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BIOMIMETIC NANOENGINEERED MATERIALSFOR DELIVERY BIOMIMETIC NANOENGINEERED MATERIALSFOR Editedby:
Elsevier
Radarweg29,POBox211,1000AEAmsterdam,Netherlands TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates ©2019ElsevierInc.Allrightsreserved
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Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythe Publisher(otherthanasmaybenotedherein).
Notices
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Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluating andusinganyinformation,methods,compounds,orexperimentsdescribedherein.Inusingsuch informationormethodstheyshouldbemindfuloftheirownsafetyandthesafetyofothers,including partiesforwhomtheyhaveaprofessionalresponsibility.
Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assume anyliabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterofproductsliability, negligenceorotherwise,orfromanyuseoroperationofanymethods,products,instructions,orideas containedinthematerialherein.
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Publisher: MatthewDeans
AcquisitionEditor: SabrinaWebber
EditorialProjectManager: AliAfzal-Khan
ProductionProjectManager: SojanP.Pazhayattil
CoverDesigner: MarkRogers
TypesetbySPiGlobal,India
Abouttheeditorsxi
1.Introductiontosmartdrugdeliverysystems1 PramodDarvin,AneeshChandrasekharan,T.R.SanthoshKumar
1.1 Overview1
1.2 Stimuli-responsiveSDDS2
1.3 Conclusion8 References8
2.Nanofiber-basedanticancerdrugdeliveryplatform11
ArathyramRamachandraKurupSasikala,AfeeshRajanUnnithan, ChanHeePark,CheolSangKim
2.1 Introduction11
2.2 State-of-the-artnanofiberfabrication13
2.3 Implantableelectrospunnanofibersaslocaltherapysystems forcancertherapy15
2.4 Conclusionandchallenges28 References30
3.Transdermaldrugdeliveryviamicroneedlepatches37
AminGhavamiNejad,BrianLu,XiaoYuWu
3.1 Introduction37
3.2 DrugdeliveryviaMNpatchesfordiabetestreatment38
3.3 DrugdeliveryviaMNpatchesforcancertreatment44
3.4 Conclusion49 Acknowledgments49 References49
4.Nanohybridscaffoldstructuresforsmartdrugdelivery applications53
S.Sowmya
4.1 Introduction53
4.2 Drugdeliveryunderelectricalstimulation54
4.3 Drugdeliveryundermagneticstimulation55
4.4 pH-sensitivescaffoldsfordrugdelivery57 References58
5.3Dbioprintingforactivedrugdelivery61
JoshuaLee,AfeeshRajanUnnithan,ChanHeePark,CheolSangKim
5.1 Theadventofthree-dimensionalbioprinting61
5.2 Currentbioprintingresearch63
5.3 3Dbioprintingforactivedrugdelivery66 References70 Furtherreading72
6.Nanotechnologyinimprovingmedicaldevicesforsmart drugdelivery73
LudwigErikAguilar
6.1 Introduction73
6.2 Stents75
6.3 Boneimplants79
6.4 Nanomodificationtechniquesusedfordrugdeliveryinmedicaldevices80
6.5 Stimuli-responsivepolymersforbiomedicaldevicedrugdelivery84
6.6 Conclusion86 References88
7.Radiofrequency-sensitivenanocarriersforcancer drugdelivery91
N.SanojRejinold,YeuChunKim
7.1 Introduction91
7.2 RF-sensitivetherapeuticnanocarriersforcancernanotherapy92
7.3 Gold-basedRF-sensitivenanocarriers93
7.4 MNPsasRF-sensitivenanocarriers94
7.5 QD-basedRF-sensitivenanocarriers97
7.6 Carbon-basedRF-sensitivenanocarriers98
7.7 Cobalt-basedNPsforRFcancertherapy98
7.8 Tin-basedNPsasRF-sensitivenanocarriers99
7.9 Liposomes99
7.10 Summaryandfutureoutlooks101 Acknowledgment101 References101
8.Targetingpeptide-modifiedpolymericnanoparticlesfor cardiac-specificdrugdeliveryapplications107
MuthunarayananMuthiah,JasonMcCarthy
8.1 Introduction107
8.2 Cardiovasculardisease108
8.3 CTPpeptide-mediatedtargetingtocardiomyocytes108
8.4 IdentificationandapplicationofPCMpeptideforcardiactargeting110
