as targeted drug delivery systems Standpoint on the priority of TNTs andCNTs feature

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feature

Standpoint on the priority of TNTs and CNTs as targeted drug delivery systems

YasminRanjous,GézaRegdonJr.,KláraPintye-HódiandTamásSovány,t.sovany@pharm.u-szeged.hu

Conventional drug delivery systems have limitations according to their toxicity and poor solubility, bioavailability, stability, and pharmacokinetics (PK). Here, we highlight the importance of

functionalized titanate nanotubes (TNTs) as targeted drug delivery systems. We discuss the differences in the physicochemical properties of TNTs and carbon nanotubes (CNTs) and focus on the use of

functionalization to improve their characteristics. TNTs are promising materials for drug delivery systems because of their superb properties compared with CNTs, such as their processability, wettability, and biocompatibility. Functionalization improves nanoparticles (NPs) via their surface modification and enables them to achieve the targeted therapy.

Introduction

Conventionaldrugsoftenhavepoorsolubility,PK, biopharmaceuticalproperties,andstabilityor causetoxicity[1].Bycontrast,nanotechnology- baseddrugdeliverysystemscanimprovethe solubility,absorption,permeation,retentiontime, andbioavailabilityofdrugmoleculesintarget tissues,aswellasimprovingtheirstabilityand, therefore,enhancingtheshelf-lifeandaccept- abilityofdrugsbyincreasingeithertheiruptake efficacyorpatientcompliance[2].

Nanosizeddeliverysystemscanbeinternal- izedbycellsmoreeffectivelycomparedwith micro-sizedparticles.Inaddition,NPscanbe formulatedinvariousshapes,sizes,andcom- positions,andcanbemodifiedphysicochemi- callyandfunctionallytoobtainspecific propertiesdependingontherequirementsof boththedrugmoleculeandthetargetedorgan [1].Nanotubeshaveanidealinnerdiameterof 5–6nmforloadingwithlargebiological

molecules,withasurfaceareafivetimeshigher thanthatofotherNPs.Furthermore,cellinter- nalizationishigherinthecaseoftubularNPs comparedwiththeirsphericalcounterparts(H.P.

Kulkarni,PhDthesis,UniversityofNorthCarolina atChapelHill,2008).

Thefirstnanotubestobediscoveredwere CNTs.Thefirstsynthesismethodwas

describedbyLijimain1991,whereasTNTswere firstsynthesizedbyHoyerviatemplate-assisted synthesisin1996(reviewedinRef.[3]).

Nevertheless,overthepastdecades, numeroussynthesisrouteswithvarious advantagesanddisadvantageshavebeen developed(Tables1and2).

Structureandclassification

AlthoughbothCNTsandTNTshaveatubular structure,therearegeneraldifferencesintheir structure.CNTsareallotropesofcarbonmade fromgraphene/graphiteandarerolledupinto

concentriccylinderswithvariouswallnumbers, onwhichtheirclassificationisbased.

Single-walledCNTs(SWNTs)haveadiameter of1nmandlengthuptocentimeters,prepared byrollingasinglegraphenesheettoforma cylinder.TheconductingpropertiesofSWNTs dependonthewrappingnature[10],whichis representedbychiralvectors(n,m).Azigzag structureisobtainedwhenm=0,anarmchairis obtainedwhenn=m,andachiralstructureis obtainedwhenmliesbetweenthezigzagand thearmchairstructurevalues.

Althoughdouble-walledCNTs(DWNTs)gen- erallyhavethesamemorphologyandproperties asSWNTs[11],theyalsoexhibitseveraladvan- tages,suchassignificantlyimprovedresistance tochemicals,thesamethermalandelectrical stabilityasmultiwalledCNTs(MWNTs),butthe sameflexibilityasSWNTs[12].

MWNTshaveadiameterfrom2nmto100nm andalengthoftensofmicrons.Theyhavetwo FeaturesPERSPECTIVE

1704 1359-6446/ã2019ElsevierLtd.Allrightsreserved.

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structuralmodels:the‘RussianDoll’model, whengraphitesheetsareorderedinconcentric cylinders(Fig.1),andthe‘Parchment’model [11],whenasinglesheetofgraphiteisrolledin arounditself.Thelayershavedifferentchiralities withinconsiderableinterlayerelectronic coupling,andcanshiftrandomlybetween metallicandsemiconductingvarieties.Themain advantageofMWNTsisthattheirstiffnessis higherthanthatofSWNTs,especiallyduring compression[12].Thelength-to-diameterratio ofMWNTsis>1000000giventhattheyare nanometersindiameterandseveralmillimeters inlength[3].

Bycontrast,TNTsarerolledupintoaspiral (Fig.1).withaninnercavityof~4nmandhavean amorphousorcrystallinestructuredepending onthespecificelectrochemicalparameters[8].

TheTNTsobtainedafteranodizationareamor- phousandnotphotoactive,whereashigh temperatureannealingconvertsamorphous TNTsintoacrystallineform(anataseorrutile) and,hence,broadenstheirapplicationrange.

