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WoodheadPublishingSeriesin Biomaterials EMERGINGAPPLICATIONS OFCARBONNANOTUBESIN DRUGANDGENEDELIVERY Editedby
PRASHANTKESHARWANI
AssistantProfessor,DepartmentofPharmaceutics, SchoolofPharmaceuticalEducationandResearch, JamiaHamdard,NewDelhi,India
WoodheadPublishingisanimprintofElsevier
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ISBN:978-0-323-85199-2
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TypesetbyTNQTechnologies
Contributors
MohammadA.S.Abourehab
DepartmentofPharmaceutics,CollegeofPharmacy,UmmAl-QuraUniversity,Makkah, SaudiArabia;DepartmentofPharmaceuticsandIndustrialPharmacy,Collegeof Pharmacy,MiniaUniversity,Minia,Egypt
MustafaA.Alheety
DepartmentofNursing,Al-HadiUniversityCollege,Baghdad,Iraq
DuyguBeduk
DepartmentofBiotechnology,GraduateSchoolofNaturalandAppliedSciences,Ege University,Bornova,Izmir,Turkey
SanghamitraChatterjee
DepartmentofChemistry,InstituteofChemicalTechnology,Matunga,Mumbai, Maharashtra,India
PavanKumarChintamaneni
DepartmentofPharmaceutics,GITAMSchoolofPharmacy,GITAM-Hyderabad Campus,Hyderabad,Telangana,India
RambabuDandela
DepartmentofIndustrialandEngineeringChemistry,InstituteofChemicalTechnology
Mumbai-IndianOilOdishaCampus,Bhubaneswar,Odisha,India
MahdiehDarroudi
DepartmentofPhysiology,FacultyofMedicine,MashhadUniversityofMedicalScience, Mashhad,Iran
CerenDurmus
DepartmentofBiotechnology,GraduateSchoolofNaturalandAppliedSciences,Ege University,Bornova,Izmir,Turkey
LopamudraGiri
DepartmentofIndustrialandEngineeringChemistry,InstituteofChemicalTechnology Mumbai-IndianOilOdishaCampus,Bhubaneswar,Odisha,India
IsraelGonzález-Méndez
InstitutodeInvestigacionesenMateriales,UniversidadNacionalAutónomadeMéxico, CircuitoExteriorCiudadUniversitaria,MéxicoCity,Mexico
KenguvaGowtham
DepartmentofIndustrialandEngineeringChemistry,InstituteofChemicalTechnology
Mumbai-IndianOilOdishaCampus,Bhubaneswar,Odisha,India
SimgeBalabanHanoglu
DepartmentofBiotechnology,GraduateSchoolofNaturalandAppliedSciences,Ege University,Bornova,Izmir,Turkey
DuyguHarmanci
CentralResearchTestandAnalysisLaboratoryApplicationandResearchCenter,Ege University,Bornova,Izmir,Turkey
GowthamKenguva
DepartmentofIndustrialandEngineeringChemistry,InstituteofChemicalTechnology Mumbai-IndianOilOdishaCampus,Bhubaneswar,Odisha,India
PrashantKesharwani
DepartmentofPharmaceutics,SchoolofPharmaceuticalEducationandResearch,Jamia Hamdard,NewDelhi,Delhi,India;UniversityInstituteofPharmaSciences,Chandigarh University,Mohali,Punjab,India
RenatR.Khaydrov
InstituteofNuclearPhysics,UzbekistanAcademyofSciences,Tashkent,Uzbekistan
MajidKhazaei
DepartmentofPhysiology,FacultyofMedicine,MashhadUniversityofMedicalScience, Mashhad,Iran;MetabolicSyndromeResearchCentre,MashhadUniversityofMedical Science,Mashhad,Iran
PraveenT.Krishnamurthy
DepartmentofPharmacology,JSSCollegeofPharmacy(JSSAcademyofHigher Education&Research),Ooty,TamilNadu,India
G.KusumaKumari
DepartmentofPharmacology,JSSCollegeofPharmacy(JSSAcademyofHigher Education&Research),Ooty,TamilNadu,India
JavierLara-Romero
FacultaddeIngenieríaQuímica,UniversidadMichoacanadeSanNicolásdeHidalgo, Morelia,Michoacán,México
AhmedR.Mahmood
DepartmentofMedicalLaboratoryTechnology,ImamJa’afarAl-SadiqUniversity, Kirkuk,Iraq
AbdulwahhabH.Majeed DepartmentofChemistry,CollegeofScience,DiyalaUniversity,Diyala,Iraq
LeqaaA.Mohammed
DepartmentofChemistry,CollegeofScience,DiyalaUniversity,Diyala,Iraq
SeyedehElnazNazari
DepartmentofPhysiology,FacultyofMedicine,MashhadUniversityofMedicalScience, Mashhad,Iran
AmmuV.V.V.RaviKiran
DepartmentofPharmacology,JSSCollegeofPharmacy(JSSAcademyofHigher Education&Research),Ooty,TamilNadu,India
MajidRezayi
MedicalToxicologyResearchCentre,MashhadUniversityofMedicalScience,Mashhad, Iran;MetabolicSyndromeResearchCentre,MashhadUniversityofMedicalScience,
Mashhad,Iran;DepartmentofMedicalBiotechnologyandNanotechnology,Schoolof Science,MashhadUniversityofMedicalScience,Mashhad,Iran
ErnestoRivera
InstitutodeInvestigacionesenMateriales,UniversidadNacionalAutónomadeMéxico, CircuitoExteriorCiudadUniversitaria,MéxicoCity,México
SmrutiRekhaRout
DepartmentofIndustrialandEngineeringChemistry,InstituteofChemicalTechnology Mumbai-IndianOilOdishaCampus,Bhubaneswar,Odisha,India
AndreaRuiu
