immunity (IL-21) or directlyby antigens and upon activation they differentiate into plasma cells producing antigen specific antibodies

increase in production of IL-6 and propagation of CD56+cells (natural killer cells) indicated that these fullerenes haveactivated the part of PBMCs that belongs to the innateimmunity [64] Innate arm of the immune system is a partof universal host defense mechanism present in plants andanimals with molecular modules having probably evolvedbefore the division into these two kingdoms [65] In humanswhen the first line of defense represented by the physicalbarrier of skin and mucosa is compromised an antigennonspecific response against the pathogen is delivered bythe innate immune system This system is initiated withina few minutes following the beginning of infection Theinnate immune system is composed of many serum proteins(including acute phase proteins and cytokines) and cellswith phagocytes (macrophages neutrophils and dendriticcells (DC)) and natural killer (NK) cells being essential forfunctioning of the system (Figure 1) [66]

Liu et al have demonstrated in a murine H22 hepatomamodel that fullerene derivatives (GdC

82(OH)22) were

able to activate T lymphocyte and to increase the ratio ofCD4+CD8+ T cells improving anticancer activity In addi-tion they have showed an enhanced production of cytokineTNF-alpha by macrophages confirming the induction ofcomplete immune response both innate and adaptive andreducing a tumour neoformation in this model by around

60 [67] Furthermore the same group has demonstratedthat water-soluble fullerenol C

60(OH)20

nanoparticles haveimmunomodulatory ability on both T cells and macrophages(Figure 1) These nanoparticles increased the Th1 response(IL-2 IFN-gamma and TNF-alpha) decreasedTh2 response(IL-4 IL-5 and IL-6) and were able to increase the pro-duction of TNF-alpha by T cells and macrophages almostthreefold [68] Previous study by Zhu et al has alsorevealed fullerenol C

60(OH)119909immunomodulatory activity

on macrophages whose activation busted the innate immu-nity and therefore considerably inhibited the enlargement ofmurine H22 hepatocarcinoma [69]

Interaction between dendritic cells (DC) and naturalkiller (NK) cells may be crucial in shaping the innateresponse Namely DCs activateNK cells via production of IL-12 and IL-18 or via expression of NK-activating ligands [70]In addition DCs are the most important antigen presentingcells (APC) whose main function is to ingest process andpresent antigen to T cells having a crucial role in networkingthe innate and adaptive immune responses Influence offullerenes on DC has also been reported (Figure 1) In mousemodel gado fullerenol (GdC

82(OH)22)(n) nanoparticles

induced maturation and activation of DC as well asenhancement of Th1 immune response (IFN-gamma)thus providing understanding for great antitumour activity


of (GdC82(OH)22)(n) nanoparticles [71] Interestingly

a recent study has shown that the same gado fullerenolnanoparticle could disturb and block proline-richmotif frombinding to SH3 domain which are rather common inprotein-protein interaction frequently used during theestablishment of immune or cellular regulatory responses[72] Previously the same group has published observationthat this nanoparticle significantly reduces activity ofmatrix metalloproteinases-9 (MMP-9) which contributes toinhibition of neoplastic growth in human pancreatic cancergrafts in a nude mouse model Since MMPs are knownto participate in angiogenesis and variety of immuneinteractions it is expected that suppression of MMP activitywill result in decline of tumour survival and invasion [73]

A gene microarray analysis on zebrafish embryos mi-croinjected with a sublethal dose of hydroxylated fullerenes(C60(OH)24) demonstrated significant change in expression

of different genes involved in immune response [74] Thesame group using another fish model (Pimephales promelas)and using quantitative PCR has confirmed that hydroxylatedfullerenes caused changes at the mRNA levels of highlyconserved genes involved in innate immunity [75] A recentcomputational study has shown that C

60fullerenes can act

as ligands for toll-like receptors (TLRs) and therefore canbe recognized as pathogens inducing proinflammatoryimmune response (IL-8 MCP-1) [76] Additionally strongsplenic inflammation with increased production of IL-2 andTNF-alpha was observed in mice spleen tissue [77] How-ever some studies emphasized strong anti-inflammatoryresponses of fullerene C

60 In adjuvant-induced arthritis in

rats [78] C60

decreased neutrophil phagocytic activity andproduction of antinuclear antibodies resulting in inflam-mation decline and also facilitated in restitution of spleenmorphology Furthermore inorganic fullerene-like nanopar-ticles (molybdenum disulfide nanoparticles) significantlydecreased proinflammatory immune response (IL-1beta IL-6 IL-8 and TNF-alpha) in nontransformed human bronchialcells [79]

A very challenging area in immunology is certainly vac-cine development Anovel approach to combat infectious dis-eases is evolution of nanovaccines which will be able to cureand prevent diseases better than currently used vaccinesExplicitly nanoparticles are used to deliver components towhich is desired a specific immune response to increaseadjuvant activity and to enhance antigenicity of the vaccinecomponents [62] A recent study by Xu et al has proved thatfullerenol nanoparticles can act as virus-like particles and canbe used as the dual-functional nanoadjuvant for HIV DNAvaccine Namely they have proved that this vaccine designenables innate immune response via activation of multipleTLRs and their signaling pathways resulting in decrease ofantigen dosage and frequency in immunization while keep-ing immunity levels capable of battling the HIV infection atan early stage [80] Hence fullerenol nanovaccine was able totrigger desirable immune response and to enhance targetingof specific components of immune system

