TheAdvancingofZincOxideNanoparticlesfor BiomedicalApplicationsdownloads.hindawi.com/journals/bca/2018/1062562.pdf · 2019-07-30 · adipocytes, which showed that ZnO NPs could be

Review ArticleThe Advancing of Zinc Oxide Nanoparticles forBiomedical Applications

Jinhuan Jiang1 Jiang Pi1 and Jiye Cai 12

1State Key Laboratory of Quality Research in Chinese Medicines Macau University of Science and Technology Macau China2Department of Chemistry Jinan University Guangzhou China

Correspondence should be addressed to Jiye Cai tjycaijnueducn

Received 4 February 2018 Revised 13 May 2018 Accepted 21 May 2018 Published 5 July 2018

Academic Editor Francesco Paolo Fanizzi

Copyright copy 2018 Jinhuan Jiang et al )is is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Zinc oxide nanoparticles (ZnO NPs) are used in an increasing number of industrial products such as rubber paint coating andcosmetics In the past two decades ZnO NPs have become one of the most popular metal oxide nanoparticles in biologicalapplications due to their excellent biocompatibility economic and low toxicity ZnO NPs have emerged a promising potential inbiomedicine especially in the fields of anticancer and antibacterial fields which are involved with their potent ability to triggerexcess reactive oxygen species (ROS) production release zinc ions and induce cell apoptosis In addition zinc is well known tokeep the structural integrity of insulin So ZnO NPs also have been effectively developed for antidiabetic treatment MoreoverZnO NPs show excellent luminescent properties and have turned them into one of the main candidates for bioimaging Here wesummarize the synthesis and recent advances of ZnONPs in the biomedical fields which will be helpful for facilitating their futureresearch progress and focusing on biomedical fields

1 Introduction

Recently biomedical nanomaterials have received moreconcerns because of their prominent biological character-istics and biomedical applications With the development ofnanomaterials metal oxide nanoparticles show promisingand far-ranging prospect for biomedical field especially forantibacteria anticancer druggene delivery cell imagingbiosensing and so on [1]

Zinc oxide nanoparticles (ZnO NPs) as one of the mostimportant metal oxide nanoparticles are popularlyemployed in various fields due to their peculiar physical andchemical properties [2 3] ZnO NPs are firstly applied in therubber industry as they can provide wearproof of the rubbercomposite improve performance of high polymer in theirtoughness and intensity and antiaging and other functions[4 5] Because of the strong UV absorption properties ofZnO they are increasingly used in personal care productssuch as cosmetics and sunscreen [6] In addition ZnO NPshave superior antibacterial antimicrobial and excellent UV-blocking properties )erefore in the textile industry the

finished fabrics by adding ZnO NPs exhibited the attractivefunctions of ultraviolet and visible light resistance anti-bacteria and deodorant [7] Apart from the applicationsmentioned above zinc oxide can also be used in otherbranches of industry including concrete production pho-tocatalysis electronics electrotechnology industries and soon [4 8]

It is generally known that zinc as an essential trace el-ement extensively exists in all body tissues including thebrain muscle bone skin and so on As the main componentof various enzyme systems zinc takes part in bodyrsquosmetabolism and plays crucial roles in proteins and nucleicacid synthesis hematopoiesis and neurogenesis [2ndash5]Nano-ZnO with small particle size makes zinc more easilyto be absorbed by the body )us nano-ZnO is commonlyused as a food additive Moreover ZnO is graded asa ldquoGRASrdquo (generally recognized as safe) substance by the USFood and Drug Administration (FDA) [9] With theseproperties ZnO NPs have received more attention in bio-medical applications Compared with other metal oxide NPsZnO NPs with the comparatively inexpensive and relatively

HindawiBioinorganic Chemistry and ApplicationsVolume 2018 Article ID 1062562 18 pageshttpsdoiorg10115520181062562

less toxic property exhibit excellent biomedical applicationssuch as anticancer drug delivery antibacterial and diabetestreatment anti-inflammation wound healing and bio-imaging [1 10ndash12]

Herein in this review we will summarize the methods ofsynthesis and recent exciting progress on the use of ZnONPsin the biomedical fields

2 Synthesis of ZnO NPs

)e biological activity of nanoparticles depends on factorsincluding surface chemistry size distribution particlemorphology and particle reactivity in solution )ereforethe development of nanoparticles with controlled structuresthat are uniform in size morphology and functionality isessential for various biomedical applications

)e ZnO NPs occurring in a very rich variety of size andshape will provide a wide range of properties )e methodsfor stable ZnO NPs preparation have been widely developedin recent years which mainly include the chemical pre-cipitation method sol-gel method solid-state pyrolyticmethod solution-free mechanochemical method and bio-synthesis method

21 Chemical Precipitation )e most popular method forZnO NPs preparation is chemical precipitation whichusually involves two reaction reagents a highly purifiedzinc forerunner such as zinc acetate (Zn(CH3COO)2middot2H2O) zinc nitrate (Zn(NO3)2) or zinc sul-fate (ZnSO4) and a solution of precipitator such as sodiumhydroxide (NaOH) or ammonium hydroxide (NH3middotH2O)[13] Typically the precipitator is added dropwise to thedissolved zinc precursor until the pH level reached about10 )en completely mix these solutions to get a whiteintermediate of zinc hydroxide Ultimately the sample ofzinc hydroxide (Zn(OH)2) was converted to ZnO aftersintering at high temperature

Controlled parameters in this methodmainly include theconcentration of zinc forerunner and precipitator the molarratio of two reagents and the reaction and calcinationtemperature

Bisht et al synthesized ZnO NPs using the chemicalprecipitation method using Zn(CH3COO)2middot2H2O andNaOH in a molar ratio of 1 5 Intermediate products werecalcined at 200degC for 2 h in a muffle furnace to obtain whitefine powder ZnO with the size of 1867plusmn 22 nm [14]

Bettini et al introduced a simplified precipitation ap-proach in ZnO NPs using ZnSO4 and NaOH solution witha molar ratio of 1 2 which was carried out under vigorousstirring for 12 h at room temperature )e obtained whiteprecipitate was washed several times and separated bycentrifugation [15ndash17] Finally the precipitate (ZnO) wasdried in an oven at 100degC for 6 h )e prepared ZnO NPswith a flake-like structure showed a size distribution about100 nm

)e obtaining of ZnO NPs by the chemical pre-cipitation method is not only simple and easily controlledbut also easy industrialized However due to the surface

effect of nanoparticles the precursor of nanooxide pre-pared by the chemical precipitation method could formagglomerates easily

22 Sol-Gel Method A novel sol-gel synthesis of ZnO NPswas firstly presented by Spanhel and Anderson [18] whichmainly involved three major steps

(1) Preparation of zinc precursor

A sample of Zn(CH3COO)2middot2H2O was dissolved inethanol placed into a distillation apparatus and thenrefluxed for few hours at atmospheric pressure )e solutionwas boiled nearly at 80degC and stirred to obtain the con-densate and hygroscopic reaction mixture

(2) Preparation of ZnO clusters

)e hygroscopic mixture was diluted to ethanolic so-lution with the addition of LiOHmiddotH2O powder )e sus-pension will become transparent with the help of anultrasonic bath )is procedure could accelerate the releaseof OH ions and the reaction at low temperature under airconditions could prevent rapid particle growth and getZnO sols

(3) Crystal growth

Crystal growth is a self-induced procedure occurring atroom temperature But the amount of LiOH which couldstrongly affect the crystals growth rate shape and sizeshould be well controlled LiOH-induced ZnO growth canbe briefly summarized as followsZn CH3COO( 11138572 middot 2H2O + 2LiOH⟶ Zn(OH)2

+ 2CH3COOLi + 2H2O

Zn(OH)2 + 2H2O⟶ Zn(OH)42minus

+ 2H+

Zn(OH)42minuslarrrarr ZnO + H2O + 2OHminus

(1)

Some other alkalis can also be used for ZnO growth forinstance Rani et al synthesized ZnO NPs using NaOHinstead of LiOH and successfully obtained ZnONPs with thelargest crystallite size of 14 nm at 9 pH value [19]

)e sol-gel method is the subject of much interest inview of the simplicity low cost and relatively mild condi-tions of synthesis which could offer a simple route toquantum size ZnO particles

23 Solid-State Pyrolytic Method )e solid-state pyrolyticmethod was first developed by Wang et al with advantagesof low cost and easy operation for the growth of high-qualityZnO nanoparticles [20]

)e typical synthesis procedure is as follows Zn(CH3COO)2middot2H2O and NaHCO3 are mixed at roomtemperature )e mixture is pyrolysed at the reactiontemperature Zn(CH3COO)2middot2H2O is converted intoZnO while NaHCO3 is transformed into CH3COONa andcan be eventually cleaned out with deionized waterSubsequently white ZnO NPs can be obtained via the

2 Bioinorganic Chemistry and Applications

thermal decomposition process )e particle sizes can beregulated by selecting different pyrolytic temperaturesUsing this method Wang et al obtained ZnO NPs ofdifferent sizes in the range of 8ndash35 nm

24 Solution-Free Mechanochemical Method Solution-freemechanochemical preparation of ZnO NPs is a two-stepsynthesis method )e first step is to grind Zn(CH3COO)2and H2C2O4middot2H2O powder mixtures for a certain time toform ZnC2O4middot2H2O nanoparticles [21]

Zn(CH3COO)2 (solid large particles) +H2C2O4middot2H2O(solid large particles)ZnC2O4middot2H2O (solid particles)+ 2CH3COOH (liquid and gas) +H2C2O4middot2H2O (solidparticles)

)e second step is the thermal decomposition ofZnC2O4middot2H2O nanoparticles at a very high temperature toget ZnO NPs

ZnC2O4middot2H2O ZnC2O4 + 2H2Ouarr

ZnC2O4middot2H2O ZnO + CO2uarr + COuarr+ 2H2Ouarr

CO + O2 CO2uarr

2H2C2O4middot2H2O + O2 4CO2uarr + 4H2Ouarr

CH3COOH (liquid) CH3COOH (gas)uarr(2)

)e advantages of this method are the low productioncosts and high homogeneity of the crystalline structure andmorphology But the morphology of the ZnO NPs stronglydepends on the milling time of the reactant mixture a longertime of milling led to a smaller particle size )e obtainedZnO NPs show an average size ranging from 24 to 40 nm

Pardeshi and Patil synthesized ZnO NPs with differentmorphologies and crystallite sizes using this method byvarying the calcination temperature from 400degC to 900degC Itwas found that zinc oxide calcined from 400degC to 550degCexhibited the same crystallite growth rate (38ndash50 nm) [22]

25 BiologicalMethods Physical and chemical methods forZnO NPs preparations have widely developed Nowadaysthe development of green chemistry has attracted more andmore attention because it is mostly environmentallyfriendly [23] A broad variety of plant extract are used forthe biosynthesis of ZnO NPs such as the leaf of Azadirachtaindica (L) [23] Cochlospermum religiosum (L) [24]Plectranthus amboinicus [25] Andrographis paniculata[26] Aloe barbadensis [27 28] the peel of rambutan(Nephelium lappaceum L) [29] the root extract of Polygalatenuifolia [30] the rhizome extract of Zingiber officinale[31] the flower extract of Trifolium pratense [32] Jaca-randa mimosifolia [33] the seeds of Physalis alkekengi L[34] and so on Biosynthetic and environment friendlytechnology for the synthesis of ZnO NPs are believed to bemore ecofriendly economical (low priced) nontoxic andbiocompatible than chemical and physical methods ZnONPs prepared by this method exhibited strong potential forbiomedical applications such as its excellent anticancer andantibacterial activity