TNTsareclassifiedaccordingtothesynthesis parametersusedtoprepareTNTs,suchaswith template-assistedsynthesis,hydrothermal treatments,orelectrochemicaltreatments(H.P.

Kulkarni,PhDthesis,UniversityofNorthCarolina atChapelHill,2008),whichcausevariationsin theirphysicalfeatures(e.g.,length,andinner diameterandouterdiameterdistributions).

Comparisonofthephysicochemical properties

CNTshavehighlyhydrophobicsurfacesbecause theypreservetheapolarcharacteristicsofnative graphene/graphitenanosheetsandare insolubleinaqueoussolutions[13],wherethe surfacechargeofCNTsisafunctionofthepHof thesolution[14].However,theirsolubilitycanbe enhancedbyfunctionalization[12],whichcan alsofacilitatetheirmovementinthebodyand reduce both the blockage of body organ

pathwaysandtoxicity,partiallybyhindering theaccumulationofhighlyapolarmoleculesin tissue.Nevertheless,thegradeoftoxicity(invivo andinvitro)isdeterminedbydiversefactors, suchassize,shape,purity,surfacechemistry, andtheexistenceoftransitionmetalcatalysts.

Furthermore,itappearsthattheeffectofCNTs onorgansisrelatedtotheadministrationroute used[15].Intravenous,oral,anddermalad- ministrationofCNTscancauseonlymild symptoms,whereasinhalationcanresultin severeinflammationandtoxicitytothe respiratorysystem.Bycontrast,anotherstudy reportedthatnosignificantlunginflammation ortissuedamagewasobservedfollowingdirect inhalationofCNTs.

TABLE1

ComparisonofCNTpreparationmethods

Method Product Advantages Disadvantages Refs

Arcdischarge SWNTs0.6–1.4nmindiameteror;

MWNTswith1–3nminnerand 10nmouterdiameter

Upscalableforvolumeproduction;

nanotubediameterdistributioncan vary;yieldupto90%

Solidgraphitesourcerequired;

requireshightemperature;SWNTs onlyobtainedwithuseofmetal

[4]

Laserablation SWNTs1–2nmindiameterand5–

20m^m^long,^or^fullerenes High-qualitynanotubes;yieldupto 70%

Solidgraphitesourcerequired;not suitableformanufactureofMWNTs becauseofshortlength

[5]

Chemicalvapordeposition(CVD) SWNTs0.6–4nmindiameteror MWNTs10–240nmindiameter

Distinguishedconfigurationand positionalcontrol

Two-stepmethod;typicalyieldis 30%;oftenriddledwithdefects

[6]

Plasma-enhancedCVD SWNTsorMWNTs Nosolidgraphitesourcerequired Complicatedprocess [6]

AlcoholcatalyticCVD SWNTs1nmindiameter SWNTsproducedonlargescaleand atlowcost

Obstaclesincreatinghigh-purity SWNTs

[6]

HydrothermalMethods MWNTswith10–100nminnerand 50–150nmouterdiameter nanorods,nanowires,nanobelts andnano-onions

Startingmaterialsstableatambient temperature;lowtemperature (150–180C)required;no hydrocarbonorcarriergasrequired

[7]

TABLE2

ComparisonofTNTpreparationmethods

Method Advantages Disadvantages Refs

Electrochemicaltreatment Self-organizedTNTlayerswithlarge(~100nm) diameter;suitableforsurfacemodificationofTi implants

Lengthvaries(2–101m^m);^not^suitable^for^many

biomedicalapplicationsbecauseofsizeandpotential clearancebyreticuloendothelialsystem

[8]

Template-assistedsynthesis Variable(50–400nm)diameterbasedontemplate poresize

[9]

Hydrothermaltreatment Small(5–10nm)diameterand100–1000nmlength;

variabledimensions,porosityandspecificsurface dependingontemperature,NaOHconcentration, sonicationandacidicpost-treatment

StronglyagglomeratedTNTs,whichneedtobe dispersedbeforebioapplication;nanosheetsresultas byproducts(~10%ofbatch)

[8]

TNT MWCNT

Drug Discovery Today

FIGURE1

Schematicrepresentationofthestructuraldifferencesbetweentitanatenanotubes(TNTs)and multiwalledcarbonnanotubes(MWCNTs).