Since nanovaccines have a great potential in site-specificdelivery of antigens improved bioavailability of antigencomponents and a reduced side effect profile [81] they may

have a major role in the vaccine design in the future Thisis incredibly important specially for the infections withcurrently no available vaccines which are global healthburden such as hepatitis C or HIV distributed worldwidewith a number of infected individuals constantly rising

8 Conclusion

This review represents an overview of the most relevant pub-lications on fullerene C

60and its derivatives applications with

the antiprooxidative features being a central to the topicAntioxidative properties are implied in majority of observedphenomena caused by fullerenes (radiation-induced injuryprotection neuroprotection anti-inflammatory agent drugand gene delivery antitumour therapy adjuvantwithin differ-ent treatments and bone reparation) However prooxidativecharacteristics were utilized in photodynamic and sonody-namic treatments Furthermore fullerenes have potentialto modulate immune cells function leading to effects oncytokine production in order to create the cytokine milieuthat is favourable for appropriate immune responseThis fea-ture is explored for vaccine design but full understanding offullerene nanoparticle and immune system interactions are tobe further elucidated Nevertheless this promising strategyin vaccine development is exceptionally valuable in rapiddiscovery of new vaccines as potential tools for therapeuticand prophylactic purposes

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgment

This study was supported by a grant from the Ministryof Education Science and Technological Development ofthe Republic of Serbia Grant no III45005 ldquoFunctionalfunctionalized and accomplished nanomaterialsrdquo

References

[1] P J Krusic E Wasserman P N Keizer J R Morton and K FPreston ldquoRadical reactions of C

60rdquo Science vol 254 no 5035

pp 1183ndash1185 1991[2] J W Arbogast A P Darmanyan C S Foote et al ldquoPhotophys-

ical properties of sixty atom carbon molecule (C60)rdquo Journal ofPhysical Chemistry vol 95 no 1 pp 11ndash12 1991

[3] J P Kamat T P A Devasagayam K I Priyadarsini and HMohan ldquoReactive oxygen species mediated membrane damageinduced by fullerene derivatives and its possible biologicalimplicationsrdquo Toxicology vol 155 no 1ndash3 pp 55ndash61 2000

[4] C M Sayes J D Fortner W Guo et al ldquoThe differentialcytotoxicity of water-soluble fullerenesrdquoNano Letters vol 4 no10 pp 1881ndash1887 2004

[5] C M Sayes A M Gobin K D Ausman J Mendez J LWest and V L Colvin ldquoNano-C60 cytotoxicity is due to lipidperoxidationrdquo Biomaterials vol 26 no 36 pp 7587ndash7595 2005


[6] H J Johnston G R Hutchison F M Christensen KAschberger and V Stone ldquoThe biological mechanisms andphysicochemical characteristics responsible for drivingfullerene toxicityrdquo Toxicological Sciences vol 114 no 2 pp162ndash182 2009

[7] K Stankov I Borisev V Kojic L Rutonjski G Bogdanovic andA Djordjevic ldquoModification of antioxidative and antiapoptoticgenes expression in irradiated K562 cells upon fullerenolC60(OH)

24nanoparticle treatmentrdquo Journal of Nanoscience and

Nanotechnology vol 13 no 1 pp 105ndash113 2013[8] J Cadet T Douki J-L Ravanat and P Di Mascio ldquoSensitized

formation of oxidatively generated damage to cellular DNA byUVA radiationrdquo Photochemical amp Photobiological Sciences vol8 no 7 pp 903ndash911 2009

[9] J Cadet T Douki and J-L Ravanat ldquoOxidatively generateddamage to the guaninemoiety of DNAmechanistic aspects andformation in cellsrdquoAccounts of Chemical Research vol 41 no 8pp 1075ndash1083 2008

[10] M Y Eropkin E Y Melenevskaya K V Nasonova et al ldquoSyn-thesis and biological activity of fullerenols with various contentsof hydroxyl groupsrdquo Pharmaceutical Chemistry Journal vol 47no 2 pp 87ndash91 2013

[11] S Kato R Kikuchi H Aoshima Y Saitoh and N MiwaldquoDefensive effects of fullerene-C

60liposome complex against

UVA-induced intracellular reactive oxygen species generationand cell death in human skin keratinocytes HaCaT associ-ated with intracellular uptake and extracellular excretion offullerene-C

60rdquo Journal of Photochemistry and Photobiology B

Biology vol 98 no 2 pp 144ndash151 2010[12] S Kato H Aoshima Y Saitoh and N Miwa ldquoFullerene-

C60liposome complex defensive effects against UVA-induceddamages in skin structure nucleus and collagen type IIVfibrils and the permeability into human skin tissuerdquo Journal ofPhotochemistry and Photobiology B Biology vol 98 no 1 pp99ndash105 2010

[13] B Halliwell ldquoReactive oxygen species and the central nervoussystemrdquo Journal of Neurochemistry vol 59 no 5 pp 1609ndash16231992