InstitutodeInvestigacionesenMateriales,UniversidadNacionalAutónomadeMéxico, CircuitoExteriorCiudadUniversitaria,MéxicoCity,México
AmirhosseinSahebkar
AppliedBiomedicalResearchCenter,MashhadUniversityofMedicalScience,Mashhad, Iran;BiotechnologyResearchCenter,PharmaceuticalTechnologyInstitute,Mashhad UniversityofMedicalSciences,Mashhad,Iran;DepartmentofBiotechnology,Schoolof Pharmacy,MashhadUniversityofMedicalSciences,Mashhad,Iran
KendraSorroza-Martínez
InstitutodeInvestigacionesenMateriales,UniversidadNacionalAutónomadeMéxico, CircuitoExteriorCiudadUniversitaria,MéxicoCity,Mexico
SunaTimur
CentralResearchTestandAnalysisLaboratoryApplicationandResearchCenter,Ege University,Bornova,Izmir,Turkey;DepartmentofBiotechnology,GraduateSchoolof NaturalandAppliedSciences,EgeUniversity,Bornova,Izmir,Turkey;Departmentof Biochemistry,FacultyofScience,EgeUniversity,Bornova,Izmir,Turkey
Backgroundofcarbonnanotubes fordrugdeliverysystems MahdiehDarroudi1,SeyedehElnazNazari1,PrashantKesharwani2, MajidRezayi3, 4, 5,MajidKhazaei1, 4 andAmirhosseinSahebkar6, 7, 8 1DepartmentofPhysiology,FacultyofMedicine,MashhadUniversityofMedicalScience,Mashhad, Iran; 2DepartmentofPharmaceutics,SchoolofPharmaceuticalEducationandResearch,JamiaHamdard, NewDelhi,Delhi,India; 3MedicalToxicologyResearchCentre,MashhadUniversityofMedical Science,Mashhad,Iran; 4MetabolicSyndromeResearchCentre,MashhadUniversityofMedicalScience, Mashhad,Iran; 5DepartmentofMedicalBiotechnologyandNanotechnology,SchoolofScience, MashhadUniversityofMedicalScience,Mashhad,Iran; 6AppliedBiomedicalResearchCenter,Mashhad UniversityofMedicalScience,Mashhad,Iran; 7BiotechnologyResearchCenter,Pharmaceutical TechnologyInstitute,MashhadUniversityofMedicalSciences,Mashhad,Iran; 8Departmentof Biotechnology,SchoolofPharmacy,MashhadUniversityofMedicalSciences,Mashhad,Iran
1.1Introduction Biotechnologyresearchershavedevelopedakeeninteresttowardnanotechnologyandhavebeenfocusingonworkingwithnanomaterialsin recentdecades[1,2].Becauseoftheiruniqueproperties,nanomaterialsare particularlywell-suitedforbiomedicalapplications.Theyarefacileto synthesize,canbemodifiedinsize,containtunablesurfacechemistry, providelargesurface-to-volumeratios,andaregenerallybiocompatible[3]. Allofthesefeaturesmakenanomaterialspromisingforalmostallaspectsof biotechnology,overcomingthemanyshortcomingsinexistingconventionalmaterials[4].FollowingapioneeringstudybyHiguchietal.on albuminnanoparticles,itwassuggestedthatnanomedicinecouldbean effectivetooltotargettumorsandcancercellsastheabilitytoavoidimmunesystemclearanceisenhanced[5].Nanoparticleshaveshowntohave positiveresultsagainstcoronaryarterydisease,andcancercells,byeffectivelyavoidingclearancefromimmunesystemclearance[6 9].Nanoparticlescanbeusedtodeliveralargevarietyofpharmaceuticalsinaway thatissafer(throughtargetednanomedicinesbylimitingtheamountof drugdelivered)andmoreeffective[10].Biologicalandmedicalnanomaterialshavebeenusedforyears,includingliposomes[11],carbon nanoparticles[12 17],dendrimers[18],ceramicnanoparticles[19],iron oxidenanoparticles[20],titaniumdioxidenanoparticles[21],magnetic nanoparticles,polymernanocomposites[18],silicaandmetalnanoparticles [22].Additionally,manydifferenttypesofnanomaterialshavebeen
EmergingApplicationsofCarbonNanotubesinDrugandGeneDelivery ISBN978-0-323-85199-2
https://doi.org/10.1016/B978-0-323-85199-2.00009-1
proposedasmeansofdrug/genedeliverythatrespondtoexternalstimuli. Inaddition,drugsreleasefromwithinthesenanocarriersaretriggeredby changesinpH,redoxpotential,enzymeactivation,thermalgradients, magnetic fields,light,andultrasound[23].
Amongthenanomaterials,carbonnanotubes(CNTs)havedrawn tremendousinterestinthebiomedical fieldbecauseofboththeirpromising properties,includinghighdrugloadingcapacity[24],highstability[25], needle-likestructure,highsurfacearea[25],biocompatibility[26], flexible interactionwithcargo,considerablestrength,outstandingmechanicaland electricalproperties[27],andtheabilitytodeliverdrugstospecifictissues [28].Despitetheadvantages,italsohassomedisadvantagesrelatedto toxicityandlowbiodegradability[29,30].AlthoughCNTsexhibitsome undesirableproperties,theyarestillbeingutilizedinmedicineininnovative ways,suchasindrugdeliverysystems,genedelivery,genetherapy,diagnosticapplications,aswellasbiosensorsandvaccinedelivery[29].CNTs haveavarietyofappealingpropertiesinbiomedicalapplications,asshown in Table1.1.