3 Biomedical Applications ofZnO Nanoparticles

ZnO NPs as a new type of the low-cost and low-toxicitynanomaterial have attracted tremendous interest in variousbiomedical fields including anticancer antibacterial anti-oxidant antidiabetic and anti-inflammatory activities aswell as for drug delivery and bioimaging applications [9 12]Here we summarized the recent progress on the use of ZnONPs in biomedicine ZnO NPs less than 100 nm are con-sidered to be relatively biocompatible which support theirbiomedical applications and represent a powerful propertyin promoting the biomedical research

31AnticancerActivity Cancer a condition of uncontrolledmalignant cell proliferation is typically treated by chemo-therapy radiotherapy and surgery in the past several decadesAlthough all these therapies seem to be very effective for killingcancer cells in theory these nonselective therapy methods alsointroduce a lot of serious side effects [35] Recentlynanomaterial-based nanomedicine with high biocompatibilityeasily surface functionalization cancer targeting and drugdelivery capacity has demonstrated the potential to overcomethese side effects Zn2+ is an essential nutrient for adults andZnO nanomaterials are considered to be safe in vivo Takinginto account these advantages ZnO NPs can be selected asbiocompatible and biodegradable nanoplatforms and can alsobe explored for cancer treatment [36 37] )e anticanceractivity of ZnONPs in different cancers is presented in Table 1

311 Anticancer Activity by Inducing Cancer Cell Apoptosis)e mitochondrial electron transport chain is known to beassociated with intracellular ROS generation and anticanceragents entering into cancer cells could destroy the electrontransport chain and release huge amounts of ROS [58 59]However excessive ROS will lead to mitochondrial damageand result in the loss of protein activity balance that finallycauses cell apoptosis [60] ZnO NPs present certain cyto-toxicity in cancer cells mainly by themselves based ona higher intracellular release of dissolved zinc ions followedby increased ROS induction and induced cancer cell deathvia the apoptosis signaling pathway

Sharma et al explored the effects of ZnO NPs on humanliver cancer HepG2 cells and its possible pharmacologicalmechanism [42] ZnO NPs-exposed HepG2 cells presentedhigher cytotoxicity and genotoxicity which were associatedwith cell apoptosis mediated by the ROS triggered mito-chondrial pathway)e loss of the mitochondrial membranepotential could open outer membrane pores which wouldresult in the release of some related apoptotic proteins in-cluding cytochrome c into the cytosol and activate thecaspase Mechanistic studies had proved that the loss ofmitochondrial membrane potential-mediated HepG2 cellapoptosis was mainly due to the decrease in mitochondrialmembrane potential and Bcl-2Bax ratios as well as ac-companying with the activation of caspase-9 Besides ZnONPs could noticeably activate p38 and JNK and induce andattract p53ser15 phosphorylation but was not dependent on

Bioinorganic Chemistry and Applications 3

Table 1 )e anticancer effects of ZnO NPs in different human cancer cell lines

Cancer type Effect and mechanism

Colon cancer

ZnO NPs suppressed cell viability in Caco-2 cell linevia increased ROS and induced IL-8 release [38]ZnO NPs and fatty acids could induce lysosomal

destabilization in Caco-2 cells [39]ZnONPs induced Caco-2 cells cytotoxicity associated

with increased intracellular Zn ions [40]ZnO NPs conjugated with peptides had a higherantiproliferation in HT-29 colon cancer cells than

other Au NPs and Fe3O4 NPs [41]

Hepatocarcinoma

ZnO NPs caused ROS generation and oxidative DNAdamage and lead to mitochondrial-mediated

apoptosis in HepG2 cells [42]ZnO NPs selectively induce apoptosis in HepG2 cells

which was also mediated by ROS via the p53pathway [43]

Dox-ZnO nanocomplex can act as a drug deliverysystem to increase the internalization of the

anticancer drug Dox in SMMC-7721 cells [44]

Breast cancer

Ecofriendly formulated ZnO NPs arrest the cell cyclein the G2M phase and upregulated proapoptoticgenes p53 p21 Bax and JNK and downregulatedantiapoptotic genes Bcl-2 AKT1 and ERK12 ina dose-dependent manner in MCF-7 cells [45]

A doxorubicin delivery system based on zinc oxidenanomaterials can bypass the P-gp increase in thedrug accumulation in resistant MCF-7R andMCF-7S

cells [46]RGD (Arg-Gly-Asp)-targeted ZnO NPs can targetintegrin αvβ3 receptors to increase the toxicity of theZnO NPs to MDA-MB-231 cells at lower doses [47]ZnO-Fe3O4 magnetic composite nanoparticles site-

specific have no significant toxicity towardsnoncancerous NIH 3T3 cells but show obvious

toxicity at similar concentration to MDA-MB-231cells [14]

FA-functionalized PTX-ZnO NPs released sim75 ofthe paclitaxel payload within six hours in acidic pHimproved chemotherapy tolerance and increased

antitumor efficacy [48]

Lung cancer

ZnO NPs incorporated in liposomes not onlyrendered pH responsivity to the delivery carrier but

also exhibited synergetic chemo-photodynamicanticancer action [49]

Human lung adenocarcinoma cells with an EGFRmutation are sensitive to ZnO NP20 and Al-ZnONP20 which resulted in nonautophagic cell death

[50]

Ovarian cancer

ZnO NPs are able to induce significant cytotoxicityapoptosis and autophagy in SKOV3 cells throughreactive oxygen species generation and oxidative

stress [51]

Cervical cancer

DOX-ZnOPEG nanocomposites exhibited betterdose-dependent toxicity towards HeLa cell lines [52]ZnO nanoparticles showed a dynamic cytotoxic effect

in cervical carcinoma cells which induced theapoptosis through the increased intracellular ROSlevel and upregulated apoptotic gene p53 and

caspase-3 expression [53]


JNK and p38 pathways (Figure 1) ese results aordedvaluable insights into the mechanism of ZnO NPs-inducedapoptosis in human liver HepG2 cells

Moghaddam et al biosynthesized ZnO NPs using a newstrain of yeast (Pichia kudriavzevii GY1) and evaluatedtheir anticancer activity in breast cancer MCF-7 cells [45]ZnONPs have been observed to show powerful cytotoxicityagainst MCF-7 cells which was associated with the oc-currence of apoptosis more than cell cycle arrest e ZnONPs-induced apoptosis was mainly through both extrinsic

and intrinsic apoptotic pathways and some antiapoptoticgenes of Bcl-2 AKT1 and JERK2 were downregulatedwhile proapoptotic genes of p21 p53 JNK and Bax wereupregulated

ZnO NPs have been widely used in cancer therapy andreported to induce a selective cytotoxic eect on cancer cellproliferation Chandrasekaran and Pandurangan in-vestigated the cytotoxicity of ZnO nanoparticles againstcocultured C2C12 myoblastoma cancer cells and 3T3-L1adipocytes which showed that ZnO NPs could be more

Table 1 Continued

Cancer type Eect and mechanism

Gastric cancer

PMMA-AAZnO NPs and PMMA-PEGZnO wereable to carry a large amount of the hydrophobic drug

(curcumin) showing highly anti-gastric canceractivity [54 55]

Human epidermal cancer

ZnO NPs induce cell death at high concentrationsand at lower concentrations they induce cell cyclearrest in the S and G 2M phase by intracellular ROS

generation in A431 cells [56]

Acute promyelocytic leukemiaHAZnO nanocomposite caused G2M cell cyclearrest and stimulated apoptosis-related increase incaspase-3 and minus7 activities of the HL-60 cells [57]

ZnO NPs

LPO

ROSERK

JNK

p38

NAC

NAC

BAX

SH

Bcl2

Δψm

SH

Release of proapoptoticfactors

Caspase 9

Caspase cascade

Apoptosis

Mitochondria

p53p53

NucleusSer15p

NACS S

Cell membrane

Figure 1 e mechanism of ZnO NPs-induced toxicity in human liver cells [42] Copyright 2012 Apoptosis


cytotoxic to C2C12 myoblastoma cancer cells than 3T3-L1cells Compared to 3T3-L1 cells it appeared that ZnO NPsinhibited C2C12 cell proliferation and caused a markedapoptosis via a ROS-mediated mitochondrial intrinsic ap-optotic pathway and p53 BaxBcl-2 ratio and caspase-3pathways [61] )ese results suggested that ZnO NPs couldselectively induce cancer cell apoptosis which could befurther served as a promising candidate for cancer therapy

312 Anticancer by Autophagy Autophagy is a highlyregulated catabolic process that activated in response todifferent kinds of stresses like damaged organelles ROSanticancer agents and protein aggregation Excessive cel-lular damage may lead to cell death by the extension ofautophagy and cellular self-consumption and result incancer cell apoptosis [62 63] Hence autophagy not onlypromotes cell survival but also activates lethal mechanismsin cancer cells thus be considered as an important event innanoparticle-induced cytotoxicity

Bai et al found that ZnO NPs with a crystal size of 20 nmresulted in a concentration-dependent loss of ovarian cancerSKOV3 cell viability [51] And further examined whetherZnO NPs could induce autophagy or not via fluorescencemicroscopy using an LC3 antibody to detect LC3-III ex-pression Visualization of LC3 immunofluorescence showeda remarkable fluorescence and an essential component ofautophagosome after exposure of SKOV3 cells at higherconcentration of ZnO NPs In addition ZnO NPs-treatedSKOV3 cells resulted in an upregulation of LC3-III and p53expression which further induced autophagic cell death

Arakha et al fabricated ZnO NPs using the chemicalprecipitation method and further evaluated their anticanceractivity [64] which found that ZnO NPs with different sizescould obviously inhibit the proliferation of fibrosarcomaHT1080 cells )e results proved that the occurrence ofautophagy in cancer cells was related to intracellular ROSgeneration HT1080 cells stained with acridine orange dyedisplayed remarkably orange and red fluorescence uponZnO NPs treatment which indicated the autophagic cellswith acidic vesicular organelles Likewise the relative level ofLC3 II was comparatively higher in ZnO NPs treated cellsthan nontreated cells which also marked the extent ofautophagy Interaction ZnO NPs with HT1080 cell hasrelatively higher ROS generation Excessive ROS resulted inbiomolecular damages including DNA damage and finallycaused cell death

Previous studies have indicated that ROS and autophagyare involved in the cytotoxicity of ZnO NPs but the reg-ulatory mechanisms between autophagy and ROS remain tobe elucidated Zhang et al investigated the regulatorymechanism of autophagy and the link between autophagyand ROS in ZnO NPs-treated lung epithelial cells [65] )eresults demonstrated that ZnO NPs could induce accu-mulation of autophagosomes and impairment of autophagicflux in A549 cells )is autophagy induction was positivelycorrelated with the dissolution of ZnO NPs in lysosomes torelease zinc ions and zinc ions released from ZnO NPs wereable to damage lysosomes leading to impaired autophagic

flux and mitochondria Impaired autophagic flux resulted inthe accumulation of damaged mitochondria which couldgenerate excessive ROS to cause cell death )is researchprovided a novel insight into the regulation mechanisms ofautophagy-lysosomes-mitochondria-ROS axis which wouldcontribute to a better understanding of the toxicity ofnanomaterials

313 Anticancer Drug Delivery Using nanoparticles intargeted drug delivery provides exciting opportunities formuch more safety and effective cancer treatment By tar-geting the specific sites of cancer cells nanoparticle-baseddrug delivery could reduce the overall amount of drugs usedand thus minimize undesirable side effects [9 66] Com-pared with other nanomaterials ZnO NPs are attractive dueto their low toxicity and biodegradable characteristics ZnONPs have acquired tremendous interest in cancer drugdelivery Different types of drugs such as doxorubicinpaclitaxel curcumin and baicalin or DNA fragments couldbe loaded onto the ZnONPs to show better solubility highertoxicity compared with individual agents and effectivedelivery into cancer cells [48 67ndash69]