8.5 AT1peptide-mediatedtargetingofthecardiovascularsystem111
8.6 Vascularsmoothmuscle-targetingligands111
8.7 Targetedmacrophageablationininflammatoryatherosclerosis112
8.8 Conclusion113
References114
9.Nanogel-basedactivedrugdelivery115
JohnsonV.John
9.1 Introduction115
9.2 SynthesisofNGs116
9.3 AdvantagesofNGsasadrugcarrier116
9.4 MechanismofactivedrugdeliveryfromNGs117
9.5 Conclusionandfutureperspective123
References123
10.Stimuli-responsivenanodrugdeliverysystemsforanticancer therapy125
RejuGeorgeThomas,YongYeonJeong
10.1 Introduction125
10.2 Internalstimuli-responsivesystem127
10.3 Externalstimuli-responsivesystem135
10.4 Summaryandfuturedirection142 Acknowledgment144 References144 Furtherreading148
11.Graphene-baseddrugdeliverysystems149
RenuGeethaBai,GhalebA.Husseini
11.1 Introduction149
11.2 Grapheneandderivatives characteristics,properties,andapplications150
11.3 Graphenenanomaterialsinnanomedicine152
11.4 Nanodrugdeliveryconcept153
11.5 Graphenematerialsindrugdelivery154
11.6 Challenges164
11.7 Conclusionandfutureperspectives164 References164
12.Targetednanoparticlesfortreatinginfectiousdiseases169
ViswanathanA.Aparna,RajaBiswas,R.Jayakumar 12.1 Introduction169
12.2 Infectiousdiseases170
12.3 Effectiveantimicrobialactivityofnanomaterials172
12.4 Targetednanoparticlesforinfectiousdiseases174
12.5 Liposomesasdrugcarriers174
12.6 Polymericnanoparticlesasdrugcarriers175
12.7 Currentscenario176
12.8 Outlook180
12.9 Conclusions180 References180
Index 187
Contributors
LudwigErikAguilar
BionanosystemEngineering,ChonbukNationalUniversity,Jeonju,RepublicofKorea
ViswanathanA.Aparna
AmritaCentreforNanosciencesandMolecularMedicine,AmritaInstituteofMedical SciencesandResearchCentre,AmritaVishwaVidyapeetham,Kochi,India
RenuGeethaBai
DepartmentofChemicalEngineering,AmericanUniversityofSharjah,Sharjah,United ArabEmirates
RajaBiswas
AmritaCentreforNanosciencesandMolecularMedicine,AmritaInstituteofMedical SciencesandResearchCentre,AmritaVishwaVidyapeetham,Kochi,India
AneeshChandrasekharan
CancerResearchProgram,RajivGandhiCentreforBiotechnology,Thiruvananthapuram, India
PramodDarvin
CancerResearchProgram,RajivGandhiCentreforBiotechnology,Thiruvananthapuram, India
AminGhavamiNejad
AdvancedPharmaceuticsandDrugDeliveryLaboratory,LeslieL.DanFacultyofPharmacy, UniversityofToronto,Toronto,ON,Canada
GhalebA.Husseini
DepartmentofChemicalEngineering,AmericanUniversityofSharjah,Sharjah,United ArabEmirates
R.Jayakumar
AmritaCentreforNanosciencesandMolecularMedicine,AmritaInstituteofMedical SciencesandResearchCentre,AmritaVishwaVidyapeetham,Kochi,India
YongYeonJeong
DepartmentofRadiology,ChonnamNationalUniversityHwasunHospital,Hwasun,South Korea
JohnsonV.John
DepartmentofChemicalandMaterialsEngineering,UniversityofAlberta,Edmonton, AB,Canada
CheolSangKim
DepartmentofBionanosystemEngineering,GraduateSchool;DivisionofMechanical DesignEngineering,ChonbukNationalUniversity,Jeonju,RepublicofKorea
YeuChunKim
DepartmentofChemicalandBiomolecularEngineering,KoreaAdvancedInstituteof ScienceandTechnology(KAIST),Daejeon,RepublicofKorea
JoshuaLee
DepartmentofBionanosystemEngineering,GraduateSchool,ChonbukNational University,Jeonju,RepublicofKorea
BrianLu
AdvancedPharmaceuticsandDrugDeliveryLaboratory,LeslieL.DanFacultyofPharmacy, UniversityofToronto,Toronto,ON,Canada
JasonMcCarthy
MasonicMedicalResearchLaboratory,Utica,NY,UnitedStates
MuthunarayananMuthiah
MasonicMedicalResearchLaboratory,Utica,NY,UnitedStates
ChanHeePark
DepartmentofBionanosystemEngineering,GraduateSchool;DivisionofMechanical DesignEngineering,ChonbukNationalUniversity,Jeonju,RepublicofKorea
N.SanojRejinold