[14] W H Xiao and G J Bennett ldquoEffects of mitochondrial poisonson the neuropathic pain produced by the chemotherapeuticagents paclitaxel and oxaliplatinrdquo Pain vol 153 no 3 pp 704ndash709 2012

[15] M Ehrich R Van Tassell Y Li Z Zhou and C L Kep-ley ldquoFullerene antioxidants decrease organophosphate-inducedacetylcholinesterase inhibition in vitrordquo Toxicology in Vitro vol25 no 1 pp 301ndash307 2011

[16] G Giordano Z Afsharinejad T Kavanagh and L CostaldquoReactive oxygen species mediate the neurotoxicity induced byorganophosphorus insecticides in mouse cerebellar granulecellsrdquo Toxicological Sciences vol 90 p 301 2006

[17] J Tong M C Zimmerman S Li et al ldquoNeuronal uptake andintracellular superoxide scavenging of a fullerene (C

60)-poly(2-

oxazoline)s nanoformulationrdquo Biomaterials vol 32 no 14 pp3654ndash3665 2011

[18] V Vorobyov V Kaptsov R Gordon E Makarova I Podolskiand F Sengpiel ldquoNeuroprotective effects of hydrated fullerenec60 cortical and hippocampal EEG interplay in an amyloid-infused rat model of Alzheimerrsquos diseaserdquo Journal of AlzheimerrsquosDisease vol 45 pp 217ndash233 2015

[19] C-M Lee S-T Huang S-H Huang et al ldquoC60 fullerene-pentoxifylline dyad nanoparticles enhance autophagy toavoid cytotoxic effects caused by the 120573-amyloid peptiderdquo

Nanomedicine Nanotechnology Biology and Medicine vol 7no 1 pp 107ndash114 2011

[20] T Opitz P Richter A J Carter A P Kozikowski H Shinozakiand K G Reymann ldquoMetabotropic glutamate receptor sub-types differentially influence neuronal recovery from in vitrohypoxiahypoglycemia in rat hippocampal slicesrdquoNeurosciencevol 68 no 4 pp 989ndash1001 1995

[21] D Giust T Da Ros M Martın and J L Albasanzldquo[60]Fullerene derivative modulates adenosine andmetabotropic glutamate receptors gene expression a possibleprotective effect against hypoxiardquo Journal of Nanobiotechnologyvol 12 no 1 article 27 2014

[22] H Tsumoto S Kawahara Y Fujisawa et al ldquoSyntheses of water-soluble [60]fullerene derivatives and their enhancing effect onneurite outgrowth in NGF-treated PC12 cellsrdquo Bioorganic andMedicinal Chemistry Letters vol 20 no 6 pp 1948ndash1952 2010

[23] H Zhang L Hou X Jiao Y Ji X Zhu and Z ZhangldquoTransferrin-mediated fullerenes nanoparticles as Fe2+-dependent drug vehicles for synergistic anti-tumor efficacyrdquoBiomaterials vol 37 pp 353ndash366 2015

[24] M Slavic A Djordjevic R Radojicic et al ldquoFullerenolC60(OH)

24nanoparticles decrease relaxing effects of dimethyl

sulfoxide on rat uterus spontaneous contractionrdquo Journal ofNanoparticle Research vol 15 no 5 pp 1650ndash1658 2013

[25] B U Srdjenovic M N Slavic K M Stankov et al ldquoSize distri-bution of fullerenol nanoparticles in cell culture medium andtheir influence on antioxidative enzymes in Chinese hamsterovary cellsrdquo Hemijska industrija 2014

[26] C-C Zhuge J-Y Xu J Zhang et al ldquoFullerenol protectsretinal pigment epithelial cells from oxidative stress-inducedpremature senescence via activating SIRT1rdquo Investigative Oph-thalmology and Visual Science vol 55 no 7 pp 4628ndash46382014

[27] R Bal G Turk M Tuzcu et al ldquoProtective effects of nanos-tructures of hydrated C

60fullerene on reproductive function in

streptozotocin-diabeticmale ratsrdquoToxicology vol 282 no 3 pp69ndash81 2011

[28] T Baati F Bourasset N Gharbi et al ldquoThe prolongation of thelifespan of rats by repeated oral administration of [60]fullerenerdquoBiomaterials vol 33 pp 4936ndash4946 2012

[29] Z Zhou R Lenk A Dellinger et al ldquoFullerene nanomaterialspotentiate hair growthrdquoNanomedicine Nanotechnology Biologyand Medicine vol 5 no 2 pp 202ndash207 2009

[30] Y Umezaki D Iohara M Anraku et al ldquoPreparation ofhydrophilic C

60(OH)

102-hydroxypropyl-120573-cyclodextrin nano-

particles for the treatment of a liver injury induced by anover-dose of acetaminophenrdquo Biomaterials vol 45 pp 115ndash123 2015

[31] F Jiao Y Liu Y Qu et al ldquoStudies on anti-tumor andantimetastatic activities of fullerenol in a mouse breast cancermodelrdquo Carbon vol 48 no 8 pp 2231ndash2243 2010

[32] T Watanabe S Nakamura T Ono et al ldquoPyrrolidiniumfullerene induces apoptosis by activation of procaspase-9 viasuppression of Akt in primary effusion lymphomardquo Biochemicaland Biophysical Research Communications vol 451 no 1 pp93ndash100 2014

