DRUGDELIVERYTRENDS
EXPECTATIONSANDREALITIESOF MULTIFUNCTIONALDRUG DELIVERYSYSTEMS
VOLUME3
Editedby
RANJITA SHEGOKAR,PhD
CapnomedGmbH,Zimmern,Germany
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Contributors
SalvanaCosta UniversidadeTiradentes(UNIT), Aracaju,Sergipe,Brazil
J.Dias-Ferreira DepartmentofPharmaceutical Technology,FacultyofPharmacy,Universityof Coimbra(FFUC),PolodasCiênciasdaSaude, AzinhagadeSantaComba,Coimbra,Portugal
A.R.Fernandes DepartmentofPharmaceutical Technology,FacultyofPharmacy,Universityof Coimbra(FFUC),PolodasCiênciasdaSaude, AzinhagadeSantaComba,Coimbra,Portugal
RohitC.Ghan AurobindoPharmaceuticalsUSA Inc.,Dayton,NJ,UnitedStates
RandeepKaur UniversityInstituteofPharmaceuticalSciences,PanjabUniversity,Chandigarh, India
MatthiasM.Knopp DepartmentofPharmacy, UniversityofCopenhagen,Copenhagen,Denmark
A.K € onigsrainer NationalCenterforPleuraand Peritoneum,UniversityofTubingen,Tubingen, Germany
KorbinianL € obmann DepartmentofPharmacy, UniversityofCopenhagen,Copenhagen,Denmark
ConradoMarques UniversidadeFederaldeSergipe (UFS),CampusLagarto,DepartamentodeMedicina,Sergipe,Largarto,Brazil
MuhanedAl-Hindawi OnTargetPharmaConsultancyLimited,NewMalden,Surrey,United Kingdom
LucianaNalone UniversidadeTiradentes(UNIT), Aracaju,Sergipe,Brazil;InstitutodeTecnologiae Pesquisa(ITP),Aracaju,Sergipe,Brazil
AdamProcopio Merck & Co.,Inc.,Kenilworth,NJ, UnitedStates
SaeedA.Qureshi Pharmacomechanics,Ottawa, ON,Canada
VivekRanjanSinha UniversityInstituteofPharmaceuticalSciences,PanjabUniversity,Chandigarh, India
M.A.Reymond NationalCenterforPleuraandPeritoneum,UniversityofT € ubingen,T € ubingen,Germany
PatríciaSeverino UniversidadeTiradentes(UNIT), Aracaju,Sergipe,Brazil;InstitutodeTecnologiae Pesquisa(ITP),Aracaju,Sergipe,Brazil
RanjitaShegokar CapnomedGmbH,Zimmern, Germany
A.A.M.Shimojo DepartmentofMaterialsEngineeringandBioprocesses,SchoolofChemicalEngineering,StateUniversityofCampinas(UNICAMP), CidadeUniversitariaZeferinoVaz Barao Geraldo,Campinas,SaoPaulo,Brazil
A.M.Silva DepartmentofBiologyandEnvironment,SchoolofLifeandEnvironmentalSciences, UniversityofTras-os-MontesandAltoDouro, VilaReal,Portugal;CentrefortheResearchand TechnologyofAgro-EnvironmentalandBiological Sciences,UniversityofTras-os-MontesandAlto Douro,VilaReal,Portugal
ElianaB.Souto DepartmentofPharmaceutical Technology,FacultyofPharmacy,Universityof Coimbra(FFUC),PolodasCiênciasdaSaude,AzinhagadeSantaComba,Coimbra,Portugal;CEB CentreofBiologicalEngineering,Universityof Minho,CampusdeGualtar,Braga,Portugal
M.C.Teixeira DepartmentofPharmaceuticalTechnology,FacultyofPharmacy,UniversityofCoimbra(FFUC),PolodasCiênciasdaSaude, AzinhagadeSantaComba,Coimbra,Portugal
DivyaTewari NoramcoInc.,Wilmington,DE, UnitedStates
PramilTiwari DepartmentofPharmacyPractice, NationalInstituteofPharmaceuticalEducation & Research(NIPER),S.A.S.Nagar,Punjab,India
NazendeGundayTureli MJRPharmJetGmbH, Uberherrn,Saarland,Germany
AkifEmreTureli MJRPharmJetGmbH, Uberherrn, Saarland,Germany
DanilloF.M.C.Veloso DepartmentofPharmacy, UniversityofCopenhagen,Copenhagen,Denmark VenkatTumuluri NovartisHealthcarePvt.Ltd., Hyderbad,India
Preface
Thebookseriestitled Expectationsand RealitiesofMultifunctionalDrugDelivery Systems coversseveralimportanttopicson drug-deliverysystems,regulatoryrequirements, clinicalstudies,intellectualpropertiestrends, newadvances,manufacturingchallenges,etc. writtenbyleadingindustryandacademic experts.Overall,thechapterspublishedinthis seriesreflectthebroadnessofnanopharmaceuticals,microparticles,otherdrugcarriers,and theimportanceofrespectivequality,regulatory, clinical,GMPscale-up,andregulatory registrationaspects.
Thisseriesisdestinedto filltheknowledge gapthroughinformationsharingandwithorganizedresearchcompilationbetweendiverse areasofpharma,medicine,clinical,regulatory practices,andacademics.
ExpectationsandRealitiesofMultifunctional DrugDeliverySystems isdividedintofour volumes:
Volume1:Nanopharmaceuticals
Volume2:DeliveryofDrugs
Volume3:DrugDeliveryTrends
Volume4:DrugDeliveryAspects
Thespecificobjectivesofthisbookseries areto:
1.provideaplatformtodiscussopportunities andchallengesindevelopmentofnano medicineandotherdrug-deliverysystems; 2.discusscurrentandfuturemarkettrends; 3.facilitateinsightsharingwithinvariousareas ofexpertise;and
4.establishcollaborationsbetweenacademic scientists,andindustrialandclinical researchers.