DepartmentofChemicalandBiomolecularEngineering,KoreaAdvancedInstituteof ScienceandTechnology(KAIST),Daejeon,RepublicofKorea
T.R.SanthoshKumar
CancerResearchProgram,RajivGandhiCentreforBiotechnology,Thiruvananthapuram, India
ArathyramRamachandraKurupSasikala
DepartmentofBionanosystemEngineering,GraduateSchool;DivisionofMechanical DesignEngineering,ChonbukNationalUniversity,Jeonju,RepublicofKorea;Collegeof MedicalandDentalSciences,UniversityofBirmingham,Birmingham,UnitedKingdom
S.Sowmya
ResearchScientist,AmritaSchoolofDentistry,AmritaVishwaVidyapeetham,Kochi,India
RejuGeorgeThomas
DepartmentofRadiology,ChonnamNationalUniversityHwasunHospital,Hwasun, SouthKorea
AfeeshRajanUnnithan
DepartmentofBionanosystemEngineering,GraduateSchool;DivisionofMechanical DesignEngineering,ChonbukNationalUniversity,Jeonju,RepublicofKorea;Instituteof TranslationalMedicine,ChemicalEngineeringDepartment,UniversityofBirmingham, Birmingham,UnitedKingdom
XiaoYuWu
AdvancedPharmaceuticsandDrugDeliveryLaboratory,LeslieL.DanFacultyofPharmacy, UniversityofToronto,Toronto,ON,Canada
Abouttheeditors Dr.AfeeshRajanUnnithan iscurrentlyworkingasaresearchfellowin ProfessorAliciaElHajgroupatUniversityofBirmingham,UK.Priortothis hewasworkingasKRF(KoreanResearchFellow)atChonbukNational University,SouthKorea.Dr.AfeeshalsoworkedasanassistantresearchprofessoratChonbukNationalUniversityfrom2013to2016.Hecompleted hisPhDinbionanosystemengineeringfromChonbukNationalUniversity in2013.Dr.AfeeshearnedhisMTechinnanomedicinefromAmritaCenter forNanosciencesandMolecularMedicineandBTechinbiotechnology fromAnnaUniversity,India.Dr.Afeesh’sprincipalresearchinterestsare intheareasrelatedtothepreparationofnanobiomaterials,smartdrug deliverysystems,hyperthermicchemotherapy,bioactivenanostructured scaffolds,electrospinning,3Dbioprinting,etc.Hehaspublishedaround 49peer-reviewedresearcharticlesinhighimpactfactorjournalswith 1523citations.
Dr.ArathyramRamachandraKurupSasikala iscurrentlyworkingasa researchfellowinDr.HaneneAli-BoucettagroupatUniversityofBirmingham,UK.BeforecomingtoUK,shewasworkingasanassistantresearch professoratChonbukNationalUniversity,SouthKorea.Sheearnedher PhDinbionanosystemengineeringfromChonbukNationalUniversity inAugust2016.Dr.ArathycompletedherMScandBScinphysicsfrom UniversityofKerala,India.Dr.ArathyalsoworkedasajuniorresearchfellowinNationalRemoteSensingCentre,ISRO(IndianSpaceResearch Organization),India.Herprincipalresearchinterestliesinthedevelopment ofmultifunctionaltherapeuticnanosystemsincorporatingbothmagnetic nanomaterialsanddrugsforthesynergisticcancertheranosticsbycombining hyperthermia,chemotherapy,andMRI(magneticresonanceimaging). Dr.Arathypublishedherresearchworksinhighimpactjournalssuchas AdvancedFunctionalMaterials,Nanoscale,ActaBiomaterialia,Scientific Reports,JournalofMaterialsChemistryB,ACSappliedmaterialsand interfaces,ChemicalEngineeringJournal,etc.Shehaspublishedaround 15peer-reviewedresearcharticlesinhighimpactfactorjournalswith443 citations.
ChanHeePark iscurrentlyworkingasanassociateprofessorintheDepartmentofBionanosystemEngineeringatChonbukNationalUniversity,
SouthKorea.HeearnedhisPhDinbionanosystemengineeringfromChonbukNationalUniversityin2012.HeworkedforNationalInstruments (USA)from2002to2009.Followingthatheworkedastheteamleader seniorresearcheratR&DDivision,ChonbukNationalUniversityAutomobileParts&moldTechnologyInnovationCenter,Jeonju.Professor Park’sresearchinterestsarerelatedtoelectrospunnanocompositematerials fordrugdelivery,microfluidics/electroanalyticalbiosensors,biodegradable metals,regenerativemedicine,nanomedicine,etc.Hepublishedhisresearch achievementsinvariouspeer-reviewedjournalswith2124citations.