Hariharan et al used the coprecipitation technique to getPEG 600 solution-modified ZnO nanoparticles (ZnOPEGNPs) following the loading of doxorubicin (DOX) to formDOX-ZnOPEG nanocomposites [52] DOX-ZnOPEGnanocomposites not only enhanced the intracellularaccumulation of DOX but also presented a concentration-dependent inhibition on cervical cancer HeLa cellproliferation Deng and Zhang also used the chemicalprecipitation method to prepare ZnO nanorods which wereapplied for carrying Dox to construct a Dox-ZnO nano-complex [44] After culture with SMMC-7721 hep-atocarcinoma cells Dox-ZnO nanocomplexes acted as anefficient drug delivery system for importing Dox intoSMMC-7721 cells and enhanced the cellular uptake of Doxdramatically Furthermore coupled with ultraviolet (UV)illumination Dox-ZnO nanocomplexes caused more celldeath through photocatalytic properties and synergisticallytriggered caspase-dependent apoptosis

Puvvada et al established a new ZnO hollow nanocarrier(HZnO) engineered with biocompatible substrates by sur-face following conjugation with targeting agent folic acid(FA) and loaded with paclitaxel (PAC) to designate as theFCP-ZnO nanocomplex [48])e FCP-ZnO nanocomplexesshowed preferential bioaccumulation and cancer cell uptakein the folate receptors overexpressed breast cancer MDA-MB-231 cells Because of FA-mediated endocytosis andintracellular release within the acidic endolysosome theFCP-ZnO nanocomplexes not only exhibited significantlyhigher cytotoxicity in vitro MDA-MB-231 cells but alsoreduced MDA-MB-231 xenograft tumours in nude mice

In order to improve the solubility and bioavailabilityof curcumin Dhivya et al fabricated two novel copolymer-encapsulated ZnO NPs for carrying curcumin CurPMMA-PEGZnO NPs and CurPMMA-AAZnO NPsnanocomposites [54 55] By means of the experimentalstudy PMMA-PEGZnO nanocomposites with the average


size less than 80nm could release curcumin more quickly inthe acidic conditions at pH sim58 Compared to constituentnanomaterials (nanocurcumin PMMA-PEG ZnO NPsand PMMA-PEGZnO) the CurPMMA-PEGZnO nano-composite performed largest observable inhibition on humangastric cancer AGS cell viability (IC50 sim001 μgmLminus1) andinduced cell cycle arrest at the S phase For another nano-composite PMMA-AAZnO NPs with a size of 42plusmn 5 nmcould carry a large amount of curcumin and also had obviousantiproliferation on AGS cancer cells

314 Targeting Functionalization Targeted nanoparticles(NPs) also provide more therapeutic benefits besidesspecificity and specific localization like high payload mul-tidrug conjugation easy tuning of release kinetics selectivelocalization and bypass of multidrug resistance mechanism[70] In order to increase the targeting effects and selectivityagainst cancer cells plenty of functionalization techniqueshave been reported for nanoparticle modification Surface-modified ZnO NPs further improved their stability andpromoted their selectivity against specific cancer cells )ecentral attention is on the functionalization of the ZnO NPssurface with different kinds of biological molecules com-prising different types of proteins peptides nucleic acidsfolic acid hyaluronan and so on [47 57 71ndash73] )e bio-compatible coating of these substances did not affect theanticancer action of ZnO NPs but further increased thetargeting effects against cancer cells and improved the safetyagainst normal cells

For example Chakraborti et al synthesized PEG-modified ZnO NPs and tested it against different breastcancer cell lines [74] It has been found that PEG-ZnO NPswere active against most of the breast cancer cell lines )emain mechanism by which PEG-ZnO kills a cancer cell is bygenerating ROS and triggering p53-dependent apoptosisleading to cell death

Namvar et al produced hyaluronanZnO nano-composite (HAZnO) through green synthesis for the firsttime for cancer treatment [57] )e HAZnO nano-composites caused morphological changes and inhibitedproliferation of cancer cells (pancreatic adenocarcinomaPANC-1 cell ovarian adenocarcinoma CaOV-3 cell colonicadenocarcinoma COLO205 cell and acute promyelocyticleukemia HL-60 cell) in dose- and time-dependent mannerEncouraging HAZnO nanocomposite treatment for 72hours did not cause toxicity to the normal human lungfibroblast (MRC-5) cell line Compared to bare ZnO NPsRGD peptide modification also increased the targeting ef-fects of ZnO NPs on integrin αvβ3 receptors overexpressedMDA-MB-231 cells [47] It appeared to increase the toxicityof the ZnO NPs to breast cancer MCF-7 and MDA-MB-231cells at lower doses

In general the anticancer activity of nanoscaled ZnOmaterials with prominent functionality may provide a newopportunity for exploiting ZnO NPs in treating cancerdiseases )e theory analysis and experimental researchproved that ZnO NPs with less side effect present greaterselectivity among normal and cancerous cells It is reported

that ZnO NPs caused cell death which mostly relates tointracellular ROS generation which further induces cancercell death via apoptosis or the autophagy signaling pathwayBut up to now the advanced anticancer mechanism study ofZnO NPs is still lacked of especially in cellular and mo-lecular mechanism strengthening )erefore in subsequentresearch work we should attach more importance to theirmolecular mechanism in vitro and vivo and overcome itslimitations in cancer therapy

32 Antibacterial Activity ZnO NPs can be selected as anantibacterial material because of its superior properties suchas high specific surface area and high activity to block a widescope of pathogenic agents But recently the antibacterialactivity of ZnO NPs is still scarcely known As shown inFigure 2 prior reports had suggested the main antibacterialtoxicity mechanisms of ZnO NPs were based on their abilityto induce excess ROS generation such as superoxide anionhydroxyl radicals and hydrogen peroxide production [10])e antibacterial activity may involve the accumulation ofZnO NPs in the outer membrane or cytoplasm of bacterialcells and trigger Zn2+ release which would cause bacterialcell membrane disintegration membrane protein damageand genomic instability resulting in the death of bacterialcells [75ndash77]

Presently Gram-negative Escherichia coli (E coli) andGram-positive Staphylococcus aureus (S aureus) aremainly chosen as model bacteria to evaluate the antibacterialactivity of ZnO NPs [77 78] Some other Gram-negativebacteria such as Pseudomonas aeruginosa (P aeruginosa)[24 79] Proteus vulgaris (P vulgaris) [80] Vibrio cholerae(V cholerae) [81] and other Gram-positive bacteria such asBacillus subtilis (B subtilis) [82] and Enterococcus faecalis(E faecalis) [83] are also investigated )e antibacterialactivity of ZnONPs in different bacterial species is presentedin Table 2

Jiang et al reported the potential antibacterial mecha-nisms of ZnO NPs against E coli [76] It showed that ZnONPs with an average size about 30 nm caused cell death bydirectly contacting with the phospholipid bilayer of themembrane destroying themembrane integrity)e additionof radical scavengers such as mannitol vitamin E andglutathione could block the bactericidal action of ZnO NPspotentially revealing that ROS production played a necessaryfunction in the antibacterial properties of ZnO NPs But Zn2+released from ZnO NPs suspensions was not apparent tocause antibacterial effect Reddy prepared ZnO NPs withsizes of sim13 nm and examined their antibacterial (E coli andS aureus) activities [78] )e results were summarized thatZnO NPs completely resisted the growth of E coli atconcentrations of about 34mM but inhibited growth ofS aureus at much lower concentrations (ge1mM) MoreoverOhira and Yamamoto also found the antibacterial (E coliand S aureus) activity of ZnONPs with small crystallite sizeswas stronger than those with large crystallite sizes [97] FromICP-AES measurement the amount of Zn2+ released fromthe small ZnO NPs were much higher than large ZnOpowder sample and E coli was more sensitive to Zn2+ than


S aureus So we can believe that eluted Zn2+ from ZnO NPsalso take a key role in antibacterial action

Iswarya et al extracted crustacean immune moleculeβ-13-glucan binding protein (Phβ-GBP) from the heamo-lymph of Paratelphusa hydrodromus and then successfullyfabricated the Phβ-GBP-coated ZnO NPs e Phβ-GBP-ZnO NPs were spherical in shape with a particle sizeof 20ndash50 nm and restrained the growth of S aureus andP vulgaris It should be noted that S aureus was moresusceptible to Phβ-GBP-ZnO NPs than P vulgaris In ad-dition Phβ-GBP-ZnO NPs could alter cell membranepermeability and trigger high level of ROS formation bothin S aureus and P vulgaris [87] Hence it highlighted thatPhβ-GBP-ZnO NPs could be considered as great antibac-terial nanomaterials

Epidemic disease cholera a serious diarrheal diseasecaused by the intestinal infection of Gram-negative bacte-riumV cholera mainly aects populations in the developingcountries [81 94] Aiming at the development of nano-medicine against cholera Sarwar et al carried out a detailedstudy about ZnO NPs against Vibrio cholerae (two biotypesof cholera bacteria (classical and El Tor)) ZnO NPs wasobserved to be more eective in hindering the growth of ElTor (N16961) biotype of V cholera which was closely as-sociated with ROS production ese results would damagebacterial membrane increase permeabilization and sub-stantially modify their morphology [85] ey also detectedthe antibacterial activity of the ZnO NPs in cholera toxin(CT) mouse models It was found that ZnO NPs couldinduce the CT secondary structure collapsed gradually andinteract with CT by interrupting CT binding with the GM1anglioside receptor [98]

Although ZnO in nanoparticle form is a promisingantibacterial agent due to its wide activity against bothGram-positive and Gram-negative bacteria the exact

antibacterial mechanism of ZnO NPs has not been wellestablished erefore studying it deeply has a lot of im-portant theoretical and realistic value In the future webelieve ZnO NPs can be explored as antibacterial agentssuch as ointments lotions and mouthwashes In addition itcan be coated on various substrates to prevent bacteria fromadhering spreading and breeding in medical devices

33 ZnO NPs for Diabetes Treatment Diabetes mellitus isa serious public health problem and theWHOhas estimatedthat in 2014 there were more than 400 million adults withdiabetes all over the world [99] Diabetes mellitus isa metabolic disease caused by the bodyrsquos incapacity toproduce insulin or by the ineective use of the insulinproduced [100 101] Zinc is a trace element and abundantlyfound mineral in all human tissues and tissue yenuids Zinc iswell known to keep the structural integrity of insulin and hasan active role in the secretion of insulin from pancreaticcells It also participates in insulin synthesis storage andsecretion [102] erefore ZnO NPs as a novel agent inorder for zinc delivery have been developed and evaluatedfor their antidiabetic potential

Kitture et al employed natural extract of red sandalwood(RSW) as an eective antidiabetic agent in conjugation withZnO NPs e antidiabetic activity was assessed with thehelp of α-amylase and α-glucosidase inhibition assay withmurine pancreatic and small intestinal extracts [103] Resultsshowed that ZnO-RSW conjugate possessed moderatelyhigher percentage of inhibition (20) against porcinepancreatic α-amylase and were more eective against thecrude murine pancreatic glucosidase than any of the twoelements (RSW and ZnO NPs) e conjugated ZnO-RSWdisplayed 6193 of inhibition in glucosidase while the bareZnO NPs and RSW showed 2148 and 590 respectively