Innovativecutting-edgedevelopmentsin micro-nanotechnologyoffernewwaysof preventingandtreatingdiseaseslikecancer, malaria,HIV/AIDS,tuberculosis,andmany more.Theapplicationsofmicro-nanoparticles indrugdelivery,diagnostics,andimagingare vast.Hence, Volume3:DrugDeliveryTrends inthebookseriesmainlyreviewsadvancesin drugdeliveryareasviatargetedtherapywith improveddrugefficiencyatalowerdose,transportationofthedrugacrossphysiological barriers,aswellasreduceddrug-relatedtoxicity.
ThecontributionbyFernandesetal. (Chapter1) discussesnewtrendsindrug deliveryareasviabioactivehybridnanowires. Nanowiresoffermultifunctionalityandtheprospectofbiofunctionalization,therebyreducing toxicityandsideeffects.Thissynergisticapproach overcomesthechallengesassociatedwithconventionalnanomedicinesandexhibitsbetterperformance.Theauthorsreviewthepotentialof nanowiresinthischapter.
ThechapterbyProcopioandTewari (Chapter 2) highlightsanotherindustrytrend i.e.,3D printing.Thisisafascinatingtopicrecently adoptedbyindustry.TheFoodandDrug Administrationhasalreadyapprovedthe first product:Spritam(levetiracetam),a3Dprinted tablet(ApreciaPharmaceuticals).Athorough overviewofmaterialrequirements,typesof
polymer,available3Dprintingtechniques,and regulatoryaspectsisprovided.Finally,theauthorspresentcasestudiesfromindustryon tunablereleasetechnologyandpastegel extrusionintableting.
ThecontributionbyAl-Hindawi (Chapter3) describesmarketingauthorizationandlicensing ofmedicinalproductsintheEuropeanUnion. Themainaimofthischapteristoprovide readerswithageneralizedoverviewofthesteps andcriteriawhileapplyinglicensesinthe EuropeanUnion.Theauthoralsohighlights variousdirectives,extensionrequests,protection periods,andlegalrequirementsguidanceto industryandresearchers.Ontheotherhand, preclinicalunderstandingiskeytoproposing productsforparticularindications.
ThechapterbyTiwarietal. (Chapter4) reviewspreclinicalconsiderationsonmicroandnanodrugdelivery,whichwillleadtothe properpositioningofproductsformarket authorization.
TheworkbyGhan (Chapter5) isaimedatdiscussingsynergisticdeliveryofnanoparticles usingtraditionalapproachesliketabletingor otherforms.Theauthorreviewsvariousnanoparticulatetreatmentsfororaldeliveryto improvebioavailability,targetspeci ficregions inthegastrointestinaltract,improvephysiologicalstabilityinthegutenvironment,and modulatereleasewhenneeded.Drugdelivery systemslikesolidlipidnanoparticles,polymeric nanoparticles,nanomicelles,andnanosuspensionarealsoreviewed.
ThechapterbyTumuluri (Chapter6) highlightsopportunitiesandchallengesin formulatingminitablets.Thisisanothertrend inoraldrugdeliverysystemsbesidesnano-oral and3Dprinteddosageforms.Theauthor describesindetailtechnologicalpotential,industrialadvantages,technologicalavailability,and thelimitationsofminitablets.
ThetopicpresentedbyNaloneetal. (Chapter7) describesthepotentialofliquidcrystallinesystemsindrugdelivery.Thischapter
discussesindetailthemechanismofformation ofliquidcrystallinesystems,typesofstructure formed,factorsaffectingformationofliquidcrystallinesystems,compositions,advantages,and limitationsoftheseformsofdrugdelivery systems.
ThechapterbyVelosoetal. (Chapter8) reviewsopportunitiesandchallengesinamorphousdrugstabilizationusingmesoporous materials.Theteamofauthorshighlightskey pointsliketheroleofmesoporousmaterials, structuralcharacterizationsofsuchsystems, physicalformsofdrugloading,andphysical performanceofmesoporousparticles.Mesoporousparticleshavehugepotentialinpharmaceuticalsasadrugdeliverysystem,incosmetics,in nutraceuticals,andinfast-movingconsumer goods(detergent,oralcare),andisahighly exploredtrendinthemarket.
Qualityisanimportantaspectinregulatory whichmakessurepatientsreceive “quality” products.Newertrendsinpharmaceuticalslike nanomedicines,drugdevicecombinations, nanoparticulate-basedtablets,etc.require specialtechniquesandanunderstandingof quality.ThechapterbyQureshi (Chapter9) asksquestionslike “whatisquality?” , “dowe evaluatequalityasperaregulatorydefinition?” , and “isthereaneedtochangethedefinitionof qualitywhenaproductisaltered?” Themain themeofthischapteristounderlinebasic conceptsof “quality” anddiscussthemwith regardtocurrentpractices.Theauthorprovides hisviewsonfurthermodificationsofcurrent testingmethodologiestoassure “realquality.”
TheworkbyReymondandKonigsrainer (Chapter10) isaimedatdiscussingthepotential ofpressurizedintraperitonealaerosolchemotherapy(PIPAC).Theauthorsreviewvarious chemotherapeuticsystemscurrentlyused invitro/exvivomodelsandthesuccessof clinicaltrialstodate.Thisgeneralizedoverview ofPIPACtechnologyprovidesreaderswith updatesfromanotherinnovativetrendin medicalpractice.
ThelastcontributionbyTureliandTureli (Chapter11) describesindustrialchallengesof upscalingandgoodmanufacturingpracticein theproductionofpharmaceuticaldrugdelivery systems.Theauthorshighlightthecurrentregulatorystatusofapprovednanomedicinesand manufacturinglimitationsandinitiatives.