FeaturesPERSPECTIVE

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Bycontrast,TNTsdisplaystronghydrophilicity becauseoftheirpartiallyhydroxylatedsurface, whichcausesanegative

z

^-potential^(after

washinguntilpH=6)that,whencombinedwith hydrogenbonds,causessuperiorwettability [16]butoftenleadstotheagglomerationofthe particles, especially in dry forms [8]. Their hydrophilicityisalsosupportedbythe capillaryeffect,resultinginthequickpenetra- tionofwaterdropletsintothetubepores,and bytheircrystallinity,giventhattheamorphous, mixedcrystallinephaseshowshighpolarity becauseoftheO–Ti–Obondsandtotheex- tensivepresenceofhydroxylgroupsontheTNT surface.Furthermore,thestructureofTNTsalso influencesthecontactangle,whichdecreases withincreasesinbothtubeandporediameters andwithincreasinganodizationvoltageor thermaltreatmentupto450C;however,be- yond450C,theirhydrophilicitydecreasesbe- causeofthedetachmentofhydroxylgroups fromthesurface[17].Thehighsurfaceenergy andpolaritycausesgoodwettabilityand,hence, improvedcelladhesion.Therefore,TNTsshowed extremelygoodbiocompatibility.Bonecellad- hesionanddifferentiationwereimprovedbythe useofTNT-coveredimplantsandwereprovento bebetterthanthosewithapureTisurface.TNTs werealsonontoxicwheninternalizedbycells [18–20];thus,theyappeartohavegoodappli- cabilityfortherapeuticuseintheclinic[21].

Despitetheirdifferentsurfacecharacteristics, CNTsandTNTsexhibitconsiderablesimilarities regardingtheirimpressivemechanical,electrical,andopticalproperties.Nanotubularstruc- turesusuallyhavegoodmechanicalproperties.

InCNTs,thecovalentbondsbetweencarbon atomsleadtohightensilestrength(upto63 GPa)andYoung’smodulusofelasticity(1–1.8 TPadependingonthediameterandthechirality ofthetube)[3].Therefore,SWNTsarestronger thansteelby10to100timesperunitweight.By contrast,MWNTshavelowerYoung’smodulus valuesthanSWNTsbecausestressisonlysup- portedbytheoutergraphiteshelfonaccountof weakintertubecohesion.Similarly,TNTsexhibit high,butonegradelowerYoung’smodulus (230GPa)andtensilestrength(680MPa)com- paredwithSWNTs.Nevertheless,thesevalues stillreflectimpressivemechanicalproperties, supportedbytheresultsofSiposetal.,who reportedthatTNTsandtheircompositesformed withvariousdrugsshowedsupremeflowability, compressibility,andcompactibilitycompared withcrystallineAPIs,thusprovingtheirsuperior processability[22–24].Intermsoftheirelectrical behavior,CNTsdisplaysemiconductingor metallicresistance,capacitance,andinductance

propertiesbecauseoftheirelectronicstructure andsymmetryofgraphene[12].SWNTscanbe eithersemiconductingormetallic,whereas MWNTsaresemiconducting.Theelectrical conductivityofself-organizedTNTsisbasedon theircrystallinestructureandistunablewiththe annealingtemperature,becausewhenthe amorphousmaterialconvertsintoanataseat 300C,itresultsinsignificantlyhighercon- ductivity,whereastheconversionofanatase intothemoreresistiverutileabove500C reducestheconductivity[25].Intermsoftheir opticalproperties,bothCNTsandTNTsshow opticalabsorbance:theabsorbanceofCNTsisin near-infrared(NIR)zone[12],whereasTNTs displaywiderphotoabsorptionproperties,al- thoughnotasgoodasTiO2NPs.However,when rareearthions(Pr³¹,Er³¹,Nd³¹,andYb³¹)were intercalatedintoTNTs,higherphotolumines- cenceemissionwasobservedcomparedwith pristineNa-TNTs[26].Overall,theseremarkable propertiesmakeCNTsandTNTsanidealtarget forarangeofdiagnostic,biomedical,or pharmaceuticalapplications.

Applications

Thehighbindingcapacityanduniquephysi- cochemical,especiallyelectricalpropertiesof nanotubescanbewellutilizedinspecificmol- eculerecognitionandotherdiagnosticappli- cations.CNTscanbeusedasbiosensorsto diagnosediseases,recordthepulseandtem- peratureofapatient,andmeasurebloodglu- cose,orotherbiomolecules,suchasH₂O₂, organophosphatepesticides,orcancermarkers, indiagnosisandtreatment[12,27–29].Inaddi- tion,theirgoodbiocompatibilityandmechani- calpropertiesalsomakenanotubularstructures suitablefortissue-engineeringapplications.

CNTscanimprovethemechanicalstrengthof implantedcathetersand,hence,reduce thrombusformationincardiovascularsurgeries [12].CNT-coatedpolyurethanehashighinter- connectedporosity,bioactivity,andnanostruc- turedsurfacetopography.Thus,CNTscanbe usedasbioactivescaffoldsinbonetissueen- gineeringandprovidenewproperties,suchas electricalconductivity,tothesescaffolds[30],or, whenfilledwithcalcium,theycanbeused directlyasabonesubstitute,withimproved mechanicalpropertiesbecauseoftheirhigh tensilestrength[3].Consequently,theycanhelp indirectingcellgrowth[12].Correspondingly, TNTcoatingsonscaffoldsreinforcecellgrowth onthebiodegradablephotopolymerscaffolds [31]andalsopromoteboneformationbyhas- teningosteoblastgrowthby300–400%com- paredwithnon-anodizedTisurfaces[32].This

effectwasfurtherimprovedwhenTNTswere coatedwithbiocompatiblepolymerfilmscom- prisingchitosanandpoly(lactic-co-glycolicacid), whensuperiorosteoblastadhesionandcell proliferationwereachieved,comparedwith uncoatedTNTs[33].