[33] Z Hu W Guan W Wang Z Zhu and Y Wang ldquoFolacin C60

derivative exerts a protective activity against oxidative stress-induced apoptosis in rat pheochromocytoma cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 20 no 14 pp 4159ndash41622010

[34] Z Hu Y HuangW Guan J Zhang FWang and L Zhao ldquoTheprotective activities of water-soluble C60 derivatives against


nitric oxide-induced cytotoxicity in rat pheochromocytomacellsrdquo Biomaterials vol 31 no 34 pp 8872ndash8881 2010

[35] A B Kornev A S Peregudov V M Martynenko et alldquoSynthesis and biological activity of a novel water-solublemethano[60]fullerene tetracarboxylic derivativerdquo MendeleevCommunications vol 23 no 6 pp 323ndash325 2013

[36] MRHamblin andPMrozAdvances in PhotodynamicTherapyBasic Translational and Clinical Artech House 2008

[37] S K Sharma L Y Chiang and M R Hamblin ldquoPhotody-namic therapy with fullerenes in vivo reality or a dreamrdquoNanomedicine vol 6 no 10 pp 1813ndash1825 2011

[38] A Abdulmalik A Hibah B M Zainy et al ldquoPreparation ofsoluble stable C60human serum albumin nanoparticles viacyclodextrin complexation and their reactive oxygen produc-tion characteristicsrdquo Life Sciences vol 93 no 7 pp 277ndash2822013

[39] A Ikeda T Iizuka NMaekubo et al ldquoCyclodextrin complexed[60]fullerene derivatives with high levels of photodynamicactivity by long wavelength excitationrdquo ACS Medicinal Chem-istry Letters vol 4 no 8 pp 752ndash756 2013

[40] Z Lu T Dai L Huang et al ldquoPhotodynamic therapy with acationic functionalized fullerene rescuesmice from fatal woundinfectionsrdquo Nanomedicine vol 5 no 10 pp 1525ndash1533 2010

[41] J Shi X Yu L Wang et al ldquoPEGylated fullereneiron oxidenanocomposites for photodynamic therapy targeted drugdelivery and MR imagingrdquo Biomaterials vol 34 no 37 pp9666ndash9677 2013

[42] J Shi LWang J Gao et al ldquoA fullerene-basedmulti-functionalnanoplatform for cancer theranostic applicationsrdquoBiomaterialsvol 35 no 22 pp 5771ndash5784 2014

[43] N Yumita Y Iwase T Watanabe et al ldquoInvolvement ofreactive oxygen species in the enhancement of membranelipid peroxidation by sonodynamic therapy with functionalizedfullerenesrdquo Anticancer Research vol 34 no 11 pp 6481ndash64872014

[44] X Guo S Yang R Cui et al ldquoApplication of polyhydroxylatedfullerene derivatives in hemoglobin biosensors with enhancedantioxidant capacityrdquoElectrochemistryCommunications vol 20no 1 pp 44ndash47 2012

[45] X L Yang C J Li Y P Wan P Smith G W Shangand Q Cui ldquoAntioxidative fullerol promotes osteogenesis ofhuman adipose-derived stem cellsrdquo International Journal ofNanomedicine vol 9 no 1 pp 4023ndash4031 2014

[46] H Liu X Yang Y Zhang A Dighe X Li and Q Cui ldquoFullerolantagonizes dexamethasone-induced oxidative stress andadipogenesis while enhancing osteogenesis in a cloned bonemarrow mesenchymal stem cellrdquo Journal of OrthopaedicResearch vol 30 no 7 pp 1051ndash1057 2012

[47] Q Liu L Jin B HMahonM D Chordia F H Shen and X LildquoNovel treatment of neuroinflammation against low back painby soluble fullerol nanoparticlesrdquo Spine vol 38 no 17 pp 1443ndash1451 2013

[48] V Dragojevic-Simic V Jacevic S Dobric et al ldquoAnti-inflammatory activity of fullerenol C

60(OH)

24nano-particles in

a model of acute inflammation in ratsrdquo Digest Journal ofNanomaterials and Biostructures vol 6 no 2 pp 819ndash827 2011

[49] Y Zhang LWang Y Sun et al ldquoConjugation of dexamethasoneto C60 for the design of an anti-inflammatory nanomedicinewith reduced cellular apoptosisrdquo ACS Applied Materials andInterfaces vol 5 no 11 pp 5291ndash5297 2013

[50] I Z Siemion and A Kluczyk ldquoTuftsin on the 30-year anniver-sary of Victor Najjarrsquos discoveryrdquo Peptides vol 20 no 5 pp645ndash674 1999

[51] Y Xu J Zhu K Xiang et al ldquoSynthesis and immunomodulatoryactivity of [60]fullerene-tuftsin conjugatesrdquo Biomaterials vol32 no 36 pp 9940ndash9949 2011

[52] F Fluri D Grunstein E Cam et al ldquoFullerenols and glu-cosamine fullerenes reduce infarct volume and cerebral inflam-mation after ischemic stroke in normotensive and hypertensiveratsrdquo Experimental Neurology vol 265 pp 142ndash151 2015