Insummary,Iamsurethisbookvolumeand thecompletebookserieswillprovideyougreat
insightsinareasofmicro-nanomedicines,drug deliverysciences,newtrends,andregulatory aspects.
Alltheeffortsofexperts,scientists,andauthorsarehighlyacknowledgedforsharingtheir knowledge,ideas,andinsightsaboutthetopic.
RanjitaShegokar,PhD Editor
Bioactivehybridnanowires:anewin trendforsite-speci ficdrugdeliveryand targeting
A.R.Fernandes1,J.Dias-Ferreira1,M.C.Teixeira1, A.A.M.Shimojo2,PatríciaSeverino3,4,A.M.Silva5,6, RanjitaShegokar7,ElianaB.Souto1,8
1DepartmentofPharmaceuticalTechnology,FacultyofPharmacy,UniversityofCoimbra(FFUC),Polo dasCi^ enciasdaSaude,AzinhagadeSantaComba,Coimbra,Portugal; 2DepartmentofMaterials EngineeringandBioprocesses,SchoolofChemicalEngineering,StateUniversityofCampinas (UNICAMP),CidadeUniversitariaZeferinoVaz BaraoGeraldo,Campinas,SaoPaulo,Brazil; 3UniversidadeTiradentes(UNIT),Aracaju,Sergipe,Brazil; 4InstitutodeTecnologiaePesquisa(ITP), Aracaju,Sergipe,Brazil; 5DepartmentofBiologyandEnvironment,SchoolofLifeandEnvironmental Sciences,UniversityofTras-os-MontesandAltoDouro,VilaReal,Portugal; 6CentrefortheResearch andTechnologyofAgro-EnvironmentalandBiologicalSciences,UniversityofTras-os-MontesandAlto Douro,VilaReal,Portugal; 7CapnomedGmbH,Zimmern,Germany; 8CEB CentreofBiological Engineering,UniversityofMinho,CampusdeGualtar,Braga,Portugal
1.Introduction
Hyperthermia(“hyper” and “therme ” ,meaning “rise” and “heat”)isatherapeuticapproach tocancertreatment.Someresearchershave relatedthatasarcomadisappearedafteravery highfever.This findingisduetothereaction ofimmunesystemswithbacterialinfection[1]. Cancercellsarerecognizedasbeingvulnerable tohightemperatures.Thegrowthofthesecells
canbeterminatedattemperaturesranging from41to46 Corbelow47 Cforatleast 20 60min[2,3].Hyperthermiaistherefore usedlocallytopreventdiseasebyexposingthe wholebodytohightemperaturestoovercome adversesideeffectsandtoincreasetreatmentefficiency[4].
Theintroductionofmagneticnanoparticles incancerhyperthermiahasbeendeveloped andgrownsignificantlyduringthelastdecade.
Thespecialfeaturesoftheseparticlesarerelated totheircapacitytoefficientlyaccumulateatthe tumorcellsthroughtheincreasedpermeability ofthetumorvesselsandbycancer-speci ficbindingagents,makingthetreatmentmoreselective andeffective[5].Theapplicationofanalternatingmagnetic field(AMF)withtheintroductionofmagneticnanoparticlesgenerateslocal heatinthetissuesthatcontainthesenanoparticlesduetomagneticrelaxationandhysteresis loss[6].Particlecharacteristicssuchassizedistribution,shape,crystalstructure,particlemagneticanisotropyanditstemperature dependenceonmagnetization, fluidviscosity, amplitudeandfrequencyoftheAMFdirectly affectthegenerationofheat,whichinturndependsontheabsorptionefficiencyofthemagneticparticles[1,7].
Asignificantnumberofmagneticnanoparticleshavebeenstudiedoverthelastfewdecades.Examplesofwell-knownhyperthermic agentsincludeironoxide-basednanomaterials suchasmagnetite(Fe3O4)andmaghemite(gFe2O),whichcontinueattractingattentiondue totheirlackoftoxicityandexcellentbiocompatibility[8].Ferritenanoparticles(XFe2O4,where X canbeCo,Mn,Ni,Li,ormixesofthese metals),metallicnanoparticles,suchasMn,Co, Ni,Zn,Gd,Mg,andtheiroxides,ormetalalloys (FeCo,CoPd,FePt,NiPd,NiPt,NiCu)havealso beenstudiedaspossiblecandidatesforhyperthermiatreatments[9 11].
Therearenewdesignsofmagneticnanomaterialsbasedonacore/shellapproachthathave startedtogainprominenceduetotheirversatility totailorpropertiesofbothcoreandshellandto offermultifunctionality,suchascoreprotection, biofunctionalizationplatform,toxicityreduction, andincreaseinbiocompatibility.Examplesof theseparticlesaregold-orsilica-coatedferromagneticparticles[12].Magneticnanoparticlesalso holdgreatpromisefordrugdeliverybyheating thetissues.Thedrugcanbereleasedusingtwo strategies.Inthe firstapproach,thedrugmoleculesareattachedtotheparticlesthrougha linker,whichbreakswiththeheatgeneratedby
10. Drugdelivery 1.Bioactivehybridnanowires:anewintrendforsite
thepresenceofAMF,withtheconsequentrelease ofthedrug.Inthesecondapproach,thereleaseof drugstakesplacefromapolymericmatrixwith magneticmaterial[5,13].Theheatcreatedby themagnetic fieldproducescrevicesorcracksinsidethepolymericmatrix,whichreleasesthe encapsulateddrugs[5].