Giventheiruniquecharacteristics,suchas theirhollowmonolithicstructure,nanoneedle shape,considerablemolecule-bindingcapacity andversatilebindingmechanisms,nanotubes arealsoidealcarriersinotherbiomedicaland pharmaceuticalapplications.Twodifferent methodsexistforbinding:wrapping,when drugsandbiologicalmoleculesareattachedto thesurfacethroughfunctionalgroups;andfill- ing,whendrugsandbiologicalmoleculesare loadedinsideCNTs[34].

CNTsdisplayimmunogenicityanddevised antibodyresponseslinkedtoviralproteinVP1of foot-and-mouthdiseasevirus(FMDV),which couldbeutilizedforthestimulationofthe immunesystem[3].ThehighRNAbindingand internalizationcapacityalsomakeCNTssuitable forcytoplasmorcellcoretargetingandvaluable asvectorstotransfergenesanddrugsintocells tocurecancerandvariousgeneticdisorders [35].However,SWNTsaremoreusefulcompared withMWNTsbecauseoftheir1Dstructure, efficientdrug-loadingcapacity,andlargesur- facearea[36].CNTsconjugatedtosmallinter- fering(si)RNAmoleculesweresuccessfulin silencingtheexpressionofCD4cellsurface receptorsandCXCR4co-receptors,thusinhi- bitingtheinfectionofTcellsbyHIV[37].Drug- embeddedCNTscanalsobeutilizedtokill virusesinviralulcerswithoutantibodypro- ductionagainstthedrug,becauseviruses presentnointrinsicimmunogenicityforCNTs [38].CNTscancarrystreptavidinandcyto- chromeCintothecellcytoplasmviatheen- docytosispathway[12]andshowedhigh selectivitytokillcancercellsafterinternaliza- tion,achievedbyhyperthermiabecauseoftheir thermalconductivity[39].However,MWCTsare moresuitablethanareSWCTsforthermalcancer treatmentgiventhatMWNTsabsorbNIRradia- tionfasterthandoSWNTs[40].

Nevertheless,CNTscanbeappliedfordrug deliveryandtargetingwithoutexternalstimu- lationbecausetheSWCNT-anticancerdrug complexincreasesbloodcirculationtime,en- hancingpermeabilityandtheretentioneffectby tumorcells[41],asshownbythesuccessful deliveryofamphotericinB[42],thesuccessful deliveryandretentionofpolyphosphazene platinumtothebrain[43],thesuccessfuloral administrationoferythropoietin(EPO)[43]and theslowreleaseofcisplatininanaqueous FeaturesPERSPECTIVE

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environmenttoterminatethegrowthofhuman lungcancercells[44].

Basedontheirphysicochemicalproperties, TNTsofferfeweropportunitiestoattachdrugs orothermolecules;however,basedontheir uniqueproperties,suchasbiocompatibility, mechanicalstrength,andchemicalresistivity, theyareproposedtobeidealmaterialsforthe developmentofvariousmedicalimplantsand devices.Thus,TNTshavesofarbeenapplied mainlyindentistry,orthopedics,andcardio- vascularsurgery[45].

FunctionalizationofTNTsandCNTs Functionalizationistheattachingofappropriate moleculestothenanostructuresurfaceto renderthemsolubleinwater,reducetoxicity, increasebiocompatibility[46],achievetargeted drugdelivery,obtainselectivebindingtothe desiredepitope,achievecontrolleddrugrelease, facilitatecellularinternalization,enhancebio- distribution,andimprovebiofluidcirculation.

Manytypesoffunctionalizationmoleculehave beenused,suchaspolyethyleneglycol(PEG),

polyvinylpyrrolidone(PVP),cellulose, polypeptides,dextran,andsilica[2].

CNTscanbefunctionalizedcovalentlyor noncovalentlyonthetipsandsidewalls,al- thoughCNTtipshaveahigherfunctionaliza- tionaffinitycomparedwiththesidewalls[46].

Noncovalentfunctionalization,includingVan derWaalsinteractions,

p

–

p

interactions,and hydrophobicinteractions,causesminimal damagetotheCNTsurfaceandmaintainsthe aromaticstructureand,consequently,the electroniccharacteristicsofCNTs.However,the disadvantageisthatthiskindoffunctionali- zationisnotappropriatefortargeteddrug deliveryapplicationsbecauseoftheweak forcesformed[47].Bycontrast,covalentfunc- tionalizationofCNTscanbeachievedviaoxi- dizingthembystrongacids,suchasnitricand sulfuricacids[48].Hence,theformingofcar- boxylicacidgroupsbecauseofthehighneg- ativechargeincreasesthehydrophilicity,water solubility,andbiocompatibilityofCNTs[49].By contrast,thedisadvantageisthatcovalent functionalizationdamagesCNTsidewallsand,

thus,CNTscannotbeusedinsomeapplica- tions,suchasimaging[37].Nevertheless,the presenceofcarboxylicandotheroxygen- containinggroupsonthesurfaceofCNTsalso allowsthecovalentattachmentoffunctional molecules[50].Thecovalentsurfacefunctio- nalizationofCNTswithamine-terminatedPEG stabilizesCNTdispersionsinvariousmediaand reducesdeleteriouseffectsonculturedcells [51],andoxidationdebris(i.e.,thebreaking CNTsduringoxidationoroxidizing

carbonaceousnontubularstructuresinpristine CNTsamples).