ThoughCNTshaveseveraldesirablebiologicalproperties,their biosafetyisoftenanissueofconcern,particularlyinregardstotheiruseand theirbiomedicalapplications.Therefore,acomprehensiveassessmentofthe invivoimpactofCNTsisrequiredbeforewide-scalecommercial biomedicalapplicationsareundertaken.StudiesonCNTshavebeencriticizedfortheirinaccuraciesandincompleteness,rangingfromanimal modelsthataren’trepresentativeofhumanexposureroutestostudiesthat lackevenathoroughdescriptionoftheimpurities,chemistry,charge,and dimensionsofthestudiedCNTs[37].Graphenesheetsarerolledseamlessly asacylindricaltubetoformsingle-wallcarbonnanotubes(SWCNT),as wellasmulti-walledcarbonnanotubes(MWCNTs),whicharecomposed oflayersofgraphenesheetsstackedononeanother.Moreover,thereare threemainmethodsforthemanufactureofCNTs:chemicalvapordeposition(CVD),laserablation,andarcdischarge[38].Inthecurrentchapter book,wesummarizepromisingandnot-so-promisingstudiesshowingthe importanceofCNTsinavarietyofbiomedicalapplications.Manyresearch studies,particularlyperformedinyear2016 2022,areassessedwithcritical insightintowhatthesestudiesconclude.Herein,theuptakeofCNTs,the deliveryofpharmaceuticalagentsusingCNTshasbeencovered.Wealso discussconcernsraisedaboutthetoxicologyofCNTsattheendofthis studyandoutlinewhatandwherethe fieldurgentlyneedstogrow.
Table1.1 Variousapplicationsofcarbonnanotubes.
ApplicationDescriptionReferences
Diagnosingapplication
Bioimaging andbiosensing
Carbonnanotube’soptical,electronicand mechanicalpropertiesmakeitapromising materialfortheproductionof electrochemicalandopticalbiosensorsand someotherapplicationsderivingfrom CNTsbecauseoftheirhighphotostability andlackofquenching
Therapeuticalapplication
Photothermal therapy
Drugdelivery
Tissue engineering
Lab-on-chipdevices
CNTswouldproduceheatbyconverting near-infraredradiation(NIR).
Theuniqueneedle-likeshapeofcarbon nanotubeswiththeabilitytoquickly penetratecellmembranesmakesthemideal carriersofdrugs/genesduetotheirhigh surfacearea,multifunctionalsurface chemistry,lackofimmunogenicity,andhigh surfacearea.
Carbonnanotubescanbeusedintissue engineeringbecauseoftheir biocompatibility,stiffness,mimickingof naturaltissuenano fibers,celladhesionand proliferationstimulation,andabilitytoform 3Dstructures.
Miniaturizedsystemssuchaslab-on-a-chip devicesareusedtoexaminedrugs,grow cells,andmodeldiseasesusingtinyvolumes of fluid flowinginvariouschannels.The CNTswouldbeusedinLOCdevicesas membranechannels,sensors,andchannels walls.
1.2Quantitativeapproaches [31,32]
[33]
[34]
[35]
[36]
Asignificantapplicationofnanoparticlesisthedeliveryofdrugs;becauseof theirlargesurfaceareas,nanoparticlesarecapableofdeliveringlargequantities ofdrugsorothermedicalcargos[39,40].Therefore,developingefficientdrug deliverysystemsisvitaltohumanhealth[41].Theranosticwithnanotechnologyforcancerhasemergedasapromising fieldthatcouldintegratethe
treatmentanddiagnosisofcancerbycombiningnanotechnologieswith therapeuticagentstoenabletargeteddrugaccumulationincancer-specific cellswithoutaffectingnormalcells[42].Drugdeliveryproceduresshould besignificantlyimprovedtoensuresustainability,lowdisruptions,andprecise andaccuratecontrolleddeliveryofdrugs[43].Nanomaterial-baseddrug deliverysystemshaverecentlybeenstudied,andanumberofbreakthroughs havebeennotedthereafter.Therehavebeennumerousstudiesondrug deliverysystemsinrecentyears[44,45].Thebibliometricisinsufficientto assessaresearchareaoutputs;itshouldincludeotherinputssuchasliterature reviewstodiscovertheinsightofpublicationstrends[46].Thisresearchaims toexploretheresearchstatusdoneinthis fieldofstudyfrompasttothecurrent yearbyabibliometricapproachandqualitativeliteraturereview.Toensure thereliabilityoftheanalysisandinputdataforthesoftware,scientometric studiesutilizingrecognizeddatabasesuchasGoogleScholar,ISIWebof Science,andScopushavebeenaccessed.ThisstudyusedtheScopusdatabase foritsextensivecoverageandcomprehensivecontent.
From1965to2021,bibliometricsearcheswereconductedinGoogle Scholar,Scopus,PubMed,andWebofScienceCoreCollections (n ¼ 70,300).Datawereobtainedfromtheonlineversionofthecore collectioninWebofScienceonJanuary15,2022[47].The “Carbon nanotube*” OR “CNT*” OR “SWCNT*” OR “MWCNT*” toidentify allarticlesrelatedtotreatmentfrom1990to2022thatcontainthekeyword inthetitlelist,and189,358publicationswereencountered.Also,articles usingthekeyword “DrugDelivery*” AND “Carbonnanotube*” OR “CNT*” OR “SWCNT*” OR “MWCNT*” toidentifyallarticlesfrom 1990to2022thatcontainthekeywordinthetitlewhich,4748publicationsmettheselectioncriteria.Uponfurtherscreening,only3137publicationswerecategorizedthrough “DrugDelivery*” AND “Carbon Nanotube*” OR “CNT*” OR “MWCNT*” OR “SWCNT*” keywordsthatwereutilizedforfurtheranalysis.Moreover,moredataforthis studybasedontitlesearchwerederivedfromSCOPUS,andthetimespan wasfrom1985to7rdFebruary7,2022.Also,bibliometricstudieswere carriedoutontheGoogleScholarandPubMeddatabases,resultingin 70,300publicationsand1353publications.Thisdatacollectionwithan initialtitlesearch “DrugDelivery*” inthe “TitleofArticle” hasbeendone onanotherwell-knowndatabaseScopus[47].Therewerealmost38,996 documentswiththetitleof “DrugDelivery*”;andnearly125,277documentswiththetitleof “CarbonNanotube*” whilethe “CNT*” OR “MWCNT*” titlesearchtermswereusedtoretrievethedata.Thesearch
returned3571documentsfromSCOPUSdatabase.Aftercarefulinspection,atotalof1846publicationswereidentifiedassuitableforsubsequent analysisfromSCOPUSdatabase.Thesearchreturned1230reviewpapers, 201letters,and149conferencepapers(Fig.1.1).Besides,IndexKeywords captureanarticle’scontentwithgreaterdepthandvariety[46].