Nanowires,nanowhiskers,nanofibers,nanotubes,andotherone-dimensionalnanostructures havedemonstratedhugeabilitiesforimproving theelectrical,optical,thermal,andmechanical propertiesofabroadrangeoffunctionalmaterialsandcomposites[14].Theseenhancements substantiallyexceedthoseofferedbymicro-or nanosizedparticles.Mostofthemethodsused fortheirsynthesisarerelativelyexpensiveand difficulttoscaleup[15].Theunderlyingprinciplesforthesynthesisofone-dimensionalmaterialsoffersignificantchallengesinthecontrolof diameter,structure,andcompositionintheaxial andradialcoordinates,whichareessentialfor thesynthesisofmaterialswithdesignedand tunablefunctionality[16].
Nanowires,besidestheirmagneticperformance,alsohaveasoaninterestindeveloping intrinsicmobilitytriggeredbyaphotochemical reaction.Examplesofapplicationsofmagnetic segmentednanowiresare:
1. Magneticalignmentandwirelessmanipulation(Au/polypyrrole/Ni)[17]
2. Magnetic fieldsensorsandspintronicnanodevices(Co/CuandFeCoNi/Cu)[18]
3. Photochemicalconversionandhydrogen generation(Ag/ZnO)[ 19 ]
4. DetectionofDNAmolecules(CdTe/Au/ CdTe)[ 20 ]
5. Magneticcontrolofbiomoleculedesorption (FeCo/Cu)[21]
6. Exchange-coupledpatternedmedia(Ni/ CoPt)[ 22 ]
7. Nanosensors(Au/Co)[23]
8. Catalyticactivities(Pt/Ni)[24]
9. Higheroxygenreductionreactionactivity (Co/Pt)[ 25 ,26 ]
Magneticnanoparticles(includingnanowires) arerecognizedasnanoparticleswithunique physicochemicalpropertiesandaremostly differentfromthoseofconventionalmaterials, speci ficallytheelectromagneticproperties.Magneticnanoparticlesshowgoodmagneticorientation,smallsize,biodegradability,andreactive functionalgroups[27].Thebiocompatibilityof magneticnanoparticlescanbeimprovedby combiningthemwithavarietyoffunctional moleculessuchasenzymes,antibodies,cells, DNA,orRNA.Thecoatingofothermaterials suchaspolyethyleneglycol(PEG),chitosan, lipids,andproteinswithgoodbiocompatibility canstabilizemagneticnanoparticlesinphysiological fluidsandprovidechemicalfunctionality foradditionalmodifications[28].
2.Typesofnanowires
Inthelastfewyears,magnetichybridnanowireshavebeenintensivelystudiedformany applications,suchasopticsandmedicine.There aretwotypesofmorphologiesinhybrid nanowires:
1. Radialstructures(core/shelltype);and 2. Axialstructures(segmentedorlayeredtype).
Thenanowiresthatpresentacore/shellstructureexplainmanyphysicalcharacteristicsinthe magnetismofthenanoparticles.Thehard/soft core/shellnanoparticleshavebeenstudiedand revealinterestingmagneticproperties,i.e., reversibletuningoftheblockingtemperature [29],improvedmicrowaveabsorption[30],optimizedhyperthermia[31],andenhancedcoercivity[32].Themagneticsegmentednanowires havemultifunctionalandstructuraladvantages comparedtotheircounterparts,singlecomponentnanowires.Theliteraturereports thatmagneticsegmentednanowiresare
composedofalternatingstructuresofferromagnetic/ferromagneticorferromagnetic/nonmagneticmaterials,suchasNi/Cu[33],Ni/Au[34], Co/Cu[35],NiFe/Cu[36],CoNi/Cu[37], FeCoNi/Cu[38],FeGa/Cu[39],Co/Pt[40], NiFe/Pt[41],andNiCoCu/Cu[42],among others.
3.Productionmethods
Thepropertiesofmanysystemsarebasically dependentofthematerialtypeusedinproduction;however,inthecaseofnanowiresthe materialgeometryisalsoimportant.Thusto produceandmaximizeallthepropertiesof nanowiresrequiresreliableandcontrolledsyntheses.Thesynthesismethodscanbegrouped intotwocategories:(1)top-downand(2) bottom-upsynthesis.
3.1Top-downmethod
Themostconventionaltop-downmethodin thefabricationofnanowiresislithography. Lithographyisbasedonthedepositionofaresistantmaterial,forexample,poly(methylmethacrylate),thathasthefunctiontoactasa photographic filmfortheproductionofapattern afterexposureanddevelopmentusinga patternedmask.Theresolutionofthistechnique isdependentonthewavelengthoflightusedin photolithographyandsometimesisnotsuitable forsmallnanowires[43].Toobtainpatterns withahigherresolution,normallyelectronbeamlithographyisthemethodused,which doesnotuseamaskandhasdirect-writeexposure[44].Thusnanowirescanbeobtainedby etchingtheextraneousmaterialfromthewafer. Resistancecanbeapplieddirectlybecausethe etchmaskcanserveasthetemplateforthedepositionofamuchmorestablemaskmaterial,for example,gold.Materialthatcanbeusedto
etchapatternis,forexample,potassiumhydroxide(awetchemicaletchant)oranotherelectrochemicaletchant.Withthesematerialsitis possibletoproducetaperedcylindricalwires oncetheetchingisunderneaththemask[45]. Onewaytoobtaincylindricalverticalwiresis tochangethewetchemicaletchwithahighly anisotropicdeepreactiveionetch[46].Nanospherelithographyisanotherapproachthat promiseshigherresolutionbycombiningthe self-assemblyofamonolayerofnanospheresof polystyrene,forexample,ontoasubstrateina close-packedlattice[47].Thenanospheresserve asamodelforthedepositionofametalor anothermaterialandareremovedafterdeposition.Nanoscalepatternscanbeproducedbymechanicaltransferusingnanoimprintlithography [48,49].
3.2Bottom-upmethod
Incontrasttotop-downtechniques,bottomupsynthesisofferstheopportunitytocontrol nanowirecompositionduringgrowth.