Similarly,thesurfacecharacteristics,suchas thenegativechargeatphysiologicalpHcaused bythepresenceofhydroxylgroupsontheir surfaceabovetheirisoelectricpoint(pH3.7), enableTNTstoreactwithavarietyoffunctional molecules[52].ThefunctionalizationofTNTs improvestheirstabilityforvectorization applicationsandenablesthemtocarry therapeuticmolecules[53].Tables3and4detail methodsforthefunctionalizationofCNTsand TNTs,respectively.

TABLE3

FunctionalizationpossibilitiesofCNTs

Reagent(s) Aimoffunctionalization/grafting Refs

Nitricacid(HNO3) CarboxylicgroupscoveredMWNTs;increasesolubility [54]

NH2(CH2CH2O)2–CH2CH2NH2 NH2coveringofMWNTs;increasesolubility;decreaseaggregation;decreasecytotoxic effects

[55]

Second-generationpoly(amidoamine)dendrimer (G2-PAMAM)

IncreasesurfacebindingabilityofDNAprobebysupplyinglargenumberofaminogroups [56]

Folatemoiety Selectivedestructionofcancercellslabeledwithfolatereceptortumormarkers;

NIR-triggeredcelldeathwithoutharmingreceptor-freenormalcells

[39]

Phospholipid-PEG2000-NH2 PhotothermalcancertreatmentinmicebyNIRirradiation [51]

HNO3andsalicylaldehyde Reducereactionstepnumberandreactiontime [50]

HNO3andH2SO4mixture;1-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride;N-hydroxysuccinimide;

P-glycoproteinantibody

Specificrecognitionofmultidrug-resistanthumanleukemiacells(K562R) [57]

TABLE4

FunctionalizationpossibilitiesofTNTs

Reagent(s) Aimoffunctionalization/grafting Res

Dopamine;Trisbuffer;bone morphogeneticprotein2(BMP2)

Enhanceboneosseointegration [58]

3-isocyanatopropyltriethoxy;PEG;

polyethyleneimine(PEI)

EnhanceTNTdispersioninwaterandreactivity [53]

Allyltriethoxysilane;propyltriethoxysilane Formstablesuspensionsintetrahydrofuran(THF) [59]

Antimicrobialpeptides(HHC-36) Preventformationofbiofilms(basedonbactericideandbacteriostaticeffect) [60]

3-aminopropyltriethoxysilane;RGD peptide

Promoteinitialattachmentandproliferationofhumanmesenchymalstemcells(hMSCs) [61]

KRSR Increaseosteogenicdifferentiationandpre-osteoblastadhesionandspreadonTNTsurface [62]

N,N-carbonyldiimidazole;11-hydroxy- undecylphosphonicacid;EGFandBMP2

growthfactors

IncreasingnumberandactivityofMSCs [63]

Gelatin-stabilizedgoldNPs ImproveMC3T3-E1osteoblastcelladhesionandpropagation(achieved) [64]

Chitosan Achievesustainedreleaseofloadeddrug(seleniumorquercetin)fromTNTs [65,66]

FeaturesPERSPECTIVE

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Concludingremarks

Drugdeliverydevicesbasedonnanotubular structuresareidealformoderntheranostic applicationsbecauseoftheiradvantageous properties.However,theycanbeartheriskof toxicityattributable totheirsize,surface charge,chemicalcomposition,chemicalre- activity,chemicalstructure,crystalstructure, shape,solubility,anddegreeofagglomera- tion.Moreover,nanomaterialscancauseoxi- dativestressanddamagephagocytosisinside thecells,reducecellviability,andsuppresscell proliferationbyproducingreactiveoxygen speciesorremaininginthebodybecauseof theirabilitytoevadethereticuloendothelial system.

Despitemanypromisingresultsandnumer- ousadvantages,pristineCNTsareinsolublein waterandmostsolvents;thus,theycannotbe usedimmediatelyinbiomedicalapplications.

Furthermore,theybearaconsiderableriskof toxicityandcarcinogenicitybecausetheyac- cumulateinthehumanbodybecauseoftheir stronglyhydrophobicnatureandresidualmetal catalysts,whichincreasestheirabilitytopro- duceO² anions,lipidperoxidation,orphysical blockagegeneratedfromagglomerationathigh doses,giventhatCNTsalsohaveastrong electrostaticattraction.