[53] C Kepley ldquoFullerenes in medicine will it ever occurrdquo Journalof Nanomedicine amp Nanotechnology vol 3 no 6 p 1 2012

[54] E Oberdorster ldquoManufactured nanomaterials (fullerenes C60)induce oxidative stress in the brain of juvenile largemouth bassrdquoEnvironmental Health Perspectives vol 112 no 10 pp 1058ndash1062 2004

[55] G CWaissi-Leinonen I Nybom K Pakarinen J Akkanen MT Leppanen and J V Kukkonen ldquoFullerenes(nC

60) affect the

growth and development of the sediment-dwelling invertebrateChironomus riparius larvaerdquo Environmental Pollution vol 206pp 17ndash23 2015

[56] Y Nakagawa A Inomata A Ogata and D Nakae ldquoCom-parative effects of sulfhydryl compounds on target organellaenuclei and mitochondria of hydroxylated fullerene-inducedcytotoxicity in isolated rat hepatocytesrdquo Journal of AppliedToxicology 2015

[57] Y Su J-Y Xu P Shen et al ldquoCellular uptake and cytotoxicevaluation of fullerenol in different cell linesrdquo Toxicology vol269 no 2-3 pp 155ndash159 2010

[58] J G Saathoff A O Inman X R Xia J E Riviere andN A Monteiro-Riviere ldquoIn vitro toxicity assessment of threehydroxylated fullerenes in human skin cellsrdquo Toxicology inVitro vol 25 no 8 pp 2105ndash2112 2011

[59] A E Nel E Nasser H Godwin et al ldquoAmulti-stakeholder per-spective on the use of alternative test strategies for nanomaterialsafety assessmentrdquoACS Nano vol 7 no 8 pp 6422ndash6433 2013

[60] B-X Chen S R Wilson M Das D J Coughlin and BF Erlanger ldquoAntigenicity of fullerenes antibodies specific forfullerenes and their characteristicsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 95 no18 pp 10809ndash10813 1998

[61] B C Braden F A Goldbaum B-X Chen A N Kirschner SRWilson and B F Erlanger ldquoX-ray crystal structure of an anti-Buckminsterfullerene antibody Fab fragment biomolecularrecognition of C

60rdquo Proceedings of the National Academy of

Sciences of the United States of America vol 97 no 22 pp 12193ndash12197 2000

[62] B S Zolnik A Gonzalez-Fernandez N Sadrieh and M ADobrovolskaia ldquoMinireview nanoparticles and the immunesystemrdquo Endocrinology vol 151 no 2 pp 458ndash465 2010

[63] D Monti L Moretti S Salvioli et al ldquoC60 carboxyfullereneexerts a protective activity against oxidative stress-inducedapoptosis in human peripheral blood mononuclear cellsrdquo Bio-chemical and Biophysical Research Communications vol 277 no3 pp 711ndash717 2000

[64] H Bunz S Plankenhorn and R Klein ldquoEffect of buckminster-fullerenes on cells of the innate and adaptive immune system anin vitro study with human peripheral bloodmononuclear cellsrdquoInternational Journal of Nanomedicine vol 7 pp 4571ndash45802012


[65] J A Hoffmann F C Kafatos C A Janeway Jr and R AB Ezekowitz ldquoPhylogenetic perspectives in innate immunityrdquoScience vol 284 no 5418 pp 1313ndash1318 1999

[66] C A Janeway Jr and R Medzhitov ldquoInnate immune recogni-tionrdquo Annual Review of Immunology vol 20 pp 197ndash216 2002

[67] Y Liu F Jiao Y Qiu et al ldquoThe effect of GdC82(OH)

22

nanoparticles on the release ofTh1Th2 cytokines and inductionof TNF-120572mediated cellular immunityrdquoBiomaterials vol 30 no23-24 pp 3934ndash3945 2009

[68] Y Liu F Jiao Y Qiu et al ldquoImmunostimulatory properties andenhanced TNF-alpha mediated cellular immunity for tumortherapy by C

60(OH)

20nanoparticlesrdquo Nanotechnology vol 20

no 41 Article ID 415102 2009[69] J Zhu Z Ji J Wang et al ldquoTumor-inhibitory effect and

immunomodulatory activity of fullerol C60(OH)xrdquo Small vol

4 no 8 pp 1168ndash1175 2008[70] T Kanto and N Hayashi ldquoImmunopathogenesis of hepatitis C

virus infection multifaceted strategies subverting innate andadaptive immunityrdquo Internal Medicine vol 45 no 4 pp 183ndash191 2006

[71] D Yang Y Zhao H Guo et al ldquo[GdC82(OH)

22]119899nanoparti-

cles induce dendritic cell maturation and activate Th1 immuneresponsesrdquo ACS Nano vol 4 no 2 pp 1178ndash1186 2010

[72] S-G Kang T Huynh and R Zhou ldquoMetallofullerenolGdC

82(OH)

22distracts the proline-rich-motif from putative

binding on the SH3 domainrdquo Nanoscale vol 5 no 7 pp 2703ndash2712 2013

[73] S-G Kang G Zhou P Yang et al ldquoMolecular mechanism ofpancreatic tumor metastasis inhibition by GdC