Thetotalnumberofrecordsis1846,andthetotalnumberofarticlesis 1332inthesampleperiodfrom2012to2022.Thereare160author contributionsin160journalsand10sub-divisionsinthepublications.4637 wordswereidentifiedasfrequentlyusedinthisliterature,and1457institutionscontributedtheirarticlesfrom62countries(Fig.1.2).
In Fig.1.2c (inset),documentsarecategorizedaccordingtotypeina detailedclassification.Thearticleswith52%and1441recordsrepresenta significantportionofthetotal.Reviewdocumentsaccountedfor36%of thetotalrecords,with993records.Totaldocumentsnumbered1332in7 categoriesaccounted,duetotheircredibilityandacceptanceinscientific communities,articlesarestronglypreferredasthedocumenttypebythe authors.
Figure1.1 Prisma flowdiagram.
Figure1.2 (a)Thenetworkofkeywords,(b)clusteringofkeywords,and(c)categories ofthesubjectarea,andinsetcategoriesbyarticletype.
Keywordsarehighlyinfluentialonthemechanismandeffectivenessof documentsearches.Keywordsserveascriticallinksamongtherangeof availabledocumentstobeidentifiedasinformationsources.In Fig.1.2a,the toptwokeywordsarecarbonnanotubesanddrugdelivery,with459and 337occurrences,respectively.Inordertoidentifythedocumentimmediatelyandinatimelymanner,itisobviousthattheexactlinkwordsor phrasesshouldbeused.Basedonthescreeningofthe25topkeywords,we foundthatthemostpopularkeywordsfallintotwocategories:thecompoundnameandtheapplicationofthecompound.Anothereffective keywordwithmorethan50occurrencesiscarbonnanotube,walled
carbon,single-walled,multi-walled,moleculardynamic,deliverysystem, multi-walledcarbon,drugrelease,wallcarbon,andcancertherapy.These keywordswillbehelpfulinidentifyingthedocumentthatbestdescribes carbonnanotubesandtheirapplicationsforfutureresearchers. Fig.1.3 displaystheoccurrencesofthekeywords.
Tounderstandthedifferentphasesofgrowthofthepublication numbers,thecollecteddatawasorganizedchronologically. Fig.1.3 depicts
Figure1.3 (a)Trendtopicgrowthbetween2012and2022,and(b)averagearticle publishedperyeartimespan2012 22.
theschematicrepresentationofyearlyincreasesinrecordnumbers. Researchoncarbonnanotubeanddrugdeliveryshowsaslowonsetwith fewpublicationsbetween2012and2016.Thetrendwasdownwardfrom 2016to2017.Asexhibitedinthetrendtopicgrowth,anincreasewas depictedin2017basedonbothkeywordscarbonnanotube,anddrug deliverysystem,whichthereisagoodconsolidationwithpublication trends.By2022,therewillbeanincreasingtrendinpublications.The recordsshowedgrowthbetween2017and2020from9%to14%.There were135,164,and178recordspublishedin2019,2020,and2021, respectively,andapercentageof10%,12%,and14%wasrecorded.New developmentsandapplicationindrugdeliveryandcarbonnanotubes relatedmaterialsexplainstheincreaseinpublicationssince2017.
Fig.1.4 presentsarankingofthecountriesinvolvedincarbonnanotubesresearchaccordingtothenumberofdocumentstheyhaveproduced. India,theUnitedStates,andChinaproducethemostdocuments,with 576,518,and514.Chinahad6257citations,whiletheUnitedStateshad 3419.ItisnoteworthythattheChinaachievedahigherratioofcitationsto documentsthanUSA.Iranisranked4thoverall,followedbytheUnited Kingdomin4thplace,Italyin6thplace,andSouthKoreain7thplace. TherehasbeenanoticeableincreaseinresearchinCarbonnanotubeusage inthedrugdeliverysystemasshownbythereportedachievements.The majorityofthecontributionsoriginatefromChina,India,andtheUnited States.Severalcountrycollaborationclustersshowtheimportanceofgroup researchcontributionsandthecurrenttrends.Chart4Cdepictingvarious clusteringpatternsofCluster1identifiesitasthemostproductive. Furthermore, Fig.1.4a presentsageographicmapofthecountriesinvolved. ThisgraphisdrawnbytheVOSviewerpackage(www.vosviewer.com), whichisatoolforcomprehensivesciencemappinganalysisforquantitative researchinbibliometrics[48,49].Also,theredcolorintensitystatesthefour highestnumberofrelateddocumentspublishedineachcountry.Fromthe datainthegraph, Fig.1.4a exhibitedthatbetween50countries,India, China,andtheUnitedStateshavespecializedstudiesearlierthanother countrieswiththemostsignificantnumberofnormalizedstrongcollaborationlinkstoothercountrieswiththerateof20%ofpublication.China, theUnitedStates,andIranhavetherateof18.6%,18.5%,and12%, respectively,afterIndiainthementionedtopic.Athree-fieldplot(Sankey Diagram)listingtherespectiveinstitute,authors,andkeywordsonthe consideredtopicisshownin Fig.1.4c.This figureshowstherelationship amongtopinstitutes,topauthors,andtopauthors’ keywords.Thetop five
Figure1.4 Publicationofcarbonnanotubeindrugdeliverysystemresearchpapers: topcountriesandclusters(aandb),and(c)three-fieldplotoftop-author,topcountries;andtopauthors’ keywordsontheconsideredtopic.
institutesinwhichthesedocumentswerepublishedincluded “Ministryof EducationChina” (58DOC), “IslamicAzadUniversity” (53Docs), “ChineseAcademyofSciences” (42Docs), “CNRScenternationaldela ResearcheScientifique ” (35Doc),and “TehranUniversityofMedical Sciences” (31Docs).Thetop fiveauthorsalsoincludeJain,N.K,Mehra, N.K.,Kostarelos,K.,Raissi,H.,andBianco,H.,basedondrugdelivery andcarbonnanotubekeywords.