Bycontrast,TNTshaveexhibitedpromising toxicologicalprofilesandgoodbiocompatibility innumerousstudiesandavitalaffinityforbone celladhesionanddifferentiation,whichallows theiruseindentistry,orthopedics,andcardio- vascularsurgery.Therefore,andasaresultof theirtubularstructure,CNT-similarchemical resistivity,mechanicalstrength,andelectron mobility,TNTsmightbepromisingalternatives fordevelopingmedicalimplantsanddevices.

Nevertheless,despitetheseadvantages,TNTs, especiallyhydrothermallysynthetizedfreeTNTs, arepoorlystudiedintermsoftheiruseindrug deliveryapplications,possiblybecauseoftheir hydrophilicnature,whichimprovestheir biocompatibilityanddecreasestheriskofad- verseeffects,butalsoactsnegativelyontheir absorptionandcellinternalizationproperties.

Thus,functionalizationmightbekeytoim- provingtheirapplicability,giventhattherange ofpossibilitiesisalmostaswideasforCNTs.

NoncovalentbindingsbasedonvanderWaals forces,hydrogenbondsor

p

–

p

interactionsare easilyachievable,whichmaintainthearomatic structureandelectroniccharacteristics;

obtainingcovalentfunctionalizationwithether- oresterificationofthefreesurface-OHgroupsis alsopossible.Withtheselectionoftheappro- priatefunctionalgroups,thesurfaceproperties

and,therefore,theirabsorptionand internalizationcapacitycouldbeimproved withouttheconsiderableelevationoftheriskof toxicity.Furthermore,theirsimilarmechanical, electrical,andopticalparameterscouldprovide thesamelevelofprocessabilityandrangefor externalstimuli-adjustedtargetingpossibilities asCNTs.

Intermsoftheirlowtoxicityandadvanta- geousphysicochemicalproperties,thefurther investigation,use,andapplicationofhydro- thermallysynthetizedTNTsisrecommendedfor thedevelopmentofnewadvanceddrug deliverysystems.

References

1 Suri,S.S.etal.(2007)Nanotechnology-baseddrug deliverysystems.J.Occup.Med.Toxicol.2,16 2 Raliya,R.etal.(2016)Perspectiveonnanoparticle

technologyforbiomedicaluse.Curr.Pharma.Des.22, 2481–2490

3 Mahajan,D.(2017)Carbonnanotubes:areviewon synthesis,electricalandmechanicalpropertiesand applications.AsianJ.Appl.Sci.Technol.1,15–20 4 Ebbesen,T.andAjayan,P.(1992)Large-scalesynthesis

ofcarbonnanotubes.Nature358,220

5 Sivaram,A.(2004)Laserablationprocessforsingle- walledcarbonnanotubeproduction.J.Nanosci.

Nanotechnol.4,317–325

6 Khurshed,A.etal.(2016)Synthesisofcarbon nanotubesbycatalyticchemicalvapourdeposition:a reviewoncarbonsources,catalystsandsubstrates.

Mater.Sci.Semicond.Process.41,67–82 7 Gogotsi,Y.andLibera,J.A.(2000)Hydrothermal

synthesisofmultiwallcarbonnanotubes.J.Mater.Res.

15,2591–2594

8 Boudon,J.etal.(2014)Titanatenanotubesasa versatileplatformfornanomedicine.InNanomedicine (Seifalian,A.,ed.),pp.403–429,OneCentralPress, Altricham,UK

9 Rørvik,P.M.etal.(2009)Template-assistedsynthesisof PbTiO3nanotubes.J.Eur.Ceram.Soc.29,2575–2579 10Odom,T.W.etal.(1998)Atomicstructureand

electronicpropertiesofsingle-walledcarbon nanotubes.Nature391,62–64

11Mamedov,A.A.etal.(2002)Moleculardesignofstrong single-wallcarbonnanotube/polyelectrolyte multilayercomposites.Nat.Mater.1,190–194 12Kumar,S.P.etal.(2012)Pharmaceuticalapplicationof

carbonnanotube-mediateddrugdeliverysystem.Int.J.

Pharm.Sci.Nanotechnol.5,1685–1696

13Liu,Z.etal.(2009)Carbonnanotubesinbiologyand medicine:invitroandinvivodetection,imagingand drugdelivery.NanoRes.2,85–120

14Dezfoli,A.R.A.etal.(2013)Structuralpropertiesof wateraroundunchargedandchargedcarbon nanotubes.Kor.J.Chem.Eng.30,693–699

15Smart,S.K.etal.(2006)Thebiocompatibilityofcarbon nanotubes.Carbon44,1034–1047

16Wang,F.etal.(2013)Bioinspiredmicro/nano fabricationondentalimplant–boneinterface.Appl.

Surf.Sci.265,480–488

17Indira,K.etal.(2015)AreviewonTiO2nanotubes:

influenceofanodizationparameters,formation mechanism,properties,corrosionbehavior,and biomedicalapplications.J.Bio.Tribo.Corr.1,28

18Papa,A.-L.etal.(2012)Titanatenanotubes:towardsa novelandsafernanovectorforcardiomyocytes.