82(OH)

22and

its implication for de novodesign of nanomedicinerdquoProceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 38 pp 15431ndash15436 2012

[74] B Jovanovic T Ji and D Palic ldquoGene expression ofzebrafish embryos exposed to titanium dioxide nanoparticlesand hydroxylated fullerenesrdquo Ecotoxicology and EnvironmentalSafety vol 74 no 6 pp 1518ndash1525 2011

[75] B Jovanovic L Anastasova EW Rowe and D Palic ldquoHydrox-ylated fullerenes inhibit neutrophil function in fatheadminnow(Pimephales promelas Rafinesque 1820)rdquo Aquatic Toxicologyvol 101 no 2 pp 474ndash482 2011

[76] M Turabekova B Rasulev M Theodore J Jackman DLeszczynska and J Leszczynski ldquoImmunotoxicity of nanopar-ticles a computational study suggests that CNTs and C

60

fullerenes might be recognized as pathogens by Toll-like recep-torsrdquo Nanoscale vol 6 no 7 pp 3488ndash3495 2014

[77] N Ding N Kunugita T Ichinose et al ldquoIntratracheal adminis-tration of fullerene nanoparticles activates splenicCD11b+ cellsrdquoJournal of Hazardous Materials vol 194 pp 324ndash330 2011

[78] L E Vesnina T VMamontovaMVMikityuk et al ldquoFullereneC60

exhibits immunomodulatory activity during adjuvant-induced arthritis in ratsrdquo Eksperimentalrsquonaya i KlinicheskayaFarmakologiya vol 75 no 8 pp 15ndash20 2012

[79] M Pardo T Shuster-Meiseles S Levin-Zaidman A Rudichand Y Rudich ldquoLow cytotoxicity of inorganic nanotubes andfullerene-like nanostructures in human bronchial epithelialcells relation to inflammatory gene induction and antioxidantresponserdquo Environmental Science amp Technology vol 48 no 6pp 3457ndash3466 2014

[80] L Xu Y Liu Z Chen et al ldquoMorphologically virus-likefullerenol nanoparticles act as the dual-functional nanoadju-vant for HIV-1 vaccinerdquo Advanced Materials vol 25 no 41 pp5928ndash5936 2013

[81] M Zaman M F Good and I Toth ldquoNanovaccines and theirmode of actionrdquoMethods vol 60 no 3 pp 226ndash231 2013

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Polymer ScienceInternational Journal of



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TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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MetallurgyJournal of


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MaterialsJournal of


Nano

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Journal ofNanomaterials


peroxides and superoxides produced during the waterradiolysis In the case of gamma radiation and X-rayswhere low linear energetic transfer is present a predominantproportion of the radiation damage results from the indirectmechanism Fullerenol C

60(OH)24

has been proven to bepromising protector against ionizing radiation Stankov et alhave shown better cell survival in fullerenol-pretreatedirradiated leukemic cells and significant overexpression ofantiapoptotic Bcl-2 and Bcl-xL genes as well as antioxidativecytoprotective genes such as GSTA4 MnSOD NOS CATand HO-1 [7] Unlike ionizing radiation UVA radiationhas far less energy but it also affects cells in an oxygen-dependent manner Cellular targets are various includingDNA proteins and membranes 8-Oxo-78-dihydroguaninehas been identified in several cell types as the major DNAoxidation product of UVA radiation [8] This ubiquitousDNA oxidation product can be produced by hydroxyl rad-ical (∙OH) singlet oxygen (1O

2) one-electron oxidants or

peroxynitrite [9] In the research of Eropkin and coworkersdifferent forms of fullerenols demonstrated dual activityFullerenols C

60(OH)18ndash24 and C

60(OH)30ndash38 showed a pro-

tective effect against UVA-induced phototoxicity as well asbroad spectrum of antiviral activity in vitro against actualstrains of human influenza virus A(H1N1) and A(H3N2)avian influenza A(H5N1) human herpes simplex virusadenovirus and respiratory-syncytial virus Fullerenols didnot show toxic effects toward human and animal cells ofvarious tissue origins [10] Kato et al have used fullerene-C60liposome complex as UVA protector The complex of

250ndash500 ppm restored HaCaT keratinocytes viability afterthe UVA-irradiation of 10 Jcm2 According to fluorescentimmunostaining C

60was mainly located around the outside

of nuclearmembranewithout impairment of cellmorphology[11] Further the complex was administered on the surfaceof three-dimensional human skin tissue model rinsed outbefore each UVA-irradiation at 4 Jcm2 and thereafter addedagain followed by 19-cycle repetition for 4 days (sum76 Jcm2) Skin damage involved breakdown of collagen typeIIV DNA strand cleavage and pycnosiskaryorrhexis andwas significantly reduced by the complex [12]