1.3CNTmorphologyandstructure Thecylindricalsheetofgraphenewithcarbonatomsbondedassp2 hybridizationisthoughttoresemblehollowfullerenetubes.Thecarbon nanotubesarecomposedofcarbonsheetsmadefromrolledgraphite,which isasourceofcarbonallotropesaswellasgraphiteandfullerenes[50].In many fields,carbonnanotubesareusedintheformofbuckytubes,with theircylindricalshapeanduniqueproperties.Inadditiontotheirmechanical,thermal,optical,andelectricalproperties,theyalsopossessthe followingcharacteristics[51].Highstiffnessandrobustnessaboundin nanotubes,whichalsopermitreversiblecollapseandbuckling.Inhexagonal networks,thehighaxialYoung’smodulus(degreeofstiffness)resultsin tensilestrengthsof150GPaduetothehighC Cbondrigidity[52].CNTs arethusamongthemostrigidmaterialsknownwhilestillbeingableto buckle(elasticdeformation)whensubjectedtocompressionforces[53].In additiontotherudimentaryconstituents,carbonassembliesformmany differentconfigurationsandshapes[54].Underhighpressure,nanotubes canbeassimilated,resultinginastrong,infinite-lengthwirebyreplacing severalsp2 bondswithsp3.TheuncoveredCNTswerediscoveredinrecent yearsbyIrjima,whodescribedmulti-walledCNTsincarbonsootproducedbythedevelopmentoftheC60moleculeinanarcevaporation methodforthe firsttime[54].
Figure1.4 Cont'd
1.4Classi ficationofCNTs Nanotubesmayindeedbealienatedintovariousclassificationsbasedupon thenumberofsheetsofgrapheneexistentintheCNTs.Thefollowingare thereforesub-dividedinto:
1.4.1Single-walledCNTs(SWCNTs) Single-walledCNTsareformedbyorientingagraphenesheetonasingle wall.AcatalystisrequiredforthesynthesisofSWCNTs,resultinginanonpureCNTwithoutcomplexitywithareadilytwistedstructure[55]. Sometimes,theyappearas fluffyblackpowderorgranular flakeswitha metallicappearance[56].AvarietyofSWCNTsareavailable,whichcanbe trundledupasaseamlesstubeinmultipleways.Whenorganizedaccording totheirchiralityanddiameter,SWCNTsmayactmorelikeclearly delineatedsemiconducting,metallic,orsemi-metallicstructures[57].There isanewtechniquepublishedinUSpatientsforpreparingarraysortightly packedbundlesofsingle-walledCNTs,withadiameteroflessthan0.2m thatwouldbehelpfulinmeetingcommerciallyfeasiblereactionrequirements[51].
1.4.2Multi-walledCNTs(MWCNTs) ThesearetheCNTsthatcontainmultilayeredgraphenerolledover themselveshavevaryingdiametersrangingfrom2to50nmwhichinturn dependsonthenumberoftubes[58].Itssynthesisiscatalyst-free,andthe MWCTsarehighlycomplexandcannotbetwistedeasily[51].Thesetubes haveadistanceofapproximately0.34nminbetweenlayers[59].Their typicalformappearsinformof fluffyblackandgranularpowders.Thereare MWCNTsoftwodifferenttypesbasedonthegraphiticsheetarrangement pattern.Asanexampleofthis,wecanlookattheRussian-dollmodel wherethegraphiticsheetsformconcentricallyalignedsheets,forexample,a lengthof(0,14)SWCNTsurroundingashorterlength(0,12)SWCNT. Graphiteisrolledarounditselfinthesecondmodel,resemblingascrollof parchmentorarolled-upnewspaper[60].
1.4.3Double-walledcarbonnanotubes(DWCNTs) ThereisanothertypeofCNTthatissimilartoSWCNTswhichalsohas twoconcentriclayersthatencloseboththeinnerandoutertubesofthese nanotubes.Thesenanotubesareofseriousconcerninthepharmaceutical industry[55].
1.4.4CNTtypesbasedonchirality
ChiralityisacrucialfactorindeterminingtheelectricalpropertiesofCNTs. Dependingonthechirality,CNTscanbecategorizedasanarmchair, zigzag,andchiral,asillustratedin Fig.1.5 [60].Inthearmchair,an arrangementofbondsinoneofthechairsisperpendiculartothetubeaxis; inzigzag,thereisanarrangementofbondsinwhichthetubehasaVshape perpendiculartothetubeaxis.Chiralorhelicalconfigurationareboth contrarytotheabovetwotypes[57,61].Conductivityandelectrical characteristicsofCNTsarebotheffectiveindicatorsofCNTchiralityand maybeusedasabasisfornanoelectronicdevices[62,63].Basedontheir structuraltransformations,preparationtechnique,andsolubilitycharacteristics,CNTsarecategorizedintospecificcontexts,suchasfunctionalized, surfactant-assisted,solventdispersed,andbiomolecularassistednanotubes [64].
(a) Armchair(b) Chiral
(c) SWCNTs(d) MWCNTs
Armchair
Zigzag Figure1.5 Typeofcarbonnanotubes.
1.5Drugloadingoncarbonnanotubes Theterm “drugloading” referstothecombinationofdrugandcarrier, whichdeliverstheactivemedicationtothetargetcellsortissues.CNTsare widelyusedforthispurpose,particularlyforlarge-scaledrugdelivery becauseoftheirhighsurface-to-volumeratioandsphere-shapedshape[65]. Moreover,amphiphilicorhydrophilicpolymersonCNTsurfacescanincreasetheirloadingcapacity[66,67].Inadditiontothis,thechemical functionalizationofnanotubes’ surfacescouldalsoenhanceCNTs’ biocompatibility[68,69].ModificationofCNTscanbeachievedthrough thecovalentattachmentofPEGlayersontheirsurface,PAMAMdendrimersontheirsurface,amphiphilicdeblockcopolymersontheirsurface, ordispersingthemodifiedmaterialsinamatrixofhyaluronicacid.The mechanicalstrengthofCNTs,likeSWCNTs,enhancesthepropertiesof bothpolymericandnon-polymericcomposites[70].Itisalsonoteworthy thatthesenanomaterialscanalsocarrypharmaceuticalagentsbyencapsulatingthemwithinhollowcavities[71],adsorbingthemwithinthewallsof CNTs,andbindingthemtotheirsurfacesuponfunctionalization[72].A drugdeliverysysteminvolvingencapsulationhasmoreadvantagesbecause thedrugsarereleasedinaspecificwaywithinthetargetedcellswhile preventingtheirdegradation[73]. Table1.2 showshowtherapeuticdrugs
Table1.2 Mechanismofloadingdrug.