Bacteria

ZnO NPsZn2+

H2O2

O2bull

bullOH

Figure 2 Schematic illustration of antibacterial activity of ZnO NPs


In 2015 Nazarizadeh and Asri-Rezaie carried out a studyto compare the antidiabetic activity and oxidative stress ofZnO NPs and ZnSO4 in diabetic rats It found that ZnO NPswith small dimensions at higher doses (3 and 10mgkg) hada much greater antidiabetic effect compared to ZnSO4(30mgkg) It was evidenced by an outstanding reduction ofblood glucose and increasing insulin levels as well as im-proving serum zinc status in a time- and dose-dependentmanner However severely elicited oxidative stress partic-ularly at higher doses was also observed by the alterederythrocyte antioxidant enzyme activities increased inmalondialdehyde (MDA) production and marked re-duction of serum total antioxidant capacity [100]

)e hyperglycemia can directly enhance an in-flammatory state by regulating C-reactive protein (CRP) andcytokines such as interleukins which is involved in thedevelopment of cardiovascular diseases Hussein et alfabricated ZnO NPs using hydroxyl ethyl cellulose asa stabilizing agent to alleviate diabetic complications [104] Itreported that ZnO NPs could significantly decrease

malondialdehyde (MDA) and fast blood sugar and asym-metric dimethylarginine (ADMA) levels )e inflammatorymarkers interleukin-1 (IL-1α) and CRP were also notablydecreased after ZnO NPs treatment concomitant with anincrease in nitric oxide (NO) and serum antioxidant enzyme(PON-1) levels in diabetic rats

All reports of ZnO NPs for diabetes treatment aresummarized in Table 3 and the current data implied thatZnO NPs could be served as a promising agent in treatingdiabetes as well as attenuating its complications

34 Anti-Inflammatory Activity Inflammation is part of thecomplex biological response of body tissues to harmfulstimuli such as pathogens damaged cells or irritants [111]Since the advent of nanoparticles and considering thesebiological activities of zinc ions the anti-inflammatory ef-fects of ZnO NPs have also attracted much attention

Atopic dermatitis (AD) is a chronic inflammatory skindisease characterized by the impairment of the skin-barrier

Table 2 )e antibacterial effects of ZnO NPs in different bacterial species

Material Size(nm) Bacterial species Antibacterial mechanism

ZnO NPs 30 E coli Destroy the membrane integrity and ROSproduction [76]

Ag-ZnO composite 64 S aureus and GFP E coli ROS and the release of Ag+ and Zn2+ [84]

ZnO NPs sim80 V cholera

Depolarization of the membranestructure increased permeabilization anddamage of DNA and generation of

ROS [85]ZnO NPs sim20 E coli 11634 Hydrogen peroxide (H2O2) [86]ZnO NPs E coli and S aureus Release of Zn2+ [78]Phβ-GBP-coated ZnO NPs (Phβ-GBP-ZnO NPs) 20sim50 S aureus and P vulgaris Alter the bacterial cell membrane

permeability and high level of ROS [87]

ZnO nanocatalyst sim18 B subtilis E coli K pneumonia andS typhimurium H2O2 OHminus and other ROS [88]

CdO-ZnO nanocomposite 27E coli P aeruginosa Klebsiella

pneumonia S aureus P vulgaris andBacillus spp

ROS (OHminus H2O2 and O22minus) and the

release of Zn2+ and Cd2+ [89]

ZnO quantum dots 4 E coli MG1655 Cupriavidusmetallidurans CH34 )e toxicity is mainly from Zn2+ [90]

ZnOkaoline nanocomposites S aureus E coli E faecalis andP aeruginosa

Zn2+ and consequent diffusion of theseions into the cytoplasm [91]

ZnO nanostructures (ZnO-NSs) 70sim80 S aureus S typhimurium P vulgaris andK pneumoniae ROS damage to cell membranes [92]

ZnO NPs 40

Streptococcus mutans (MTCC497)S pyogenes (MTCC1926) Vibrio cholerae

(MTCC3906) Shigella flexneri(MTCC1457) and Salmonella typhi

(MTCC1252)

ROS and the release of Zn2+ [93]

ZnO NPs 90sim100 V cholera and enterotoxic E coli (ETEC) Inhibit adenylyl cyclase activity andcAMP levels are decreased [94]

Ge-ZnO NPs 20 P aeruginosa and E faecalis Penetrated the cell and caused bacterialcell death [83]

SAZnO composites E coli and S aureus ROS production [95]

ZnOGA NPs 115plusmn44 E coli and S aureus

Attributed to the high affinity of GA forthe bacterial cell membrane and the

increased lipophilicity upon the additionof GA [96]


functions which was involved with complex interactionbetween genetic and environmental factors [112 113]Textiles have the longest and most intense contact with thehuman skin Wiegand explored the role of ZnO-functionalized textile fibers in the control of oxidativestress in AD in vitro and in vivo [114] )e study found thatit is an obvious improvement of AD pruritus and subjectivesleep quality when AD patients wore the ZnO textilesovernight on 3 consecutive days )is is a possibly due to thehigh antioxidative and strong antibacterial capacity of theZnO textile

Ilves et al investigated whether different-sized ZnO NPswould be able to penetrate injured skin and injured allergicskin in the mouse ADmodel [115])eir experiments clearlygave evidences of that only nanosized ZnO (nZnO) was ableto reach into the deep layers of the allergic skin but bulk-sized ZnO (bZnO) stayed in the upper layers of bothdamaged and allergic skin Compared with bZnO nZnOexerted higher anti-inflammatory properties by decreasing

drastically on proinflammatory cytokines (IL-10 IL-13IFN-c and )2 cytokines) in the mouse model of AD)ese results demonstrated that ZnO NPs with a small sizehad great effects on reducing skin inflammation in ADmodels

)e anti-inflammatory activity of ZnO NPs is notconfined to atopic dermatitis treatment but has also shownto be very effective for other inflammatory diseases Giventhe known more anti-inflammatory activity of ZnO NPsNagajyothi et al described a straightforward inexpensiveand ecofriendly ZnO NPs using the root extract of P ten-uifolia and the anti-inflammatory activities were in-vestigated in LPS-stimulated RAW 2647 macrophages [30]ZnO NPs exposed remarkable anti-inflammatory activity bydose-dependently suppressing NO production as well as therelated protein expressions of iNOS COX-2 IL-1β IL-6and TNF-α )atoi et al prepared the ZnO NPs underphotocondition using the aqueous extracts of two mangroveplants Heritiera fomes and Sonneratia apetala and found

Table 3 ZnO NPs for diabetes treatment

Type of NPs Size Drug loadedsynergy Effects

ZnO NPs 60ndash95 nm spherical mdash Mitigated the diabeticcomplications [104]

ZnO NPs sim20 nm spherical mdashA significant decrease in fasting

blood glucose and increase in high-density lipoprotein levels [105]

ZnO NPs 10ndash30 nm )iamine ZnONPs in combination with thiamine-improved diabetes therapy [106]

ZnO NPs mdash mdash ZnO NPs effectively reversed diabetes-induced pancreatic injury [107]

ZnO-RSW NPs sim20 nm Conjugated redsandalwood (RSW)

ZnO-RSWNPs showed excellent activityagainst the crude murine pancreaticglucosidase as compared to the

individual ZnO NPs and the RSWextract [103]

ZnO NPs mdash mdash

ZnO NPs acted as a potent antidiabeticagent evidenced by improved glucosedisposal insulin levels and zinc status in

diabetic rats [100]

ZnO NPs sim10 nm mdash

ZnO NPs presented pleiotropicantidiabetic effects via improved insulinsignaling enhanced glucose uptakedecreased hepatic glucose outputdecreased lipolysis and enhancedpancreatic beta cell mass [108]

ZnO NPs CeO2 NPsAg NPs

ZnO NPs 55 nm CeO2 NPs 54 nm AgNPs 225 nm mdash

ZnO NPs and Ag NPs had more potentantihyperglycemic activity than CeO2

NPs [109]

ZnO NPs Spherical 96ndash115 nm hexagonal57plusmn 03 nm mdash

ZnO NPs displayed better antidiabeticpotential (IC50 6678 μgmL) than

ZnNO3 (IC50 9133 μgmL) in terms ofthe α-amylase inhibition activity [26]

ZnO NPs mdash VildagliptinZnO NPs and vildagliptin have

synergistic effects on the therapy of type-2 diabetes [110]

ZnO NPs 10ndash15 nm spherical mdash

ZnO NPs could improve glucosetolerance and higher serum insulin andreduce blood glucose nonesterified fatty

acids and triglycerides [101]


that ZnO NPs had a higher potential for anti-inflammatory(79) in comparison with silver nanoparticles (691) [116]

)e reports of ZnO NPs with anti-inflammatory activityare summarized in Table 4 Hence ZnO NPs also have thepotential to be utilized for anti-inflammatory treatment

35 ZnONPs for Bioimaging ZnO NPs exhibit efficient blueemissions and near-UV emissions which have green oryellow luminescence related to oxygen vacancies thereforefurther extending its application into bioimaging field[12 36 120]

Using a simple sol-gel method Xiong et al preparedstable aqueous ZnOpolymer core-shell nanoparticles(ZnOpoly(MAA-co-PEGMEMA))for the first time )eZnOpolymer core-shell nanoparticles exhibited highquantum yield and very stable broad photoluminescence inaqueous solutions As shown in Figure 3 within humanhepatoma cells ZnO-1 (derived from LiOH) with an averagesize of 3 nm showed green fluorescence while ZnO-2 (de-rived from NaOH) with an average size of 4 nm appearedyellow It was worth to note that these nanoparticles did notshow any remarkable toxicity for human hepatoma cellswhen their concentrations were less than 02mgmLFurthermore the luminescence was very stable duringcell culturing and the cells were alive at 45min of exposureSo as a type of safe and cheap luminescent labels the

ZnOpolymer core-shell nanoparticles can be used asfluorescent probes for cell imaging in vitro [121]

Jiang et al constructed ZnO nanosheets for the imagingof cultured cells )ey treated drug sensitive leukemia lineK562 cells with ZnO nanosheets and the yellow-orange lightemission was clearly observed around or inside the cellsunder UV irradiation (365 nm) at room temperature [122]ZnO nanostructures were successfully attached onto orpenetrated into the cells which suggested that ZnO nano-sheets with visible yellow-orange emission could act asa feasible label for the bioimaging

Tang et al prepared ZnO NPs by using the chemicalprecipitation method It exhibited emission colors of bluegreen yellow and orange [123] )e emission color can bechanged via adjusting the pH of the precipitation solutionsTo stabilize ZnO NPs in water they encapsulated the ZnONPs with silica to form ZnOsilica core-shell nano-structures )e obtained ZnOsilica core-shell nano-particles exhibited excellent water stability and the visibleemissions of ZnO were retained It could be successfullyattached to the NIH3T3 cells surface and displayed differentfluorescent colors with different emission wavelengths

)e typical researches about biological imaging of ZnONPs are summarized in Table 5 Based on its advancedintrinsic fluorescence ZnO nanomaterial can also be used asa promising candidate for cell imaging and pathologicalstudies

Table 4 ZnO NPs with anti-inflammatory activity

Type of NPs Size Effects

ZnO-functionalized textile fibers mdashA rapid improvement of AD severity pruritus andsubjective sleep quality when AD patients wore theZnO textiles overnight on 3 consecutive days [114]

ZnO NPs mdash

ZnO NPs exerted higher anti-inflammatoryproperties by decreasing drastically onproinflammatory cytokines in the mouse

model of AD [115]

ZnO NPs Spherical 3303ndash7348 nmZnO NPs relieved inflammation and displayeda dose-dependent effect in the suppression of

related protein expressions [30]