3 Neuroprotection

Oxidative stress on nervous tissue can produce damageby several interacting mechanisms including increases inintracellular free Ca2+ and release of excitatory amino acids aswell as excessive production of reactive oxygen species in thepresence of ldquocatalyticrdquo iron or copper ions Free radical reac-tions are also involved in the neurotoxicity of aluminum andin damage to the substantia nigra in patients with Parkinsonrsquosdisease [13] Oxidative stress generated in this regard causesphysical damage to neurons by demyelination mitochon-drial dysfunction microtubular damage and apoptosis [14]Ameliorating properties of fullerene derivatives on acetyl-cholinesterase (AChE) inhibition induced by organophos-phates have been investigated by Ehrich and coworkers [15]Organophosphorus compounds (OP) are widely used as

insecticides and their primary mechanism of action is inhi-bition of AChE which is followed by cholinergic poisoningRapid AChE inhibition occurring after OP exposure hasbeen reported to result in oxidative stress as indicated byreduction in glutathione increases in reactive oxygen speciesand production of stress proteins [16] Ehrich et al used henbrain and human neuroblastoma SH-SY5Y cells as modelsystems Cells were incubated with eight different derivatizedfullerene compounds before challenge with paraoxon ordiisopropylphosphorofluoridate (DFP) Activities of brainand SH-SY5Y AChE with OP compounds alone ranged from55 to 83 lower than nontreated controls after paraoxon andfrom 60 to 92 lower than nontreated controls after DFPMost of the incubations containing 1 and 10 120583M fullerenederivatives brought AChE activity closer to untreated con-trols with improvements in AChE activity The fullerenederivatives demonstrated significant antioxidant capabilityin neuroblastoma cells at 1 120583M concentrations No fullerenederivative at 1 120583M significantly affected neuroblastoma cellviability [15] The other group has generated nanocomplexof fullerene C

60formulated with poly(N-vinyl pyrrolidine)

(PVP) or poly(2-alkyl-2-oxazoline)s (POx) homopolymerand random copolymer Tracking of the selected formula-tions during cellular uptake and their intracellular distribu-tion were performed in catecholaminergic neurons C

60-POx

and C60-PVP complexes exhibited similar physicochemical

properties and antioxidant activities C60-POx complex but

not C60-PVP complex was efficiently taken up by neurons

and attenuated the increase of intraneuronal superoxideinduced by angiotensin II stimulation [17]

Bearing in mind that free radical injury has been specif-ically implicated in the pathogenesis of different neurode-generative disorders Vorobyov and coworkers have usedamyloid-120573 (A120573) rat model of Alzheimerrsquos disease (AD) tostudy the effects of hydrated fullerene C

60(C60HyFn) Inter-

relations between EEG frequency spectra from the frontalcortex and the dorsal hippocampus (CA1) were consideredInfusion of A1205731ndash42 protein into the CA1 region two weeksbefore EEG testing decreased hippocampal theta predomi-nance and eliminated cortical beta predominance observedin baseline EEG of rats infused with saline or with C

60HyFn

alone In contrast these A1205731ndash42 effects were eliminated inrats pretreated with C

60HyFn Further to clear up the role

of dopaminergic mediation in AD peripheral injection of adopamine agonist apomorphine was applied In rats infusedwith C

60HyFn or A1205731ndash42 alone APO attenuated the cor-

tical beta predominance while pretreatment with C60HyFn

decreased the apomorphine effect in the A1205731ndash42-treated ratsAltogether intrahippocampal injection of A1205731ndash42 dramati-cally disrupts cortical versus hippocampal EEG interrelationsand pretreatment with C

60HyFn eliminates this abnormality

[18] In another model against 120573-amyloid- (A120573)(25ndash35-)induced toxicity toward Neuro-2A cells scientists investi-gated C

60fullerene derivative incorporating poly(ethylene

glycol) (PEG-C(60)-3) and its pentoxifylline-bearing hybrid(PTX-C(60)-2) PEG-C(60)-3 and PTX-C(60)-2 significantlyreduced A120573(25ndash35-) induced cytotoxicity with comparableactivities in decreasing reactive oxygen species and main-taining the mitochondrial membrane potential A120573(25ndash35)







60


60






60derivative formed


4 Drug Delivery



60and then com-




60-Tf


60-TfAS declined by

half [23]





2O2stress for



60display the




60olive oil








60(OH)20aggre-



60




60in





2through



60HSA













6alone)






60-IONP-PEG



60-






60-IONP-








60(OH)119909


2O2as well [44]






60was











2-etuftsineC

60and C

60etuftsine-







60(OH)24




C60(OH)24 and C





60





60(poly-C


C60




NK

IP-10

Chemoattractants

Cell proliferation

Antiviral activity



IL-1 IL-6

Inflammation

Proliferation

Proliferation

IL-2

clonal expansion

clonal expansion

IL-21

B cell

Antibodies

IL-12IL-12

IL-21

IL-10IL-2

IL-18

TNF-120572

IFN-120574

MIP-1120572

TGF-120573

C60

CD8+ T cell

CD8+ T cell

CD4+ T cell

CD4+ T cell

IL-2 IFN-120574

and IFN120574




82(OH)22) were



60(OH)20















rats [78] C60





8 Conclusion






Acknowledgment


References



























60)-poly(2-




















60(OH)
























60(OH)

24nano-particles in









60) affect the

















22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials









60


60






60derivative formed


4 Drug Delivery



60and then com-




60-Tf


60-TfAS declined by

half [23]





2O2stress for



60display the




60olive oil








60(OH)20aggre-



60




60in





2through



60HSA













6alone)