Inthistechniqueoftheproductionofnanowires,theanisotropicgrowthofnanowiresis normallydoneusingnanoparticlecatalystsand gas-phaseprecursors.Themostusedmethodof productionisvapor/liquid/solidgrowth.In thismethod,gaseousprecursorsareusedto obtainthedesirednanowiresandtheseprecursorsaredissolvedintoaliquid-metalcatalyst, forexample,inthecaseofsiliconnanowires theprecursorusedisSiCl4.Afterthecatalystis supersaturated,solidnanowirecrystallization fromtheliquidcatalystbegins[50,51].Inthis process,themetalshouldformadropletinthe liquidstatethatwillserveasthecatalyst.This droplet,insomecases,willmeltatalowertemperaturewhencomparedtopuremetal,dueto itseutecticcomposition.Inthecaseofthesynthesisofbinaryorternarycompounds,which aremetalswithlowmeltingpoints,thevapor/ liquid/solidsystemcanbeself-catalyzed[52]. Thesolution/liquid/solidmethodisanother techniqueofnanowireproductionsimilarto
thevapor/liquid/solidmethod;however,in thiscasenanowireprecursorsaredissolvedin ahigh-boilingliquidandthecatalystsaresuspendedinthisliquid[53].Substrates,suchas anodicaluminumoxide,canbeusedastemplate solutionfornanowiregrowth,usingelectrochemicaldepositionandafter fillingthechannels inthetemplate[54].Controlofgrowthalongthe axesofnanowiresisnecessaryfortheintroductionofsurfactantscapableofchangingthesurfaceenergyofcrystalfacets,forexample, hexadecyltrimethylammoniumbromide. Anisotropyofnanowiresiseasytoachieveby thecontrolofsurfacechemistry[55](Tables1.1 and1.2 and Fig.1.1).
4.Applicationsofnanowires
Nanowirebiosensorsconsistoftypical fieldeffecttransistor-baseddevices,madeupofthree electrodesthatareverysensitivetothevariation inthechargedensitythatpromoteschangesin theelectric fieldattheexternalsurfaceofthe nanowires[64].
Nanowireshaveahighsurface-to-volumeratioandwell-de finedgeometry;theyhavehigh sensitivityandshortresponsetime.Thesecharacteristicsofferapplicationsinbiologyand chemistry.Applicationsofnanowirescanbe categorizedintotwomethodologies:electrical detectionandopticaldetection[49].
4.1Nanowiresinbioanalyticalchemistry
Oneofthebioapplicationsofnanowiresis biomoleculeanalysis.Thisapplicationincludes thestudyofmechanicalcelllysis.Cellularlysis isafundamentalprocessinthestudyofintracellularcomponents.Thereareanumberofwellestablishedmethodsthatcananalyzethecell components,suchaschemical,electrical,and mechanicalmethods.Inthecaseofchemical celllysismanystepsarenecessaryanditisan expensiveprocess,consumingmanyreagents aimedatthepurificationofbiomoleculesamples.Anotherdisadvantageisthehighprobabilityoftheoccurrenceofharmfuleffectson
FIGURE1.1 ScanningelectronmicroscopyimagesofCuSnanowires:(A)array;(B)copperoxide(CuO)nanotubes; (C)array;(D)fabricationusinganodicaluminumoxidetemplate. ImagecopiedfromMuC,HeJ,ConfinedconversionofCuSnanowirestoCuOnanotubesbyannealing-induceddiffusioninnanochannels.vol.6.2011.p.150.Availablevialicense:CCBY2.0(https:// creativecommons.org/licenses/by/2.0/).
TABLE1.1 Advantagesanddisadvantagesoftop-downandbottom-upmethods[56 58].
MethodsAdvantagesDisadvantages
Top-downEasytoconstructorderarraysofnanowires.
Thisorderfacilitateselectricalcontactwiththe nanowiresandtheirintegrationintolarge-scale devices
Compatibilityofproductionmethodswith standardmicroelectronicsindustryprocesses. Easyscale-up
Bottom-upProvidestheopportunityforthecontrolofthe compositionofnanowiresduringgrowth,which permitstheproductionofcomplexsuperlattice structures
Theapplicabilityofthephotolithographymethoddecreasesas thedesiredlengthscalediminishes,whichrequirestheuseof moreadvancedmethods,forexample,extremeultraviolet lithography,electron-beamandscanningprobelithographies
Nanowiresformedbytop-downmethodsfrequentlylack complexelectroniccharacteristics.Allthecodificationsafter growthgreatlyincreasethematerialcostofnanowire
Themajorchallengeofthesemethodsistheirintegrationinto large-scaledevices
microorganisms[65,66].Thesolutiontothis problemsistheuseofelectricalcelllysis,which islessharmfulthantheaforementionedmethod; however,itstillanexpensivemethodandhasa lowthroughput[67].Theultimatediscovery wastheuseofnanowiresbecauseoftheirsmall size(smallerthanthecells)andthecriticaladvantageisthatthenanowiretipcanpenetrateand
1.Bioactivehybridnanowires:anewintrendforsite
TABLE1.2 Drugsincorporatedinnanowires.
Activepharmaceutical ingredient(API)TypeofsystemAim
Production methodsReferences
PaclitaxelCunanowiresTotargetthespleenBottomup[59]
DexamethasonePolypyrrole nanowires
Forulcerations,deepboneinjuries, ortumors;avoidsthesideeffectsof systemictreatmentwith steroidsorchemotherapy
Bottomup[60]
CurcuminSilvernanowiresCancertreatmentBottomup[61]
DoxorubicinSilvernanowiresCancertreatmentBottomup[62]
CerebrolysinHydrogentitanate nanowires
ReductionofbrainedemaTopdown[63]
disruptthefunctionofcellularmembranes[68]. Nanowireseliminatemicroorganismsincells muchfasterthanthepreviouslydescribed methods.