ZnO NPsSpherical 96ndash115 nm

hexagonal57plusmn 03 nm

ZnO NPs exhibited excellentanti-inflammatory activity

with 6678 μgmL IC50 value [26]ZnO incorporated into TiO2 nanotubes(TNTsZnO) mdash TNTsZnO had a significant inhibitory effect on the

proliferation and adhesion of macrophages [117]

ZnO NPs and Ag NPs mdashZnO NPs had a higher potential for anti-inflammatory (79) in comparison with

Ag NPs (691) [116]

ZnO NPs 694plusmn 130 nm

)e anti-inflammatory abilities of ZnO NPs tosuppress proinflammatory cytokines IL-1β and

TNF-α and myeloperoxidase (MPO) in the coliticmice and activate Nrf2 signaling [118]

ZnO NPs mdash

Dietary supplementation with ZnO NPs waseffective in inhibiting mRNA expression of

inflammatory cytokines(IFN-c IL-1β TNF-α and NF-κB)

in the ileum in weanedpiglets [119]


4 Conclusions and Future Perspectives

ZnO NPs have exhibited promising biomedical applicationsbased on its anticancer antibacterial antidiabetic anti-inflammatory drug delivery as well as bioimaging activ-ity Due to inherent toxicity of ZnO NPs they possess stronginhibition effects against cancerous cell and bacteria byinducing intracellular ROS generation and activating apo-ptotic signaling pathway which makes ZnO NPs a potentialcandidate as anticancer and antibacterial agents In additionZnO NPs have also been well known to promote the bio-availability of therapeutic drugs or biomolecules whenfunctioning as drug carriers to achieve enhanced therapyefficiency Moreover with the ability to decrease bloodglucose and increase in insulin levels ZnO NPs have shownthe promising potential in treating diabetes and attenuatingits complications which can be further evaluated

ZnO NPs are listed as a kind of safe substance by theFDA However some critical issues of ZnO NPs still needto be further explored which include the following (1) lackof comparative analysis of its biological advantages withother metal nanoparticles (2) the limitations of ZnO NPstoxicity toward biological systems remain a controversialissue in recent researches (3) lack of evidence-basedrandomized research specifically exploring therapeuticroles in improving anticancer antibacterial anti-inflammatory and antidiabetic activities and (4) lack ofinsight into corresponding animals study about its anti-cancer antibacterial anti-inflammatory and antidiabeticactivities Following studies focused on the above-mentioned issues could further elucidate and comprehendthe potential use of ZnO nanoparticles in biomedical di-agnostic and therapeutic fields We believe that nano-materials would dramatically promote the development of

ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm

Figure 3 )e upper part is the high-resolution transmission electron microscopy (HRTEM) image of the ZnOpolymer core-shellnanoparticles and the aqueous solutions of ZnO-1 and ZnO-2 under a UV light the middle part is the DIC picture and the fluorescent imageof the human hepatoma cells labeled by ZnO-1 and the lower part is the DIC picture and the fluorescent image of the hepatoma cells labeledby ZnO-2 [121] Copyright 2008 American Chemical Society


medicine and ZnO nanoparticles are expected to makemore exciting contributions in these fields

Conflicts of Interest

)e authors declare that they have no conflicts of interest

Acknowledgments

)is work was financially supported by the Macau Scienceand Technology Development Fund (no 0282014A1) andChina Postdoctoral Science Foundation (2018M631026)

References

[1] P K Mishra H Mishra A Ekielski S Talegaonkar andB Vaidya ldquoZinc oxide nanoparticles a promising nano-material for biomedical applicationsrdquo Drug Discovery Todayvol 22 no 12 pp 1825ndash1834 2017

[2] T G Smijs and S Pavel ldquoTitanium dioxide and zinc oxidenanoparticles in sunscreens focus on their safety and ef-fectivenessrdquo Nanotechnology Science and Applicationsvol 4 pp 95ndash112 2011

[3] J A Ruszkiewicz A Pinkas B Ferrer T V PeresA Tsatsakis and M Aschner ldquoNeurotoxic effect of activeingredients in sunscreen products a contemporary reviewrdquoToxicology Reports vol 4 pp 245ndash259 2017

[4] A Kolodziejczak-Radzimska and T Jesionowski ldquoZincoxidendashfrom synthesis to application a reviewrdquo Materialsvol 7 no 4 pp 2833ndash2881 2014

[5] S Sahoo M Maiti A Ganguly J J George andA K Bhowmick ldquoEffect of zinc oxide nanoparticles as cureactivator on the properties of natural rubber and nitrile

rubberrdquo Journal of Applied Polymer Science vol 105 no 4pp 2407ndash2415 2007

[6] M D Newman M Stotland and J I Ellis ldquo)e safety ofnanosized particles in titanium dioxide- and zinc oxide-based sunscreensrdquo Journal of the American Academy ofDermatology vol 61 no 4 pp 685ndash692 2009

[7] A Hatamie A Khan M Golabi et al ldquoZinc oxidenanostructure-modified textile and its application to bio-sensing photocatalysis and as antibacterial materialrdquoLangmuir vol 31 no 39 pp 10913ndash10921 2015

[8] F X Xiao S F Hung H B Tao J Miao H B Yang andB Liu ldquoSpatially branched hierarchical ZnO nanorod-TiO2nanotube array heterostructures for versatile photocatalyticand photoelectrocatalytic applications towards intimateintegration of 1D-1D hybrid nanostructuresrdquo Nanoscalevol 6 no 24 pp 14950ndash14961 2014

[9] J W Rasmussen E Martinez P Louka and D G WingettldquoZinc oxide nanoparticles for selective destruction of tumorcells and potential for drug delivery applicationsrdquo ExpertOpinion on Drug Delivery vol 7 no 9 pp 1063ndash1077 2010

[10] Z Y Zhang and H M Xiong ldquoPhotoluminescent ZnOnanoparticles and their biological applicationsrdquo Materialsvol 8 no 6 pp 3101ndash3127 2015

[11] S Kim S Y Lee and H J Cho ldquoDoxorubicin-wrapped zincoxide nanoclusters for the therapy of colorectal adenocar-cinomardquo Nanomaterials vol 7 no 11 p 354 2017

[12] H M Xiong ldquoZnO nanoparticles applied to bioimaging anddrug deliveryrdquo Advanced Materials vol 25 no 37pp 5329ndash5335 2013

[13] M A Majeed Khan M Wasi Khan M AlhoshanM S AlSalhi and A S Aldwayyan ldquoInfluences of Co dopingon the structural and optical properties of ZnO nano-structuredrdquo Applied Physics A vol 100 no 1 pp 45ndash512010

Table 5 Typical researches about biological imaging of ZnO NPs

Materials Size and models Biological imaging

ZnOMAA-co-PEGMEMA Human hepatoma cellsWith tunable photoluminescence emission and highquantum yield under UV light ZnO-1 showed greenfluorescence while ZnO-2 appeared yellow [121]

ZnOPMAA-co-PDMAEMA Spherical 4 nmCOS-7 cells )e PDMAEMA-modified ZnO QDs emitted strongyellow luminescence under UV light [124]

ZnO-AuPEG NPs lt100 nmB16F10 cells ZnO-AuPEG NPs can penetrate into the living cellsand exhibit bright yellow fluorescence [125]

ZnO nanosheets 466plusmn 85 nmK562 cells Yellow-orange light emission was observed around orinside the cells under UV light [122]

ZnOsilica NPs 27ndash44 nmHeLa cellsMonodispersed ZnOsilica NPs with blue greenand yellow emission through using VTES TEOS and

APS as modification materials [126]

Fe3O4-ZnO NPs 157 nmdendritic cells Fe3O4-ZnO NPs emit green fluorescence under UVlight irradiation [127]

ZnOsilica NPs NIH3T3 cells

ZnOsilica NPs exhibited emission colors of bluegreen yellow and orange under 365 nm excitationvia the adjustment of the pH of the precipitation

solutions [123]

ZnOsilica NPs 55 nmnerve cells Caco-2 cells ZnOsilica QD colloidal solution exhibiteda significant blue emission [128]

ZnO nanowires 20ndash50 nmU87MG cells MCF-7 cells

ZnO nanowires exhibited green fluorescent RGDpeptide-conjugated green fluorescent ZnO NWs canbe specifically targeted to cell surface receptors in

vitro [129]


[14] G Bisht S Rayamajhi B Kc S N Paudel D Karna andB G Shrestha ldquoSynthesis characterization and study of invitro cytotoxicity of ZnO-Fe3O4 magnetic compositenanoparticles in human breast cancer cell line (MDA-MB-231) and mouse fibroblast (NIH 3T3)rdquo Nanoscale ResearchLetters vol 11 no 1 p 537 2016

[15] S Bettini R Pagano V Bonfrate et al ldquoPromising piezo-electric properties of new ZnOoctadecylamine adductrdquoJournal of Physical Chemistry C vol 119 no 34pp 20143ndash20149 2015

[16] R Pagano A Quarta S Pal A Licciulli L Valli andS Bettini ldquoEnhanced solar-driven applications of ZnOAgpatchy nanoparticlesrdquo Journal of Physical Chemistry Cvol 121 no 48 pp 27199ndash27206 2017

[17] S Bettini R Pagano L Valli and G Giancane ldquoEn-hancement of open circuit voltage of a ZnO-based dye-sensitized solar cell by means of piezotronic effectrdquoChemistry-An Asian Journal vol 11 no 8 pp 1240ndash12452016

[18] L Spanhel and M A Anderson ldquoSemiconductor clusters inthe sol-gel process-quantized aggregation gelation andcrystal-growth in concentrated ZnO colloidsrdquo Journal of theAmerican Chemical Society vol 113 no 8 pp 2826ndash28331991

[19] S Rani P Suri P Shishodia and R Mehra ldquoSynthesis ofnanocrystalline ZnO powder via solndashgel route for dye-sensitized solar cellsrdquo Solar Energy Materials and SolarCells vol 92 no 12 pp 1639ndash1645 2008

[20] Z J Wang H M Zhang L G Zhang J S Yuan S G Yanand C Y Wang ldquoLow-temperature synthesis of ZnOnanoparticles by solid-state pyrolytic reactionrdquo Nanotech-nology vol 14 no 1 pp 11ndash15 2003

[21] L Shen N Bao K Yanagisawa K Domen A Gupta andC A Grimes ldquoDirect synthesis of ZnO nanoparticles bya solution-free mechanochemical reactionrdquoNanotechnologyvol 17 no 20 pp 5117ndash5123 2006

[22] S K Pardeshi and A B Patil ldquoEffect of morphology andcrystallite size on solar photocatalytic activity of zinc oxidesynthesized by solution free mechanochemical methodrdquoJournal of Molecular Catalysis A Chemical vol 308 no 1-2pp 32ndash40 2009

[23] K Elumalai and S Velmurugan ldquoGreen synthesis charac-terization and antimicrobial activities of zinc oxide nano-particles from the leaf extract of Azadirachta indica (L)rdquoApplied Surface Science vol 345 pp 329ndash336 2015

[24] C Mahendra MMurali G Manasa et al ldquoAntibacterial andantimitotic potential of bio-fabricated zinc oxide nano-particles of Cochlospermum religiosum (L)rdquo MicrobialPathogenesis vol 110 pp 620ndash629 2017

[25] L Fu and Z X Fu ldquoPlectranthus amboinicus leaf extract-assisted biosynthesis of ZnO nanoparticles and their pho-tocatalytic activityrdquo Ceramics International vol 41 no 2pp 2492ndash2496 2015