EntryDrug
Typeofcarbon nanotube Processof immobilizationReferences
1PregabalinSWCNTEncapsulation[74]
2DoxorubicinArmchairand zigzagCNT Adsorption[75]
3IfosfamideArmchair SWCNT Encapsulation[76]
4Paclitaxelf-MWCNTEncapsulation[77]
5DoxorubicinCovalent-fMWCNT Adsorptionand encapsulatingofdrug [78]
6CisplatinCarboxyl-fMWCNTs Encapsulation[79]
7DoxorubicinMWCNT-FAEncapsulation[80]
8Cipro floxacinPEG/GelChitMWCNT Graftingin nanocompositematrix [81]
9Doxorubicinf-SWCNTEncapsulation[82]
wouldbeattachedtodifferenttypesofcarbonnanotubes.Variouschemical andelectricalmethodsareavailableforcontrollingthereleaseofdrugsfrom CNTs.CNTscanalsobesealedwithpolypyrrole(PPy) filminorderto preventdrugrelease[83].Drugdeliverysystemscouldbemademoreselectivebyusinghomingdevices,suchasepidermalgrowthfactor(EGF),or folicacid[84].Awiderangeofbiomedicalapplicationsmaybepossiblefor CNTsasadrugdeliverycarriers.
Unlikeencapsulationor “endohedralmodification” [73],theseCNTs servetomaintainthestructuralintegrityofdrugs,whichhelpstominimize theirdegradationandinturnmaximizetheirreleasefromwithinthem undercontrolledconditions[85].Duetohydrophobicandcapillaryforces, thisapproachismostusefulfordrugswithlowsurfacetension.Forinstance, Fig.1.6 showshownanoparticlesofgoldareincorporatedintothecarbon nanobottlestopreventtheuncontrolledreleaseoftheencapsulateddrug (cisplatin)[86].Whenthedrugsareloadedbyexohedralmodification(as opposedtoencapsulation),itbecomesmuchmoreexposed.Tethering referstocovalentinteractionswithnoncovalentlyattacheddrugs;asoneof thebio-conjugationmethods.Afurtherstepofoxidationisrequiredinthe tetheringprocessbeforefunctionalgroupscanbeproducedforconjugation. Additionally,acovalentbondmaychangethedrug’smolecularstructure, therebyalteringitsbioactivityandspecificity[87].Thistetheringapproach issuperiorduetostrongcovalentbondsthatproduceastableplatform
Figure1.6 Schematicillustrationofcisplatindeliverysystemandpossibleinternalizationmethodofcarbonnanotubeincludingloadingofthedrugonthesurfaceof carbonnanotube,thencisplatincarriedinside,invivostudyofcurrentnanocarrierand pH-responsivereleasingdrugleadingtodecreasingoftumorsize.
betweennanocarriersanddrugsratherthanthenon-covalentmethod, whichultimatelycausestheundesirabledissociationoftherapeuticagentsin biological fluids.CNTsaregenerallyusedtodeliverdrugstotargetcellsin thefollowingway.ModifiedCNTscontainchemicalreceptorsthatattach todrugmolecules.Drugmoleculesaretransportedbythesechemicalreceptorsinsidenanotubes[88].Dependingonthemethodused,thereceived conjugatecanbeinjectedintothebodythroughinjection,oraladministration,ordirectlyuponcontactwiththetargetedcell.Usingtheendocytosispathway,thedrug-loadedintoCNTcapsulescanbeinternalizedby thechemicalreceptorsandeventuallyemittedbythecells[88]. Fig.1.6 isa schematicillustrationofaneffectivedrugdeliverysystem.
1.5.1CNTsandcellularuptake Itiscrucialtounderstandhowdrugsaretakenupbytheprojectedcellsto comprehenddrugpharmacokineticsandpharmacodynamics.Theremustbe abetterunderstandingofbiochemicalpathwaysanddrugpermeationacross cellularmembranes.Drugswithhighsolubilityarethoughttobeabsorbed primarilythroughdiffusionthroughthelipidbilayer.However,inthecaseof highmolecularweightdrugs,suchmechanismisimpaired,aslowlipophilicityinterferesinpassingthroughthebilayerstructure[89].CNTshave remarkablepropertiesthatallowthemtobeabsorbedbyawidevarietyof cells.CNTscanpenetratecellmembranesefficientlybecauseoftheirneedlelikeshape,whichcanbeeithergoodorbaddependingontheintended application.Hence,CNTsaresuitableforarangeofbiomedicalapplications, includingthedeliveryoftherapeuticagentsandgenes[90].Althoughmany studieshavebeenconductedoncellularuptake,therearestillmanyquestions regardingcellularpathwaysinitiatedbyCNTsandthedeliveryoftherapeutic agentsandgenes[91].Furthermore,notonlyisitessentialtodeterminehow cellstakeupCNTs,butiftheCNTswilldeliverdrugsviablytothecells. Therefore,itisextremelyimportanttocarefullystudyCNTinternalization. Several(notone)pathways,dependingonthepropertiesoftheCNTs,have beenelucidatedforcellularuptakeofCNTs[92].SomecomprehensivereviewsshowthatthereisnosinglemechanismforcellularuptakeofCNTs.
Inparticular,CNTscanbeinternalizedviavariousmechanisms,including (1)directpenetrationthroughthecellmembraneor(2)passiveandactive uptake,whichhavealsobeencalledindependentanddependentpathways, accordingly[93].BelowisasummaryofthecurrentliteratureonCNTentry intovariouscells,emphasizingdimensions,celltypes,andCNTfaces(Fig.1.7).