Inanalyticalandbiologicalprocesses,the developmentofbiomoleculeseparationand analysisisessential.Intheseparationoflong DNAmolecules,conventionalgelelectrophoresishasadisadvantage:itisnecessaryto analyzebiomoleculesforseveralhours.The combinationofnanostructuresproducedby top-downapproachesandmicro fluidicsystems isusuallyproposedtoovercometheproblem. However,difficultyintheirproductionusing anelectron-beamlithographyprocessmakesit averyexpensiveandsophisticatedsystem [69,70].Ontheotherhand,nanostructuresproducedbybottom-upapproachesoffereasyfabricationandseparationofbiomolecules;however, sizelimitationcausesdifficultyintheirdevelopment.Toovercomealltheseproblems,selfassemblednanowirestructuresofmetaloxides havebeeninvestigatedduetotheirrigidityand thepossibilityofreusability[49](Table1.3).
4.2Nanowiresasbiosensorsinmedical
diagnosis
Therearemanychallengesaheadthatmustbe addressedbeforenanowirescanbesuccessfully
usedforbiomedicalapplications.Majorchallengesinclude
1. advancedtechniquesandeasymethods (neededtoincreasethesensitivityofnanowirebasedelectrochemicalcytosensorsinsignal ampli fi cation),
2. furtherresearchintonanowirestopromote celladhesion,sensitivity,andselectivity,
3. morespecializedcoatingstodecreasenonspeci fi cbonding,
4. protocolsandfurtherexperimentstodeterminetheexactnatureofthenanotoxicityof nanowiresandtheirconstituents,
5. innovativesolutionstoreducefabricationand runningcostsofnanowire-basedmicro/nanofl uidicdevicestomakethemeconomically viable,
6. witheveryemergingtechnology,standardsto avoiddoubtsaboutthelackofreproducibility, repeatability,andcompatibilityacrossplatformsandlaboratories,and
7. anopportunityforfurtheradvancesanddevelopmentsofcytosensingdevicesbasedon electrochemicalmethods[73].
Circulatingtumorcellsplayanessentialrole incancermetastasis,andknowledgeoftheir presenceinbloodsamplesofcancerpatientsis neededtounderstandmoreaboutthetypeof cancer.Hosokawaetal.haveshownanarray
TABLE1.3 Nanowiresinbioanalyticalanalyses.
NanowiretypeProductionmethodResultsReferences
Mechanical celllysis
Biomolecule separation and filtration
ZnOnanowires (diameter:100nm) onthesurfaceofa pillararrayina microchannel
ZnOnanowireswere synthesizedontheSi membrane(average porediameter:75nm)
SnO2 nanowires producedinto fusedsilica microchannels
Methodoflowtemperature hydrothermal reaction
Methodoflowtemperature hydrothermalreaction
Photolithography processandvapor/ liquid/solidtechnique
Higherextractionefficiencyfornucleicacids andproteinsthanusingchemicalcelllysis methods [71]
Easyandrapidmechanicalcelllysis
Higherextractionefficiencyforproteinsand nucleicacidsthanthatobtainedfor commerciallyavailablekits [72]
Nanowirestructurecontrolledthepore size(20 400nm)byvaryingthenumberof nanowiregrowthtimes
Highlydensenanowires,usedasa molecular filter,couldprovidehigh-throughput filtrationofDNAmolecules [49]
Asiliconnanowire-basedelectricalcell impedancesensorhasbeendevelopedforthe detectionofcancerousculturedlivinglungcells bymonitoringtheirspreadingstateatwhich thecellsstretchedandbecameextendedon nanowires[80].Thediagnosiswascarriedout bypenetrationintotheextendedmembraneof malignantcellswithrespecttohealthycells.
Siliconnanowirebiosensorshaveadvantages inmoleculardetectionbecauseoftheirhigh sensitivityandfastresponse.Apolycrystalline siliconnanowire field-effecttransistordevice wasdevelopedtoachievespecificandultrasensitivedetectionofmicroRNAswithoutlabeling andamplification,showingthatthediagnostic andprognosticvalueofmicroRNAsinavariety ofdiseasesispromising.Thusthepolysilicon nanowirebiosensordeviceispromisingfor microRNAdetection[81].
Inshort,semiconductornanowiresare emergingaspromisingbiosensorsenabling
ofmicrocavitiestoperformsize-selectivecapture ofcirculatingtumorcells[74].Anotherstudyreportedthataherringbonechipcapturedandisolatedclustersofcirculatingtumorcellsfromthe patient’sblood,whichhadacaptureefficiencyof morethan80%[75].Tsengetal.developedsiliconnanowires,whichtheycalledaNanoVelcro chip,tocaptureandreleasecirculatingtumor cellsfrombloodsampleswithhighselectivity [76,77].Sinanowireswereproducedbasedon substratesbyastandardphotolithographyand chemicalwetetchingprocess,andtheywere thenbondedtoachaoticmixtureofmicrofluidic channelstofabricatetheNanoVelcrochip.This procedureofsurfacemodificationwithcellsurfacemarkersofanti-EpCAMincreasedthe capturingefficiencyofcirculatingtumorcells orofanti-CD45-depletedwhitebloodcellson thenanowires[78,79].TheNanoVelcrochip withnanowireshasbeendevelopedforsinglecirculatingtumorcellisolationbydepositing thermoresponsivepolymerbrushes,poly(N-isopropylacrylamide),onsiliconnanowires[78]. NanoVelcrochipsarepromisingtoolsin diagnosis,becausetheycaptureandpurifycirculatingtumorcellsrapidlypriortocirculatingtumorcellmolecularanalysis[49,76].
1.Bioactivehybridnanowires:anewintrendforsite
TABLE1.4 Listofbiosensorsintheliteraturebasedonnanowires.