[26] G Rajakumar M )iruvengadam G Mydhili T Gomathiand I M Chung ldquoGreen approach for synthesis of zinc oxidenanoparticles from Andrographis paniculata leaf extract andevaluation of their antioxidant anti-diabetic and anti-inflammatory activitiesrdquo Bioprocess and Biosystems Engi-neering vol 41 no 1 pp 21ndash30 2018

[27] Y G Qian J Yao M Russel K Chen and X Y WangldquoCharacterization of green synthesized nano-formulation(ZnO-A vera) and their antibacterial activity against path-ogensrdquo Environmental Toxicology and Pharmacology vol 39no 2 pp 736ndash746 2015

[28] K Ali S Dwivedi A Azam et al ldquoAloe vera extractfunctionalized zinc oxide nanoparticles as nanoantibioticsagainst multi-drug resistant clinical bacterial isolatesrdquoJournal of Colloid and Interface Science vol 472 pp 145ndash1562016

[29] R Yuvakkumar J Suresh A J Nathanael M Sundrarajanand S I Hong ldquoNovel green synthetic strategy to prepareZnO nanocrystals using rambutan (Nephelium lappaceumL) peel extract and its antibacterial applicationsrdquo MaterialsScience and Engineering C vol 41 pp 17ndash27 2014

[30] P C Nagajyothi S J Cha I J Yang T V SreekanthK J Kim and H M Shin ldquoAntioxidant and anti-inflammatory activities of zinc oxide nanoparticles synthe-sized using Polygala tenuifolia root extractrdquo Journal ofPhotochemistry and Photobiology B Biology vol 146pp 10ndash17 2015

[31] A C Janaki E Sailatha and S Gunasekaran ldquoSynthesischaracteristics and antimicrobial activity of ZnO nano-particlesrdquo Spectrochimica Acta Part A Molecular and Bio-molecular Spectroscopy vol 144 pp 17ndash22 2015

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[34] J Qu X Yuan X HWang and P Shao ldquoZinc accumulationand synthesis of ZnO nanoparticles using Physalis alkekengiLrdquo Environmental Pollution vol 159 no 7 pp 1783ndash17882011

[35] H Sharma K Kumar C Choudhary P K Mishra andB Vaidya ldquoDevelopment and characterization ofmetal oxidenanoparticles for the delivery of anticancer drugrdquo ArtificialCells Nanomedicine and Biotechnology vol 44 no 2pp 672ndash679 2016

[36] Y Zhang T R Nayak H Hong and W Cai ldquoBiomedicalapplications of zinc oxide nanomaterialsrdquo Current molecularmedicine vol 13 no 10 pp 1633ndash1645 2013

[37] MMartinez-Carmona Y Gunrsquoko andM Vallet-Regi ldquoZnOnanostructures for drug delivery and theranostic applica-tionsrdquo Nanomaterials vol 8 no 4 p 268 2018

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[39] Y Cao M Roursgaard A Kermanizadeh S Loft andP Moller ldquoSynergistic effects of zinc oxide nanoparticles andfatty acids on toxicity to Caco-2 cellsrdquo International Journalof Toxicology vol 34 no 1 pp 67ndash76 2015

[40] X Fang L Jiang Y Gong J Li L Liu and Y Cao ldquo)epresence of oleate stabilized ZnO nanoparticles (NPs) andreduced the toxicity of aged NPs to Caco-2 and HepG2 cellsrdquoChemico-Biological Interactions vol 278 pp 40ndash47 2017

[41] J Bai Aswathanarayan and R Rai Vittal ldquoMuddegowda Uanticancer activity of metal nanoparticles and their peptideconjugates against human colon adenorectal carcinomacellsrdquo Artificial Cells Nanomedicine and Biotechnology pp1ndash8 2017 In press


[42] V Sharma D Anderson and A Dhawan ldquoZinc oxidenanoparticles induce oxidative DNA damage and ROS-triggered mitochondria mediated apoptosis in human livercells (HepG2)rdquo Apoptosis vol 17 no 8 pp 852ndash870 2012

[43] M J Akhtar M Ahamed S Kumar M M Khan J Ahmadand S A Alrokayan ldquoZinc oxide nanoparticles selectivelyinduce apoptosis in human cancer cells through reactiveoxygen speciesrdquo International Journal of Nanomedicinevol 7 pp 845ndash857 2012

[44] Y Deng and H Zhang ldquo)e synergistic effect and mecha-nism of doxorubicin-ZnO nanocomplexes as a multimodalagent integrating diverse anticancer therapeuticsrdquo In-ternational Journal of Nanomedicine vol 8 pp 1835ndash18412013

[45] A B Moghaddam M Moniri S Azizi et al ldquoEco-friendlyformulated zinc oxide nanoparticles induction of cell cyclearrest and apoptosis in the MCF-7 cancer cell linerdquo Genesvol 8 no 10 p 281 2017

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[48] N Puvvada S Rajput B N Kumar et al ldquoNovel ZnOhollow-nanocarriers containing paclitaxel targeting folate-receptors in a malignant pH-microenvironment for effectivemonitoring and promoting breast tumor regressionrdquo Sci-entific Reports vol 5 no 1 article 11760 2015

[49] N Tripathy R Ahmad H A Ko G Khang and Y B HahnldquoEnhanced anticancer potency using an acid-responsiveZnO-incorporated liposomal drug-delivery systemrdquo Nano-scale vol 7 no 9 pp 4088ndash4096 2015

[50] K J Bai K J Chuang C M Ma T Y Chang andH C Chuang ldquoHuman lung adenocarcinoma cells with anEGFR mutation are sensitive to non-autophagic cell deathinduced by zinc oxide and aluminium-doped zinc oxidenanoparticlesrdquo Journal of Toxicological Sciences vol 42no 4 pp 437ndash444 2017

[51] D P Bai X F Zhang G L Zhang Y F Huang andS Gurunathan ldquoZinc oxide nanoparticles induce apoptosisand autophagy in human ovarian cancer cellsrdquo InternationalJournal of Nanomedicine vol 12 pp 6521ndash6535 2017

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[53] M Pandurangan G Enkhtaivan and D H Kim ldquoAnti-cancer studies of synthesized ZnO nanoparticles againsthuman cervical carcinoma cellsrdquo Journal of Photochemistryand Photobiology B Biology vol 158 pp 206ndash211 2016

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[55] R Dhivya J Ranjani P K Bowen J RajendhranJ Mayandi and J Annaraj ldquoBiocompatible curcumin

loaded PMMA-PEGZnO nanocomposite induce apo-ptosis and cytotoxicity in human gastric cancer cellsrdquoMaterials Science and Engineering C vol 80 pp 59ndash682017

[56] P Patel K Kansara V A Senapati R Shanker A Dhawanand A Kumar ldquoCell cycle dependent cellular uptake of zincoxide nanoparticles in human epidermal cellsrdquoMutagenesisvol 31 no 4 pp 481ndash490 2016

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[63] S Hackenberg A Scherzed A Gohla et al ldquoNanoparticle-induced photocatalytic head and neck squamous cellcarcinoma cell death is associated with autophagyrdquoNanomedicine vol 9 no 1 pp 21ndash33 2014

[64] M Arakha J Roy P S Nayak B Mallick and S Jha ldquoZincoxide nanoparticle energy band gap reduction triggers theoxidative stress resulting into autophagy-mediated apoptoticcell deathrdquo Free Radical Biology and Medicine vol 110pp 42ndash53 2017

[65] J Zhang X Qin B Wang et al ldquoZinc oxide nanoparticlesharness autophagy to induce cell death in lung epithelialcellsrdquo Cell Death and Disease vol 8 no 7 article e29542017

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[67] J Wang J S Lee D Kim and L Zhu ldquoExploration of zincoxide nanoparticles as a multitarget and multifunctionalanticancer nanomedicinerdquo ACS Applied Materials and In-terfaces vol 9 no 46 pp 39971ndash39984 2017

[68] S B Ghaffari M H Sarrafzadeh Z FakhroueianS Shahriari and M R Khorramizadeh ldquoFunctionalizationof ZnO nanoparticles by 3-mercaptopropionic acid foraqueous curcumin delivery synthesis characterization andanticancer assessmentrdquo Materials Science and EngineeringC vol 79 pp 465ndash472 2017

[69] Y Li C Zhang L Liu Y Gong Y Xie and Y Cao ldquo)eeffects of baicalein or baicalin on the colloidal stability ofZnO nanoparticles (NPs) and toxicity of NPs to Caco-2cellsrdquo Toxicology Mechanisms and Methods vol 28 no 3pp 167ndash176 2017


[70] N Kamaly Z Xiao P M Valencia A F Radovic-Morenoand O C Farokhzad ldquoTargeted polymeric therapeuticnanoparticles design development and clinical translationrdquoChemical Society Reviews vol 41 no 7 pp 2971ndash3010 2012

[71] Z Han X Wang C Heng et al ldquoSynergistically enhancedphotocatalytic and chemotherapeutic effects of aptamer-functionalized ZnO nanoparticles towards cancer cellsrdquoPhysical Chemistry Chemical Physics vol 17 no 33pp 21576ndash21582 2015

[72] K C Biplab S N Paudel S Rayamajhi et al ldquoEnhancedpreferential cytotoxicity through surface modification syn-thesis characterization and comparative in vitro evaluationof TritonX-100 modified and unmodified zinc oxide nano-particles in human breast cancer cell (MDA-MB-231)rdquoChemistry Central Journal vol 10 no 1 2016

[73] Y Y Ma H Ding and H M Xiong ldquoFolic acid func-tionalized ZnO quantum dots for targeted cancer cell im-agingrdquo Nanotechnology vol 26 no 30 article 305702 2015

[74] S Chakraborti S Chakraborty S Saha et al ldquoPEG-functionalized zinc oxide nanoparticles induce apoptosisin breast cancer cells through reactive oxygen species-dependent impairment of DNA damage repair enzymeNEIL2rdquo Free Radical Biology and Medicine vol 103pp 35ndash47 2017

[75] L E Shi Z H Li W Zheng Y F Zhao Y F Jin andZ X Tang ldquoSynthesis antibacterial activity antibacterialmechanism and food applications of ZnO nanoparticlesa reviewrdquo Food Additives and Contaminants Part A vol 31no 2 pp 173ndash186 2014

[76] Y Jiang L Zhang D Wen and Y Ding ldquoRole of physicaland chemical interactions in the antibacterial behavior ofZnO nanoparticles against E colirdquo Materials Science andEngineering C vol 69 pp 1361ndash1366 2016

[77] R K Dutta B P Nenavathu M K Gangishetty andA V Reddy ldquoAntibacterial effect of chronic exposure of lowconcentration ZnO nanoparticles on E colirdquo Journal ofEnvironmental Science and Health Part A vol 48 no 8pp 871ndash878 2013

[78] K M Reddy K Feris J Bell D G Wingett C Hanley andA Punnoose ldquoSelective toxicity of zinc oxide nanoparticlesto prokaryotic and eukaryotic systemsrdquo Applied PhysicsLetters vol 90 no 21 article 213902 2007

[79] B N Singh A K Rawat W Khan A H Naqvi andB R Singh ldquoBiosynthesis of stable antioxidant ZnOnanoparticles by Pseudomonas aeruginosa rhamnolipidsrdquoPLoS One vol 9 no 9 Article ID e106937 2014

[80] R Ishwarya B Vaseeharan S Kalyani et al ldquoFacile greensynthesis of zinc oxide nanoparticles using Ulva lactucaseaweed extract and evaluation of their photocatalyticantibiofilm and insecticidal activityrdquo Journal of Photo-chemistry and Photobiology B Biology vol 178 pp 249ndash2582018