60-IONP-PEG



60-






60-IONP-








60(OH)119909


2O2as well [44]






60was











2-etuftsineC

60and C

60etuftsine-







60(OH)24




C60(OH)24 and C





60





60(poly-C


C60




NK

IP-10

Chemoattractants

Cell proliferation

Antiviral activity



IL-1 IL-6

Inflammation

Proliferation

Proliferation

IL-2

clonal expansion

clonal expansion

IL-21

B cell

Antibodies

IL-12IL-12

IL-21

IL-10IL-2

IL-18

TNF-120572

IFN-120574

MIP-1120572

TGF-120573

C60

CD8+ T cell

CD8+ T cell

CD4+ T cell

CD4+ T cell

IL-2 IFN-120574

and IFN120574




82(OH)22) were



60(OH)20















rats [78] C60





8 Conclusion






Acknowledgment


References



























60)-poly(2-




















60(OH)
























60(OH)

24nano-particles in









60) affect the

















22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





60(OH)20aggre-



60




60in





2through



60HSA













6alone)






60-IONP-PEG



60-






60-IONP-








60(OH)119909


2O2as well [44]






60was











2-etuftsineC

60and C

60etuftsine-







60(OH)24




C60(OH)24 and C





60





60(poly-C


C60




NK

IP-10

Chemoattractants

Cell proliferation

Antiviral activity



IL-1 IL-6

Inflammation

Proliferation

Proliferation

IL-2

clonal expansion

clonal expansion

IL-21

B cell

Antibodies

IL-12IL-12

IL-21

IL-10IL-2

IL-18

TNF-120572

IFN-120574

MIP-1120572

TGF-120573

C60

CD8+ T cell

CD8+ T cell

CD4+ T cell

CD4+ T cell

IL-2 IFN-120574

and IFN120574




82(OH)22) were



60(OH)20















rats [78] C60





8 Conclusion






Acknowledgment


References



























60)-poly(2-




















60(OH)
























60(OH)

24nano-particles in









60) affect the

















22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials









60(OH)119909


2O2as well [44]






60was











2-etuftsineC

60and C

60etuftsine-







60(OH)24




C60(OH)24 and C





60





60(poly-C


C60




NK

IP-10

Chemoattractants

Cell proliferation

Antiviral activity



IL-1 IL-6

Inflammation

Proliferation

Proliferation

IL-2

clonal expansion

clonal expansion

IL-21

B cell

Antibodies

IL-12IL-12

IL-21

IL-10IL-2

IL-18

TNF-120572

IFN-120574

MIP-1120572

TGF-120573

C60

CD8+ T cell

CD8+ T cell

CD4+ T cell

CD4+ T cell

IL-2 IFN-120574

and IFN120574




82(OH)22) were



60(OH)20















rats [78] C60





8 Conclusion






Acknowledgment


References



























60)-poly(2-




















60(OH)
























60(OH)

24nano-particles in









60) affect the

















22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials












2-etuftsineC

60and C

60etuftsine-







60(OH)24




C60(OH)24 and C





60





60(poly-C


C60




NK

IP-10

Chemoattractants

Cell proliferation

Antiviral activity



IL-1 IL-6

Inflammation

Proliferation

Proliferation

IL-2

clonal expansion

clonal expansion

IL-21

B cell

Antibodies

IL-12IL-12

IL-21

IL-10IL-2

IL-18

TNF-120572

IFN-120574

MIP-1120572

TGF-120573

C60

CD8+ T cell

CD8+ T cell

CD4+ T cell

CD4+ T cell

IL-2 IFN-120574

and IFN120574




82(OH)22) were



60(OH)20















rats [78] C60





8 Conclusion






Acknowledgment


References



























60)-poly(2-




















60(OH)
























60(OH)

24nano-particles in









60) affect the

















22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




NK

IP-10

Chemoattractants

Cell proliferation

Antiviral activity



IL-1 IL-6

Inflammation

Proliferation

Proliferation

IL-2

clonal expansion

clonal expansion

IL-21

B cell

Antibodies

IL-12IL-12

IL-21

IL-10IL-2

IL-18

TNF-120572

IFN-120574

MIP-1120572

TGF-120573

C60

CD8+ T cell

CD8+ T cell

CD4+ T cell

CD4+ T cell

IL-2 IFN-120574

and IFN120574




82(OH)22) were



60(OH)20















rats [78] C60





8 Conclusion






Acknowledgment


References



























60)-poly(2-




















60(OH)
























60(OH)

24nano-particles in









60) affect the

















22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials











rats [78] C60





8 Conclusion






Acknowledgment


References



























60)-poly(2-




















60(OH)
























60(OH)

24nano-particles in









60) affect the

















22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials






















60)-poly(2-




















60(OH)
























60(OH)

24nano-particles in









60) affect the

















22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



















60(OH)

24nano-particles in









60) affect the

















22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials







22



60(OH)







22]119899nanoparti-



82(OH)




82(OH)

22and





60















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials










CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



Documents

Review Article Applications of Anti/Prooxidant Fullerenes in … · 2019. 7. 31. · on applications of fullerene C 60 and its derivatives in nanomedicine, as well as the in uence