ThedistributionofCNTswithincellscanoccureitherpassively throughdiffusionacrossthecellmembranelipidbilayerorthroughneedle mechanisms.CNTsovercomesuchbarriersduetotheirneedle-like structureandhighrespectratios[27].CNTscanalsobeinternalizedby endocytosis,whichcanbeclassifiedinto fivegroups:phagocytoses,pinocytosis,caveolin-mediatedendocytosis,clathrin/clathrin-mediatedendocytosis,andclathrin/caveolaeindependent.Aphagocyticpathwayisthe processinwhichlargeparticles(w1 mm)entercells.Itpredominantly occurswithinneutrophils,macrophages,andmonocytes.Cellularuptake occursprimarilythroughreceptor-mediatedendocytosis,whichinvolves clathrin-coatedendocyticvacuoles.Caveolaegetsinvadedbynanomaterials 60nmindiameter,whichcontainshighlevelsofcholesterolandsphingolipids.TheCaveolin-mediatedendocytosisprocessisresponsiblefor transportingvesicularmaterialandentrappingvirusesandbacteria.Caveolin andclathrinareknowntoplayaroleincellularendocytosisandcan facilitatetheinternalizationofCNTswithadiameterof100nm.
ThemacropinocytosismechanismisthoughttotakeupCNTsthatarelarger than300nm.WhiletheentryofCNTsandtheirdrugcargomayoffermany advantages,eachmechanismalsohasdrawbacksthatshouldbeconsidered.There areseveralfeaturesthatinfluencecellularuptakes,suchasCNTtypes(MWCNTs orSWCNTs),dimension,surfacecharge, surfacefunctionalization,degreeof aggregation,functionalgroupchemistry,celltype,andagglomeration[94].
Figure1.7 Cellularuptakeofcarbonnanotubeintoendocyticvesicles.
1.5.2SizeofCNTs ThepreviousstudiesdemonstratedthatCNTswithasmallerdiameter resultinahighercellularuptake[22,95].Anumberofmechanismsare involvedinthepassageofshortCNTsthroughcellmembranes,butactive endocytosis,particularlyclathrin-mediatedendocytosis,isgenerallythe mostimportant[96,97].Indeed,theshortertheCNT,thegreaterthe chanceofpassiveinternalization.Inthisregard,Zhangetal.evaluatedcell uptakebasedonCNTparticlesizeandcomparedCNTparticlesizesof eighttypes,consistingofMWCNTsandSWCNTs,withmacrophages (RAW264.7),ranginginsizesfrom30to400nm.Theirresultsindicated thatmacrophageswereabletotakeupCNTsinmoresignifi cantquantitieswhentheirparticlesizeincreasedafterincreasingcytotoxicity,with energy-dependentphagocytosisastheprimarymechanismofcellular uptake[98].
1.5.3Degreeofagglomerationandaggregation ThedegreeofagglomerationandaggregationofCNTsmayaffecttheir internalization.AstudybySongetal.foundthathigherconcentrationsof O-MWCNTsresultedinhigheruptakewithinhumanepithelialcervical cancercells(HeLa).However,thesecellswerenotcytotoxicatconcentrationsoflessthan150 mg/mL[99].Theamountofagglomerationand toxicityincreasedslightlywhentheconcentrationofO-MWCNTswas raisedto150 mg/mL.Accordingtotheir findings,agglomerationassisted endocytosisofO-MWCNTsoccurredduetotheirabilitytointeract effectivelywithcells.AregulatedagglomerationofCNTsinsomedelivery systemsiscapableoffacilitatingthedeliveryofdrugs/genesthroughtheir highuptakeandlowtoxicity.AstudyconductedbyKurodaetal. demonstratedthataggregatedCNTsenhancesuptakeinRAW264cells [100].Thissuggeststhataggregationwouldbeeffectiveonuptake mechanisms.
1.5.4Surfacecharge CNTscanbemodifiedfortheirsurfacechargebyalteringtheelectrostatic interactionsanddispersibility.Consequently,thesurfacechargewouldbe relevanttotheuptakeofNTsbycells,aswellasotherbiologicalprocesses [101].TheSWCNTswerefunctionalizedbyBudhathoki-Upretyetal. usingpolycarbodiimidepolymerswithcarboxylicacids(COOH-CNT)or primaryamines(NH2-CNT)attachedtotheirsidechains,whichthese
complexeshavesurfacechargesofapproximately66.8and52.8mV, respectively[102,103].CationicnanotubescouldbemorereadilyincorporatedintoHeLacellsthananionicnanotubes.However,serumproteins intheculturemediaadsorbCNTsinthecellculturemediaandinfluence cellularuptakeoftheseCNTs.Itisimportanttorememberthattheproteinsadsorbtothenanomaterialsthatcellsrecognize,notthenanomaterial itself.Thatisreferredtoasthe “proteincoronaeffect” ofnanomaterials,a layerofproteinsadsorbedtoananomaterialwhenexposedtobody fluids [104].CNTscanthereforebedesignedsothattheycanbetakenupby cells.Consequently,CNTscanbedesignedtodeliverdrugsefficiently whentheirsurfacechemistryistakenintoaccount.Thereactivityof nanomaterials’ surfaceswithcellularmembranescontributestotheir toxicity.ItisthenonbiodegradabilityofCNTsthatgivesthemtheir toxicologicalproperties.ThebindingofbloodproteinsinfluencesbiologicalpathwaysoftheCNTs,andcytotoxicitycanthereforebedecreasedasa result[105].AccordingtoGeetal.,bloodproteinsbindtothesurfaceof SWCNTs,enablingchangestotheircellularinteractions.Thisultimately reducestheircytotoxicityintwodifferenthumancelllines,including humanumbilicalveinendothelialandacutehumanmonocyteleukemia (THP-1)cells.