TypeofbiosensorAimReferences
Siliconnanowire field-effecttransistorsDetectionofproteins,DNAsequences,smallmolecules, cancerbiomarkers,andviruses [83]
NanoVelcrochipwithnanowiresDevelopedforsingle-circulatingtumorcellisolation[78]
Siliconnanowire-basedelectricalcellimpedance sensor
Nanowire-based field-effectsensordevices(which canbemodifiedwithspecificsurfacereceptors)
Detectionofcancerousculturedlivinglungcells[80]
Usedasapowerfuldetectiondeviceforabroadrangeof biologicalandchemicalspeciesinsolution [84]
directelectricaldetectionofvariousbiomolecules.Acomparativeanalysisofbiofunctionalizationstrategiesneedstobe discussedtodesignanddevelopoptimummemristivebiosensorstobeimplementedinlabel-free sensingapplications.Thesurfaceofthedeviceis modifiedwithaspeci ficantigen antibodyvia: (1)directadsorptiononthedevicesurface,(2)a bioaf finityapproachusingtheappropriate combination,and(3)theoptimummemristive biosensor,whichisdefinedviathecalibration andcomparativestudyofbiosensors’ electrical responseundercontrolledenvironmentalconditions,suchashumidityandtemperature,aiming tomaximizetheperformanceofthebiosensor. Thismodifiedsystemshowspotentialforgeneralapplicationinmoleculardiagnostics,and, inparticular,fortheearlydetectionofcancer, namely,prostate[82](Table1.4).
SomeinvestigatorsoftheUniversityofSan Diegohavebeendevelopingnanowireswith thepurposeofrecordingtheelectricalactivity ofneuronsin finedetail.Theambitionofthe groupisthatonedaythisnewnanowiretechnologycouldserveasamethodtoscreendrugs usedspecificallyinneurologicaldiseases,which couldhelpresearcherstounderstandthemechanismofhowsinglecellscancommunicatein complexneuronalnetworks.Themainobjective istoallowthescientificcommunitytodelve deeperintohowthebrainworks.Inthefuture, thegoalofresearchersistoimplantthisnew nanowiretechnologyintothebrain[85].
4.3Nanowiresfordeliveryof chemotherapeutics
Sharmaetal.developednoncytotoxic,magnetic,Arg-Gly-Asp(RGD)-functionalizednickel nanowires(RGDnanowires)thatcouldtrigger specificcellularresponsesviaintegrintransmembranereceptors,resultinginthedispersal ofnanowires[86].Theirresultsshowedthat dispersalof3 mmlongnanowiresincreased considerablywithfunctionalizationbyRGD whencomparedtoPEG,throughintegrinspecificbinding,internalization,andproliferationinosteosarcomacells.Additionalresults showedthata35.5%increaseincelldensity wasobservedinthepresenceofRGDnanowires whencomparedtoanincreaseofonly15.6% withPEGnanowires.Theseresultsarevery promisingtoadvanceapplicationsofmagnetic nanoparticlesindrugdelivery,hyperthermia, andcellseparationwhereuniformityandhigh ef ficiencyincelltargetingaredesirable.
Contrerasetal.showedthatmagneticnanowireswithweakmagnetic fieldsandlow frequenciescouldinducecelldeathviaamechanismthatdoesnotinvolveheatproduction[87]. Thelow-power fieldexertedaforceonthemagneticnanowires,causingamechanicaldisturbancetothecells.Intheirresults,cellviability studiesshowedthatthemagnetic fieldandthe nanowireshadseparatelydecreaseddeleterious effectsonthecells.Ontheotherhand,when combined,themagnetic fieldandnanowires
causedcellviabilityvaluestodropbyupto39%, dependingonthestrengthofthemagnetic field andtheconcentrationofthenanowires.Cell membraneleakageexperimentsshowedmembraneleakageof20%,whichprovedthatcell deathmechanismsinducedbynanowiresand magnetic fieldsinvolvecellmembranerupture. Thustheseresultssuggestedthatmagneticnanowirescankillcancercells.Theadvantagesofthis processaretheuseofsimpleandlow-costequipmentwithexposuretoonlyveryweakmagnetic fieldsforbrieftimeperiods.
Anotheralternativeisultrasound-powered nanowiremotorsbasedonnanoporousgoldsegmentsthataredevelopedforincreasingdrug loadingcapacity.Thesenanowireporousmotors arecharacterizedbyatunableporesize,high surfacearea,andhighcapacityforthedrug payload.Thesehighlyporousnanomotorsare preparedbytemplatemembranedepositionof asilver/goldalloysegmentfollowedbydealloyingthesilvercomponent.Thechemotherapeutic drugdoxorubicinwasloadedwithinthenanoporesviaelectrostaticinteractionswithan anionicpolymericcoating.Thenanoporous goldstructurefacilitatesnear-infraredlightcontrolledreleaseofthedrugthroughphotothermaleffects,whichisagreatadvantage. Incorporationofthenanoporousgoldsegment leadstoanearly20-foldincreaseintheactive surfaceareacomparedtocommongoldnanowiremotors[88].
Thelatterworkoffersveryimportantinformationforthetreatmentofcancerpatientsata patient-speci ficlevelbasedonspeci ficdrugresponsesofcirculatingtumorcells.So,platforms forhighcaptureefficiencyofcirculatingtumor cellsareessentialforclinicalevaluationof patient-speci ficdrugresponsesofcirculatingtumorcells.Recently,nanostructure-basedplatformshavebeendeveloped.IntheKimetal. study,thebreastcarcinomacell-linewithanultralowabundancerangewascapturedby streptavidin-functionalizedsiliconnanowire platformsforevaluationofcaptureef ficiency
[89].Inthiscase,acaptureefficiencyofmore than90%wasachieved.Specificdrugresponses ofbreastcarcinomacell-linecellscapturedon theseplatformswereanalyzedusingtamoxifen ordocetaxelasafunctionofincubationtime anddose.Inaddition,circulatingtumorcells weresuccessfullycaptured,andthisstudysuggeststhatthisplatformisadaptableforclinical useintheevaluationofcirculatingtumorcells anddrugresponsetests.