Nanotoxicology7,1131–1142

19Mirjolet,C.etal.(2013)Theradiosensitizationeffectof titanatenanotubesasanewtoolinradiationtherapy forglioblastoma:aproof-of-concept.Radiother.Oncol.

108,136–142

20Fenyvesi,F.etal.(2014)Investigationofthecytotoxic effectsoftitanatenanotubesonCaco-2cells.AAPS PharmSciTech15,858–861

21Wang,Q.etal.(2016)TiO2nanotubeplatformsfor smartdrugdelivery:areview.Int.J.Nanomedicine11, 4819–4834

22Matsuno,R.etal.(2004)Polystyrene-andpoly(3- vinylpyridine)-graftedmagnetitenanoparticles preparedthroughsurface-initiatednitroxide-mediated radicalpolymerization.Macromolecules37,2203–2209 23Sipos,B.etal.(2017)Comparativestudyonthe

rheologicalpropertiesandtablettabilityofvariousAPIs andtheircompositeswithtitanatenanotubes.Powder Technol.321,419–427

24Sipos,B.etal.(2018)Investigationofthe compressibilityandcompactibilityoftitanate nanotube–APIcomposites.Materials11,2582 25Tighineanu,A.etal.(2010)ConductivityofTiO2

nanotubes:Influenceofannealingtimeand temperature.Chem.Phys.Lett.494,260–263 26Marques,T.M.F.etal.(2017)Photoluminescence

enhancementoftitanatenanotubesbyinsertionof rareearthionsintheirinterlayerspaces.J.Nanomater.

2017,3809807

27Bandaru,P.R.(2007)Electricalpropertiesand applicationsofcarbonnanotubestructures.J.Nanosci.

Nanotechnol.7,1239–1267

28Zhang,M.andGorski,W.(2005)Electrochemical sensingplatformbasedonthecarbonnanotubes/

redoxmediators-biopolymersystem.ACCChem.Res.

127,2058–2059

29Liu,G.andLin,Y.(2006)Biosensorbasedonself- assemblingacetylcholinesteraseoncarbonnanotubes forflowinjection/amperometricdetectionof organophosphatepesticidesandnerveagents.Anal.

Chem.78,835–843

30Harrison,B.S.andAtala,A.(2007)Carbonnanotube applicationsfortissueengineering.Biomaterials28, 344–353

31Minagar,S.etal.(2013)Cellresponseofanodized nanotubesontitaniumandtitaniumalloys.J.Biomed.

Mater.Res.A101,2726–2739

32Yamamoto,A.etal.(1998)Anewtechniquefordirect measurementoftheshearforcenecessarytodetacha cellfromamaterial.Biomaterials19,871–879 33Gulati,K.etal.(2012)Biocompatiblepolymercoating

oftitaniananotubearraysforimproveddrugelution andosteoblastadhesion.ActaBiomater.8,449–456 34Sahoo,N.G.etal.(2011)Functionalizedcarbon

nanomaterialsasnanocarriersforloadinganddelivery ofapoorlywater-solubleanticancerdrug:a comparativestudy.Chem.Commun.47,5235–5237 35Kam,N.W.S.etal.(2005)Functionalizationofcarbon

nanotubesviacleavabledisulfidebondsforefficient intracellulardeliveryofsiRNAandpotentgene silencing.J.Am.Chem.Soc.127,12492–12493 36Madani,S.Y.etal.(2011)Aneweraofcancertreatment:

carbonnanotubesasdrugdeliverytools.Int.J.

Nanomedicine6,2963–2979

37Liu,Z.etal.(2009)Preparationofcarbonnanotube bioconjugatesforbiomedicalapplications.Nat.Protoc.

4,1372–1381 FeaturesPERSPECTIVE

(6)

38Pantarotto,D.etal.(2003)Immunizationwithpeptide- functionalizedcarbonnanotubesenhancesvirus- specificneutralizingantibodyresponses.Chem.Biol.

10,961–966

39Kam,N.W.S.etal.(2005)Carbonnanotubesas multifunctionalbiologicaltransportersandnear- infraredagentsforselectivecancercelldestruction.

Proc.Natl.Acad.Sci.U.S.A.102,11600–11605 40Hirsch,L.R.etal.(2003)Nanoshell-mediatednear-

infraredthermaltherapyoftumorsundermagnetic resonanceguidance.Proc.Natl.Acad.Sci.U.S.A.100, 13549–13554

41Liu,Z.etal.(2008)Drugdeliverywithcarbon nanotubesforinvivocancertreatment.CancerRes.68, 6652–6660

42Barroug,A.andGlimcher,M.J.(2002)Hydroxyapatite crystalsasalocaldeliverysystemforcisplatin:

adsorptionandreleaseofcisplatininvitro.J.Orthop.