1.5.5Celltype
Cellularuptakeratesandmechanismsmayvarybythecellularsystem[106]. TheinternalizationofCNTswasevaluatedinhumanlungcancercells A549,humanlungcancercellsCalu-6,humanbreastcellsMCF-7,and mousemacrophagesJ774bySummersetal.Heinhisworkdemonstrated thatthehighestCNTuptakeoccurredintheJ774cellline[101].After exposuretoCNTsfor24h,A549cellshada w40%loweruptakethan J774(whichshowedthehighestuptake).TherewasnosignificantdifferencebetweentheMCF-7andCalu-6cells,butbothtypescomprisedof about30%J774CNTs.Additionally,macrophagescouldtakeupSWCNTs moreefficientlythan fibroblasts.Althoughmacrophagespreferentially phagocytoseparticleswithadiameterofover500nm, fibroblastsprimarily endocytoseparticleswithadiameterof200nmandless[107].Inaddition, J774cellscantakeuplargerparticlesandalsotheaggregatesofCNTs.By aggregatingCNTswithinphagocyticcells,nanoparticlesareretained withinthem,whichmakesthemidealcarriersforCNTtransportationinto tumorcells.
CNTsandtheircellularuptakehavebeenanalyzedusingawiderange oftechniques,includingatomicforcemicroscopy,transmissionelectron microscopy,dynamiclightscattering, fluorescencemicroscopy,surfaceenhancedRamanscattering,andconfocalRamanspectroscopy.The characterizationandvisualizationofcellularuptakeofCNTsarebasedon somecharacteristicsofCNTs,suchasopticalcharacteristics[107 109].The evolutionofnanotechnologybeganwithimprovementsinmicroscopy,and thisheredepictsisnolessertruthintermsofCNTcellular internationalization.
1.6Drugdeliveryusingcarbonnanotubes Inrecentdecades,biomedicalresearchershavefocusedsignificantattention onusingCNTsforvariouspurposesduetotheirhighelectrical,physicochemical,andmechanicalpropertiesandthehighaspectratioofCNTs.In addition,theyhavebeenusedasnanocarriersforthedeliveryofseveral plasmidDNAs[110],proteins[111],peptides[112],siRNAs[113],andAPI [114].
1.6.1AntineoplasticAPIs Worldwide,cancerrankssecondbehindcardiovasculardiseases.Various unwantedtoxiceffectshavebeenobservedinthesurroundinghealthy tissuesasaresultofAPIstherapy[115].Oneofthemostchallengingaspects oftherapeuticresearchremainsdrugdeliverytocancerouscells[116].This isbecausetumorcellsexpressP-glycoprotein(P-gp),whichwillblockthe entryoftherapeuticagentsintothetissue.Therefore,mostofthetumortargetedantineoplasticagentsareunexpectedlydestroyedbeforetheycan killthetargetedcells.Forthetreatmentofcancer,innovativetechnologies areneededfordeliveringtherapeuticagents[117].
Differentnanomaterialshavepreviouslybeenutilizedasdrugdelivery agents.AwidevarietyofantineoplasticagentscanbeloadedinCNTs, includingdoxorubicin,cisplatin,methotrexate,andcamptothecin.Asan example,cisplatinhasbeenusedtotreatavarietyofcancer-relateddisorders.CisplatinstimulatescellulardeathbyinhibitingDNAreplicationand cross-linkingbetweenDNAstrands.Despiteitsanticancereffect,thisdrug producesmanysideeffects,includingototoxic,nephrotoxic,andneurotoxiceffects.
Thechlorideionsinplasmacanobliteratethetherapeuticeffectofdrugs bycausinganinterferenceintheirinteractionwithwater.Duetothis,
CNTsareusedasdrugcarrierstoreducesideeffectsbypreventingthe deactivationoftherapeuticagents.Inonestudy,thesynthesisoffunctionalizedSWCNTscontainingcisplatintotargetprostatecancercelllines PC3andDU145wasreported.Cisplatinactsbypenetratingdeepwithin thecellularmembraneandselectivelyaccumulatingwithinthecytoplasmof cancerousprostatecellsbasedon findingsofcellularuptakestudies. Therefore,theencapsulationofcisplatinhasprovedtobeveryeffective factorinstabilizingitsadministrationtocancerousprostatecells[118].
Ithasalsobeenextensivelyusedfortreatingcancerwithdoxorubicin drugasananticancertherapeuticagent.Thechemicalstructureofdoxorubicinhasbeenshownin(Fig.1.4b).Thenon-covalentcomplexationof MWCNTsandfunctionalizedSWCNTswithpolyethyleneglycol(PEG) wasalsodemonstratedbyHwang[119].Inaninvestigation,itwasfound thatMWCNTscombinedwithdoxorubicinworkbetteragainstcancerous cellsthandoxorubicinalone.SWCNTshavebeensynthesizedandmodifiedwithdifferenttypesofpolysaccharidesaswellaswithdoxorubicinand folicacidinrecentyears[120].Insomecases,thereleaseoftherapeutic agentsfromwithinthesenanocarrierswasreportedtobepHdependent.In thisregard,CNTsarefunctionalizedonthesurfacetocontroltherateof drugreleaseandloadingefficiency.AccordingtoFabbroetal.research [116],anovelmethodisessentialforimprovingtheconstructionand characterizationofmodifiedCNTstoallowthemtobeapplied therapeutically.
1.6.2Anti-inflammatoryAPIs Manystudieshavebeenconductedinordertoenhancecellularuptake propertiesovertheyears.Inadditiontoimprovingthemoleculerelease profile,thisalsohelpsinreducingsideeffects[121].Meanwhile,researchers havealsobeenlookingatCNTsasameansofdeliveringanti-inflammatory APIs.Zanellaetal.(2007)investigatedananti-inflammatorydrugknownas nimesulideonbothSi-dopedcappedandpristineSWCNTsusing firstprincipalcalculations(DFT).BasedonDFTcalculations,theyreported theuseofCNTsaspotentialcarriersforaromaticresiduesandhavealso demonstratedimprovedphysisorptionwithSi-dopedSWCNTsdueto theirelectronicproperties[122].
Duetotheinefficiencyofconventionaladministrationstrategies,antiinflammatorydeliverysystemsprovidestableplasmalevelsofthetherapeuticagentoveralongerperiodoftime,allowingforextendeddrug