[81] T Chatterjee S Chakraborti P Joshi S P Singh V Guptaand P Chakrabarti ldquo)e effect of zinc oxide nanoparticles onthe structure of the periplasmic domain of the Vibriocholerae ToxR proteinrdquo FEBS Journal vol 277 no 20pp 4184ndash4194 2010

[82] Y H Hsueh W J Ke C T Hsieh K S Lin D Y Tzou andC L Chiang ldquoZnO nanoparticles affect Bacillus subtilis cellgrowth and biofilm formationrdquo PLoS One vol 10 no 6Article ID e0128457 2015

[83] M Divya B Vaseeharan M Abinaya et al ldquoBiopolymergelatin-coated zinc oxide nanoparticles showed high anti-bacterial antibiofilm and anti-angiogenic activityrdquo Journal

of Photochemistry and Photobiology B Biology vol 178pp 211ndash218 2018

[84] I Matai A Sachdev P Dubey S U Kumar B Bhushanand P Gopinath ldquoAntibacterial activity and mechanism ofAg-ZnO nanocomposite on S aureus and GFP-expressingantibiotic resistant E colirdquo Colloids and Surfaces B Bio-interfaces vol 115 pp 359ndash367 2014

[85] S Sarwar S Chakraborti S Bera I A Sheikh K M Hoqueand P Chakrabarti ldquo)e antimicrobial activity of ZnOnanoparticles against Vibrio cholerae variation in re-sponse depends on biotyperdquo Nanomedicine Nanotech-nology Biology and Medicine vol 12 no 6 pp 1499ndash15092016

[86] K Ghule A V Ghule B J Chen and Y C Ling ldquoPrep-aration and characterization of ZnO nanoparticles coatedpaper and its antibacterial activity studyrdquo Green Chemistryvol 8 no 12 pp 1034ndash1041 2006

[87] A Iswarya B Vaseeharan M Anjugam et al ldquoMultipurposeefficacy of ZnO nanoparticles coated by the crustaceanimmune molecule beta-13-glucan binding protein toxicityon HepG2 liver cancer cells and bacterial pathogensrdquo Col-loids and Surfaces B Biointerfaces vol 158 pp 257ndash2692017

[88] M Shaban F Mohamed and S Abdallah ldquoProduction andcharacterization of superhydrophobic and antibacterialcoated fabrics utilizing ZnO nanocatalystrdquo Scientific Reportsvol 8 no 1 p 3925 2018

[89] K Karthik S Dhanuskodi C Gobinath and S SivaramakrishnanldquoMicrowave-assisted synthesis of CdO-ZnO nanocompositeand its antibacterial activity against human pathogensrdquoSpectrochimica Acta Part A Molecular and BiomolecularSpectroscopy vol 139 pp 7ndash12 2015

[90] X Bellanger P Billard R Schneider L Balan and C MerlinldquoStability and toxicity of ZnO quantum dots Interplay be-tween nanoparticles and bacteriardquo Journal of HazardousMaterials vol 283 pp 110ndash116 2015

[91] K Dedkova B Janikova K Matejova et al ldquoPreparationcharacterization and antibacterial properties of ZnOkaolinenanocompositesrdquo Journal of Photochemistry and Photobi-ology B Biology vol 148 pp 113ndash117 2015

[92] M Ramani S Ponnusamy C Muthamizhchelvan J CullenS Krishnamurthy and E Marsili ldquoMorphology-directedsynthesis of ZnO nanostructures and their antibacterialactivityrdquo Colloids and Surfaces B Biointerfaces vol 105pp 24ndash30 2013

[93] S Soren S Kumar S Mishra P K Jena S K Verma andP Parhi ldquoEvaluation of antibacterial and antioxidant po-tential of the zinc oxide nanoparticles synthesized byaqueous and polyol methodrdquo Microbial Pathogenesisvol 119 pp 145ndash151 2018

[94] W Salem D R Leitner F G Zingl et al ldquoAntibacterialactivity of silver and zinc nanoparticles against Vibriocholerae and enterotoxic Escherichia colirdquo InternationalJournal of Medical Microbiology vol 305 no 1 pp 85ndash952015

[95] W Wu T Liu H He et al ldquoRheological and antibacterialperformance of sodium alginatezinc oxide compositecoating for cellulosic paperrdquo Colloids and surfaces B Bio-interfaces vol 167 pp 538ndash543 2018

[96] J Lee K H Choi J Min H J Kim J P Jee and B J ParkldquoFunctionalized ZnO nanoparticles with gallic acid for an-tioxidant and antibacterial activity against methicillin-resistant S aureusrdquo Nanomaterials vol 7 no 11 p 3652017


[97] T Ohira and O Yamamoto ldquoCorrelation between anti-bacterial activity and crystallite size on ceramicsrdquo ChemicalEngineering Science vol 68 no 1 pp 355ndash361 2012

[98] S Sarwar A Ali M Pal and P Chakrabarti ldquoZinc oxidenanoparticles provide anti-cholera activity by disrupting theinteraction of cholera toxin with the human GM1 receptorrdquoJournal of Biological Chemistry vol 292 no 44pp 18303ndash18311 2017

[99] S N Seclen M E Rosas A J Arias and C A MedinaldquoElevated incidence rates of diabetes in Peru report fromPERUDIAB a national urban population-based longitudinalstudyrdquo BMJ Open Diabetes Research and Care vol 5 no 1article e000401 2017

[100] A Nazarizadeh and S Asri-Rezaie ldquoComparative study ofantidiabetic activity and oxidative stress induced by zincoxide nanoparticles and zinc sulfate in diabetic ratsrdquo AAPSPharmSciTech vol 17 no 4 pp 834ndash843 2016

[101] R D Umrani and K M Paknikar ldquoZinc oxide nanoparticlesshow antidiabetic activity in streptozotocin-induced Type 1and 2 diabetic ratsrdquo Nanomedicine vol 9 no 1 pp 89ndash1042014

[102] R Malizia A Scorsone P DrsquoAngelo C Lo Pinto L Pitroloand C Giordano ldquoZinc deficiency and cell-mediated andhumoral autoimmunity of insulin-dependent diabetes inthalassemic subjectsrdquo Journal of Pediatric Endocrinology andMetabolism JPEM vol 11 no 3 pp 981ndash984 1998

[103] R Kitture K Chordiya S Gaware et al ldquoZnO nanoparticles-red sandalwood conjugate a promising anti-diabetic agentrdquoJournal of Nanoscience and Nanotechnology vol 15 no 6pp 4046ndash4051 2015

[104] J Hussein M El-Banna T A Razik and M E El-NaggarldquoBiocompatible zinc oxide nanocrystals stabilized viahydroxyethyl cellulose for mitigation of diabetic complica-tionsrdquo International Journal of Biological Macromoleculesvol 107 pp 748ndash754 2018

[105] A Bayrami S Parvinroo A Habibi-Yangjeh and S RahimPouran ldquoBio-extract-mediated ZnO nanoparticles microwave-assisted synthesis characterization and antidiabetic activityevaluationrdquo Artificial Cells Nanomedicine and Biotechnologyvol 46 no 4 pp 730ndash739 2018

[106] A Amiri R A F Dehkordi M S Heidarnejad andM J Dehkordi ldquoEffect of the zinc oxide nanoparticles andthiamine for the management of diabetes in alloxan-inducedmice a stereological and biochemical studyrdquo Biological TraceElement Research vol 181 no 2 pp 258ndash264 2018

[107] N S Wahba S F Shaban A A Kattaia and S A KandeelldquoEfficacy of zinc oxide nanoparticles in attenuating pan-creatic damage in a rat model of streptozotocin-induceddiabetesrdquo Ultrastructural Pathology vol 40 no 6 pp 358ndash373 2016

[108] S C Asani R D Umrani and K M Paknikar ldquoIn vitrostudies on the pleotropic antidiabetic effects of zinc oxidenanoparticlesrdquo Nanomedicine vol 11 no 13 pp 1671ndash16872016

[109] K Shanker J Naradala G K Mohan G S Kumar andP L Pravallika ldquoA sub-acute oral toxicity analysis andcomparative in vivo anti-diabetic activity of zinc oxidecerium oxide silver nanoparticles andMomordica charantiain streptozotocin-induced diabetic Wistar ratsrdquo RSC Ad-vances vol 7 no 59 pp 37158ndash37167 2017

[110] R M El-Gharbawy A M Emara and S E Abu-Risha ldquoZincoxide nanoparticles and a standard antidiabetic drug restorethe function and structure of beta cells in type-2 diabetesrdquo

Biomedicine and Pharmacotherapy vol 84 pp 810ndash8202016

[111] L Ferrero-Miliani O H Nielsen P S Andersen andS E Girardin ldquoChronic inflammation importance of NOD2and NALP3 in interleukin-1 beta generationrdquo Clinical andExperimental Immunology vol 147 no 2 pp 227ndash235 2006

[112] M Boguniewicz and D Y Leung ldquoAtopic dermatitisa disease of altered skin barrier and immune dysregulationrdquoImmunological Reviews vol 242 no 1 pp 233ndash246 2011

[113] R Jurakic Toncic and B Marinovic ldquo)e role of impairedepidermal barrier function in atopic dermatitisrdquo Acta Der-matovenerologica Croatica ADC vol 24 no 2 pp 95ndash1092016

[114] CWiegand U C Hipler S Boldt J Strehle and UWollinaldquoSkin-protective effects of a zinc oxide-functionalized textileand its relevance for atopic dermatitisrdquo Clinical Cosmeticand Investigational Dermatology vol 2013 pp 115ndash1212013

[115] M Ilves J Palomaki M Vippola et al ldquoTopically appliedZnO nanoparticles suppress allergen induced skin in-flammation but induce vigorous IgE production in the atopicdermatitis mouse modelrdquo Particle and Fibre Toxicologyvol 11 no 1 p 38 2014

[116] P)atoi R G Kerry S Gouda et al ldquoPhoto-mediated greensynthesis of silver and zinc oxide nanoparticles usingaqueous extracts of two mangrove plant species Heritierafomes and Sonneratia apetala and investigation of theirbiomedical applicationsrdquo Journal of Photochemistry andPhotobiology B Biology vol 163 pp 311ndash318 2016

[117] S Yao X Feng J Lu et al ldquoAntibacterial activity and in-flammation inhibition of ZnO nanoparticles embedded TiO2nanotubesrdquo Nanotechnology vol 29 no 24 article 2440032018

[118] J Q Li H Q Chen BWang et al ldquoZnO nanoparticles act assupportive therapy in DSS-induced ulcerative colitis in miceby maintaining gut homeostasis and activating Nrf2 sig-nalingrdquo Scientific Reports vol 7 article 43126 2017

[119] T Xia W Lai M Han M Han X Ma and L ZhangldquoDietary ZnO nanoparticles alters intestinal microbiota andinflammation response in weaned pigletsrdquoOncotarget vol 8no 39 pp 64878ndash64891 2017

[120] P Zhu Z Weng X Li et al ldquoBiomedical applications offunctionalized ZnO nanomaterials from biosensors tobioimagingrdquo Advanced Materials Interfaces vol 3 no 1article 1500494 2016

[121] H M Xiong Y Xu Q G Ren and Y Y Xia ldquoStable aqueousZnOpolymer core-shell nanoparticles with tunable pho-toluminescence and their application in cell imagingrdquoJournal of the American Chemical Society vol 130 no 24pp 7522-7523 2008

[122] H Jiang H Wang and X Wang ldquoFacile and mild prepa-ration of fluorescent ZnO nanosheets and their bioimagingapplicationsrdquo Applied Surface Science vol 257 no 15pp 6991ndash6995 2011