Res.20,274–280

43Pai,P.etal.(2006)Pharmaceuticalapplicationsof carbontubesandnanohorns.Pharm.Res.1,11–15 44Ajima,K.etal.(2005)Carbonnanohornsasanticancer

drugcarriers.Mol.Pharm.2,475–480

45Rahman,Z.U.etal.(2016)Electrochemical&osteoblast adhesionstudyofengineeredTiO2nanotubular surfacesontitaniumalloys.Mater.Sci.Eng.C58,160–168 46Prato,M.etal.(2007)Functionalizedcarbonnanotubes indrugdesignanddiscovery.ACCChem.Res.41,60–68 47Liu,Z.etal.(2007)Supramolecularchemistryonwater-

solublecarbonnanotubesfordrugloadingand delivery.ACSNano.1,50–56

48Klumpp,C.etal.(2006)Functionalizedcarbon nanotubesasemergingnanovectorsforthedeliveryof therapeutics.Biochim.Biophys.ActaBiomembr.1758, 404–412

49Nagasawa,S.etal.(2000)Effectofoxidationonsingle- wallcarbonnanotubes.Chem.Phys.Lett.328,374–380 50Wang,Y.etal.(2005)Microwave-inducedrapid

chemicalfunctionalizationofsingle-walledcarbon nanotubes.Carbon43,1015–1020

51 Moon,H.K.etal.(2009)Invivonear-infraredmediated tumordestructionbyphotothermaleffectofcarbon nanotubes.ACSNano3,3707–3713

52 Papa,A.-L.etal.(2011)Synthesisoftitanatenanotubes directlycoatedwithUSPIOinhydrothermalconditions:

anewdetectablenanocarrier.J.Phys.Chem.C115, 19012–19017

53 Papa,A.-L.etal.(2015)Dispersionoftitanate nanotubesfornanomedicine:comparisonofPEIand PEGnanohybrids.DaltonTrans.44,739–746 54 Chen,C.-C.etal.(2007)Modificationofmulti-

walledcarbonnanotubesbymicrowavedigestion methodaselectrocatalystsupportsfordirect methanolfuelcellapplications.Electrochem.

Comm.9,159–163

55 Coccini,T.etal.(2010)Effectsofwater-soluble functionalizedmulti-walledcarbonnanotubes examinedbydifferentcytotoxicitymethodsinhuman astrocyteD384andlungA549cells.Toxicology269, 41–53

56 Zhu,N.etal.(2010)SensitiveimpedimetricDNA biosensorwithpoly(amidoamine)dendrimer covalentlyattachedontocarbonnanotubeelectronic transducersasthetetherforsurfaceconfinementof probeDNA.Biosens.Bioelectron.25,1498–1503 57 Li,R.etal.(2010)P-glycoproteinantibody

functionalizedcarbonnanotubeovercomesthe multidrugresistanceofhumanleukemiacells.ACS Nano.4,1399–1408

58 Lai,M.etal.(2011)SurfacefunctionalizationofTiO2 nanotubeswithbonemorphogeneticprotein2and itssynergisticeffectonthedifferentiationof mesenchymalstemcells.Biomacromolecules12, 1097–1105

59 Byrne,M.T.etal.(2007)Chemicalfunctionalisationof titaniananotubesandtheirutilisationforthe fabricationofreinforcedpolystyrenecomposites.J.

Mater.Chem.17,2351–2358

60 Kazemzadeh-Narbat,M.etal.(2013)Multilayered coatingontitaniumforcontrolledreleaseof

antimicrobialpeptidesforthepreventionofimplant- associatedinfections.Biomaterials34,5969–5977 61 Oh,S.etal.(2013)EffectofRGDpeptide-coatedTiO2

nanotubesontheattachment,proliferation,and functionalityofbone-relatedcells.J.Nanomater.2013, 965864

62 Oliveira,W.F.etal.(2017)Functionalizationoftitanium dioxidenanotubeswithbiomoleculesforbiomedical applications.Mater.Sci.Eng.C81,597–606 63 Bauer,S.etal.(2011)CovalentfunctionalizationofTiO2

nanotubearrayswithEGFandBMP-2formodified behaviortowardsmesenchymalstemcells.Integr.Biol.

3,927–936

64 Neupane,M.P.etal.(2011)Titaniananotubes supportedgelatinstabilizedgoldnanoparticlesfor medicalimplants.J.Mater.Chem.21,12078–12082 65 Chen,X.etal.(2013)Fabricationofselenium-deposited

andchitosan-coatedtitaniananotubeswithanticancer andantibacterialproperties.Coll.Surf.B:Biointerfaces 103,149–157

66 Mohan,L.etal.(2016)Drugreleasecharacteristicsof quercetin-loadedTiO2nanotubescoatedwith chitosan.Int.J.Biol.Macromolecul.93,1633–1638

YasminRanjous GézaRegdonJr.

KláraPintye-Hódi TamásSovány*

UniversityofSzeged,InstituteofPharmaceutical TechnologyandRegulatoryAffairs,H-6720,Eötvös u.6,Szeged,Hungary

*Correspondingauthor.

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