Magneticsilicacore/shellnanovehiclespresentingatheroscleroticplaque-specificpeptide-1 asatargetingligandhavebeenprepared throughadouble-emulsionmethodandsurface modificationwithmagneticironoxide(Fe3O4) nanoparticles.Theresultsdemonstratedthatunderahigh-frequencymagnetic field,magnetic carriersincorporatingtheanticancerdrugdoxorubicincollapsed,releasingapproximately80% ofthedrugpayload,duetotheheatgenerated bytherapidlyrotatingFe3O4 nanoparticles, therebyrealizingrapidandaccuratecontrolled drugrelease.Atthesametime,themagnetic Fe3O4 couldalsokillthetumorcellsthrougha hyperthermiaeffect,i.e.,inductiveheating.The combinationofremotecontrol,targeteddosing, drug-loading flexibility,andthermotherapy andchemotherapysuggeststhatthesemagnetic nanovehicleshavegreatpotentialforapplication incancertherapy[90].
Anotherstudyshowedthatanelectroresponsivedrugreleasesystembasedonpolypyrrole nanowireswasdevelopedtoinducethelocaldeliveryoftheanticancerdrugdoxorubicin,accordingtotheappliedelectric field.These nanowireswereinitiallypreparedbyelectrochemicaldepositionofamixtureofpyrrole monomersandbiotinasdopantsintheanodic aluminaoxidemembraneasasacrificialtemplate.Additionally,theantitumoref ficacyof doxorubicinreleasedfromthesenanowiresin responsetotheexternalelectric fieldusingtwo kindsofcancercelllines,humanoralsquamous carcinomacellsandhumanbreastcancercells, wasinvestigated.Anadvantageofthese
particlesisthestrongphotothermaleffectasa resultofthenear-infraredabsorbingabilityof polypyrrolesynergisticallythat,asaconsequence,maximizeschemotherapeuticef ficacy, whichisverypromisingformanytherapeutic applications,includingcancer[91].
TodetectspecificmRNAsequences,essential inthetreatmentofcancer,molecularbeacons havebeenwidelyemployedassensingprobes. Kimetal.developedananowire-incorporated andpneumaticpressure-drivenmicrodevicefor rapid,high-throughput,anddirectmolecular beacondeliverytohumanbreastcancerMCF-7 cellstomonitorsurvivinmRNAexpression [92].Thismicrodeviceiscomposedofthree layers:(1)apump-associatedglassmanifold layer,(2)amonolithicpolydimethylsiloxane membrane,and(3)aZnOnanowire-patterned microchannellayer.Themolecularbeaconsare immobilizedusingtheZnOnanowiresbydisulfidebonding,andtheglassmanifoldandmonolithicpolydimethylsiloxanemembraneserveasa microvalve.Thecellularattachmentanddetachmentonthemolecularbeacon-coatednanowire arraycanbeeasilymanipulated.Alltheseproceduresenablethetransferofmolecularbeacons intothecellsinacontrollablewaywithhighcell viabilityandareusefultodetectsurvivinmRNA expressionquantitativelyafterdocetaxeltreatment[92].
Combinationtherapyisapromisingcancer treatmentstrategythatisusuallybasedonthe utilizationofcomplexnanostructureswithmultiplecomponents.Ultrathintungstenoxide nanowires(W18O49)weresynthesizedusinga solvothermalapproachandwereexaminedas amultifunctionaltheragnosticnanoplatform [93].Invitroandinvivoanalysesdemonstrated thatthesenanowirescouldinduceextensive heat-andsingletoxygen-mediateddamageto cancercellsunder980nmnear-infraredlaser excitation.Thecomparisonofnearinfraredinducedphotothermaltherapy/photodynamic therapyandradiationtherapyaloneshowed
thatW18O49-basedsynergistictrimodaltherapy eradicatedxenografttumors,andnorecurrence wasobserved.Inconclusion,thesenanowires haveshownsignificantpotentialforcancertherapywithinherentimageguidanceandsynergisticeffectsfromphototherapyandradiation therapy,whichwarrantsfurtherinvestigation [94].
5.Conclusions
Thischaptersummarizesthecriticalresultsobtainedusingnanowirestructuresasaplatform usefulinbioanalyticalchemistryandmedicaldiagnostics.Nowadays,therearevarioustechnical approachestodevelopnanowiresforbioapplicationsinmoleculartocellularlevels.Nanowireshavebeenintegratedwithmicrochannels, providinganovelpathwayfromthemacroscale tothenanoscalethatwillallowresearchersto observeandanalyzetargetmoleculessuchas DNA,RNA,proteins,andcirculatingtumorcells. Anotherbenefitofnanowiresistheirverysmall diametersizewithhighaspectratio;thiscan allowresearcherstousenanowiresasaprobe tiptostimulateandrecordchangesinelectrical signalsinlivingcells.Nanowireswerealsoused asbiologicalopticalsensors.Theseimprovements innanowirestructureswillallowthedevelopmentofnewbioanalyticalchemistryandmedical diagnosticstoolsthatwillopenanewageof nanotechnologywiththewidespreaduseof nanowiresforbioapplications.
Acknowledgments
Theauthorsacknowledgethe financialsupportreceivedfrom thePortugueseScienceandTechnologyFoundation(FCT/ MCT)andfromEuropeanFunds(PRODER/COMPETE)undertheprojectreferenceM-ERA-NET/0004/2015-PAIRED, cofinancedbyFEDER,underthePartnershipAgreement PT2020.
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