[123] X Tang E S G Choo L Li J Ding and J Xue ldquoSynthesis ofZnO nanoparticles with tunable emission colors and theircell labeling applicationsrdquo Chemistry of Materials vol 22no 11 pp 3383ndash3388 2010

[124] P Zhang and W Liu ldquoZnO QDPMAA-co-PDMAEMAnonviral vector for plasmid DNA delivery and bioimagingrdquoBiomaterials vol 31 no 11 pp 3087ndash3094 2010

[125] W Wu J Shen P Banerjee and S Zhou ldquoA multifuntionalnanoplatform based on responsive fluorescent plasmonic


ZnO-AuPEG hybrid nanogelsrdquo Advanced FunctionalMaterials vol 21 no 15 pp 2830ndash2839 2011

[126] H J Zhang HM Xiong Q G Ren Y Y Xia and J L KongldquoZnOsilica core-shell nanoparticles with remarkable lu-minescence and stability in cell imagingrdquo Journal of Mate-rials Chemistry vol 22 no 26 pp 13159ndash13165 2012

[127] N H Cho T C Cheong J H Min et al ldquoA multifunctionalcorendashshell nanoparticle for dendritic cell-based cancer im-munotherapyrdquo Nature Nanotechnology vol 6 no 10pp 675ndash682 2011

[128] K Matsuyama N Ihsan K Irie K Mishima T Okuyamaand H Muto ldquoBioimaging application of highly luminescentsilica-coated ZnO-nanoparticle quantum dots with biotinrdquoJournal of Colloid and Interface Science vol 399 pp 19ndash252013

[129] H Hong J Shi Y Yang et al ldquoCancer-targeted opticalimaging with fluorescent zinc oxide nanowiresrdquo NanoLetters vol 11 no 9 pp 3744ndash3750 2011


TribologyAdvances in

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Chemistry


Advances inPhysical Chemistry

Hindawiwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2018

Bioinorganic Chemistry and ApplicationsHindawiwwwhindawicom Volume 2018

SpectroscopyInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Medicinal ChemistryInternational Journal of


NanotechnologyHindawiwwwhindawicom Volume 2018

Journal of

Applied ChemistryJournal of



Biochemistry Research International


Enzyme Research


Journal of

SpectroscopyAnalytical ChemistryInternational Journal of


MaterialsJournal of



BioMed Research International Electrochemistry

International Journal of


Na

nom

ate

ria

ls


Journal ofNanomaterials

Submit your manuscripts atwwwhindawicom

less toxic property exhibit excellent biomedical applicationssuch as anticancer drug delivery antibacterial and diabetestreatment anti-inflammation wound healing and bio-imaging [1 10ndash12]

Herein in this review we will summarize the methods ofsynthesis and recent exciting progress on the use of ZnONPsin the biomedical fields

2 Synthesis of ZnO NPs

)e biological activity of nanoparticles depends on factorsincluding surface chemistry size distribution particlemorphology and particle reactivity in solution )ereforethe development of nanoparticles with controlled structuresthat are uniform in size morphology and functionality isessential for various biomedical applications

)e ZnO NPs occurring in a very rich variety of size andshape will provide a wide range of properties )e methodsfor stable ZnO NPs preparation have been widely developedin recent years which mainly include the chemical pre-cipitation method sol-gel method solid-state pyrolyticmethod solution-free mechanochemical method and bio-synthesis method

21 Chemical Precipitation )e most popular method forZnO NPs preparation is chemical precipitation whichusually involves two reaction reagents a highly purifiedzinc forerunner such as zinc acetate (Zn(CH3COO)2middot2H2O) zinc nitrate (Zn(NO3)2) or zinc sul-fate (ZnSO4) and a solution of precipitator such as sodiumhydroxide (NaOH) or ammonium hydroxide (NH3middotH2O)[13] Typically the precipitator is added dropwise to thedissolved zinc precursor until the pH level reached about10 )en completely mix these solutions to get a whiteintermediate of zinc hydroxide Ultimately the sample ofzinc hydroxide (Zn(OH)2) was converted to ZnO aftersintering at high temperature

Controlled parameters in this methodmainly include theconcentration of zinc forerunner and precipitator the molarratio of two reagents and the reaction and calcinationtemperature

Bisht et al synthesized ZnO NPs using the chemicalprecipitation method using Zn(CH3COO)2middot2H2O andNaOH in a molar ratio of 1 5 Intermediate products werecalcined at 200degC for 2 h in a muffle furnace to obtain whitefine powder ZnO with the size of 1867plusmn 22 nm [14]

Bettini et al introduced a simplified precipitation ap-proach in ZnO NPs using ZnSO4 and NaOH solution witha molar ratio of 1 2 which was carried out under vigorousstirring for 12 h at room temperature )e obtained whiteprecipitate was washed several times and separated bycentrifugation [15ndash17] Finally the precipitate (ZnO) wasdried in an oven at 100degC for 6 h )e prepared ZnO NPswith a flake-like structure showed a size distribution about100 nm

)e obtaining of ZnO NPs by the chemical pre-cipitation method is not only simple and easily controlledbut also easy industrialized However due to the surface

effect of nanoparticles the precursor of nanooxide pre-pared by the chemical precipitation method could formagglomerates easily

22 Sol-Gel Method A novel sol-gel synthesis of ZnO NPswas firstly presented by Spanhel and Anderson [18] whichmainly involved three major steps

(1) Preparation of zinc precursor

A sample of Zn(CH3COO)2middot2H2O was dissolved inethanol placed into a distillation apparatus and thenrefluxed for few hours at atmospheric pressure )e solutionwas boiled nearly at 80degC and stirred to obtain the con-densate and hygroscopic reaction mixture

(2) Preparation of ZnO clusters

)e hygroscopic mixture was diluted to ethanolic so-lution with the addition of LiOHmiddotH2O powder )e sus-pension will become transparent with the help of anultrasonic bath )is procedure could accelerate the releaseof OH ions and the reaction at low temperature under airconditions could prevent rapid particle growth and getZnO sols

(3) Crystal growth

Crystal growth is a self-induced procedure occurring atroom temperature But the amount of LiOH which couldstrongly affect the crystals growth rate shape and sizeshould be well controlled LiOH-induced ZnO growth canbe briefly summarized as followsZn CH3COO( 11138572 middot 2H2O + 2LiOH⟶ Zn(OH)2

+ 2CH3COOLi + 2H2O

Zn(OH)2 + 2H2O⟶ Zn(OH)42minus

+ 2H+

Zn(OH)42minuslarrrarr ZnO + H2O + 2OHminus

(1)

Some other alkalis can also be used for ZnO growth forinstance Rani et al synthesized ZnO NPs using NaOHinstead of LiOH and successfully obtained ZnONPs with thelargest crystallite size of 14 nm at 9 pH value [19]

)e sol-gel method is the subject of much interest inview of the simplicity low cost and relatively mild condi-tions of synthesis which could offer a simple route toquantum size ZnO particles

23 Solid-State Pyrolytic Method )e solid-state pyrolyticmethod was first developed by Wang et al with advantagesof low cost and easy operation for the growth of high-qualityZnO nanoparticles [20]

)e typical synthesis procedure is as follows Zn(CH3COO)2middot2H2O and NaHCO3 are mixed at roomtemperature )e mixture is pyrolysed at the reactiontemperature Zn(CH3COO)2middot2H2O is converted intoZnO while NaHCO3 is transformed into CH3COONa andcan be eventually cleaned out with deionized waterSubsequently white ZnO NPs can be obtained via the








CO + O2 CO2uarr














Colon cancer





Hepatocarcinoma






Breast cancer








Lung cancer




[50]

Ovarian cancer


stress [51]

Cervical cancer









Table 1 Continued


Gastric cancer







ZnO NPs

LPO

ROSERK

JNK

p38

NAC

NAC

BAX

SH

Bcl2

Δψm

SH


Caspase 9

Caspase cascade

Apoptosis

Mitochondria

p53p53

NucleusSer15p

NACS S

Cell membrane































Bacteria

ZnO NPsZn2+

H2O2

O2bull

bullOH


























ZnO NPs 40



(MTCC1252)























ZnO NPs mdash mdash


diabetic rats [100]






NPs [109]





















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls










CO + O2 CO2uarr














Colon cancer





Hepatocarcinoma






Breast cancer








Lung cancer




[50]

Ovarian cancer


stress [51]

Cervical cancer









Table 1 Continued


Gastric cancer







ZnO NPs

LPO

ROSERK

JNK

p38

NAC

NAC

BAX

SH

Bcl2

Δψm

SH


Caspase 9

Caspase cascade

Apoptosis

Mitochondria

p53p53

NucleusSer15p

NACS S

Cell membrane































Bacteria

ZnO NPsZn2+

H2O2

O2bull

bullOH


























ZnO NPs 40



(MTCC1252)























ZnO NPs mdash mdash


diabetic rats [100]






NPs [109]





















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls






Colon cancer





Hepatocarcinoma






Breast cancer








Lung cancer




[50]

Ovarian cancer


stress [51]

Cervical cancer









Table 1 Continued


Gastric cancer







ZnO NPs

LPO

ROSERK

JNK

p38

NAC

NAC

BAX

SH

Bcl2

Δψm

SH


Caspase 9

Caspase cascade

Apoptosis

Mitochondria

p53p53

NucleusSer15p

NACS S

Cell membrane































Bacteria

ZnO NPsZn2+

H2O2

O2bull

bullOH


























ZnO NPs 40



(MTCC1252)























ZnO NPs mdash mdash


diabetic rats [100]






NPs [109]





















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls








Table 1 Continued


Gastric cancer







ZnO NPs

LPO

ROSERK

JNK

p38

NAC

NAC

BAX

SH

Bcl2

Δψm

SH


Caspase 9

Caspase cascade

Apoptosis

Mitochondria

p53p53

NucleusSer15p

NACS S

Cell membrane































Bacteria

ZnO NPsZn2+

H2O2

O2bull

bullOH


























ZnO NPs 40



(MTCC1252)























ZnO NPs mdash mdash


diabetic rats [100]






NPs [109]





















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls
































Bacteria

ZnO NPsZn2+

H2O2

O2bull

bullOH


























ZnO NPs 40



(MTCC1252)























ZnO NPs mdash mdash


diabetic rats [100]






NPs [109]





















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls





















Bacteria

ZnO NPsZn2+

H2O2

O2bull

bullOH


























ZnO NPs 40



(MTCC1252)























ZnO NPs mdash mdash


diabetic rats [100]






NPs [109]





















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls











Bacteria

ZnO NPsZn2+

H2O2

O2bull

bullOH


























ZnO NPs 40



(MTCC1252)























ZnO NPs mdash mdash


diabetic rats [100]






NPs [109]





















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls



























ZnO NPs 40



(MTCC1252)























ZnO NPs mdash mdash


diabetic rats [100]






NPs [109]





















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls


















ZnO NPs mdash mdash


diabetic rats [100]






NPs [109]





















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls















ZnO NPs mdash


model of AD [115]









Ag NPs (691) [116]




ZnO NPs mdash








ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

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ZnO-1

20 nm

ZnO-2

20 μm 20 μm

20 μm 20 μm






Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls







Acknowledgments


References


























solutions [123]




vitro [129]




































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls






































































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls









































































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls











































































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls














































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls















Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls









Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls




Documents

TheAdvancingofZincOxideNanoparticlesfor BiomedicalApplicationsdownloads.hindawi.com/journals/bca/2018/1062562.pdf · 2019-07-30 · adipocytes, which showed that ZnO NPs could be