Cheol-SangKim receivedhisBSandMSdegreesinmechanicalengineeringfromChonbukNationalUniversityinKoreain1980and1982,respectively.HethenearnedhisPhDinmaterialsciencefromUniversitedeLouis PasteurinStrasbourg,Francein1988.Dr.Kimiscurrentlyaprofessoratthe DivisionofMechanicalEngineeringandDeanofCollegeofEngineeringat ChonbukNationalUniversityinKorea.PriortojoiningChonbukNational University,hehasspent2yearsattheDepartmentofBioengineeringat UniversityofPennsylvania(USA)asapostdoctoralfellow.Heworked for5yearsfrom1997asaHeadofInstituteofBiomedicalEngineering, SolcoSurgicalInstrumentsCo.,Ltd.andInstituteofInterventional Medicine,M.I.TechCo.,Ltd.,Korea.Dr.Kim’sresearchinterestsarein theareaofbiomaterialsforhardtissuereplacements,drugdelivery,design andanalysisofimplantsandartificialorgans,andanti-biofoulingtechnology. Dr.Kimownsnumerouspublicationsinhighimpactfactorjournalswith 2426citations.
CHAPTER1 Introductiontosmartdrug deliverysystems PramodDarvin,AneeshChandrasekharan,T.R.SanthoshKumar CancerResearchProgram,RajivGandhiCentreforBiotechnology,Thiruvananthapuram,India
Contents
1.1Overview Theuseofnanotechnologyandtheirapplicationshaverevolutionizedinthis century.Thedemandsrangefromtheneedsofdailylifetotheunmet demandformanagingchronicdiseasesinmedicalfield.Inthemedicalfield, tremendousapplicationsarebeingutilizedindifferentaspectsofclinical management.Theuseofnanotechnologyinpharmacologyanddrugdeliverysystemenabledthereductionofnonspecificbiodistributionanduncontrolleddrugrelease.Focustoaddressthisissueandachievedrugreleaseata preciselocationwithmorecontrolresultedinthedevelopmentofsmart drugdeliverysystems(SDDSs).TheseSMARTsystemscanreachthe precisedsitewherethedrugisintendedtorelease,andcanalsorelease thedruginresponsetospecificstimulations.Thisabilitymakesthemintelligentsystems,capableofself-regulation,integratedsensing,monitoring, andactivationbytheenvironmentaswellasstimuli.
1.2Stimuli-responsiveSDDS SDDSweredesignedtoreleasethepayloadstothespecificsiteinamore controlledmannersoastoincreasethetherapeuticefficiencyandreduce theadverseeffects.Stimuli-responsivesystemsrespondtobothexternal andinternalstimuli.Theexternalstimuliincludethemagnetic,electric, thermal,andultrasonicformofenergy.Theinternalstimuliaretheredox status,pH,andtemperatureofthesystem,biochemicalfactorslikespecific enzymes,urea,glucose,morphineresponsivesystem,andspecificbodyconditionssuchascancerandinflammationresponsivesystem.
1.2.1Temperature-responsiveSDDS Thermosensitivepolymersaredesignedtoretaintheirpayloadsaroundthe physiologicaltemperature(37oC)andthedrugswillbereleasedrapidly whenthetemperaturerisesmorethan40–45oC.Thesesystemsaresuitable forthecontrolleddeliveryofdrugsandgenes.Thermosensitivepolymers undergosol-geltransitionsinresponsetotemperatureandminutechanges inphysiologicaltemperaturereflectthesolubilitychanges.Intheclinical conditionslikeinflammationandmalignancies,thetemperatureofpathologictissuesrisescomparedtothenormaltissues.Thetemperature-responsive SDDScanrecognizethischangeintemperatureandareactivated.The advantageofusingtemperature-responsiveSDDSisthatthestimulican beappliedeitherasinternalstimuliorasexternalstimuli.Inducedtemperaturegenerationatthemalignantsitehelpsalsotoreleasethedrugintothe tumormicroenvironment.Forexample,thepoly(N-isopropylacrylamide) (PNIPAAm)isathermosensitivepolymerwithalowercriticalsolution temperatureof32oCwhichisadjustedtophysiologicaltemperatureusing additivesorsurfactants.Whenthetemperaturerisesabove27oC,thesolutionbecomescloudyandformsagel.Multiplethermo-responsivenanocarrierstructureslikehydrogels,microbeads,polymericnanotubes,micelles, core-shellthermo-responsivenanoparticles,andlayer-by-layerassembled nanocapsulehavebeendevelopedusingthermosensitivepolymersand arebeingusedasSDDS.Thermosensitivepolymerscommonlyinuse arePNIPAAm,poly(N,N-diethylacrylamide),poly(N-vinylalkylamide), poly(N-vinylcaprolactam),tetronics,pluronics,phosphazenederivative, polysaccharidederivatives,etc. [1–3].
Hydrogelsduetotheirhigh-watercontentundergoavarietyofchanges uponexternalstimulation.Theycanundergoswelling,shrinking,andsol-gel phasetransition.Cellulosederivatives,PNIPAAm,poly(lactic-co-glycolic
acid)(PLGA),polycaprolactone,andpolyurethaneamidearesomeofthe widelyusedhydrogels.PNIPAAmisoneofthehighlystudiedhydrogels fordrugdeliverypurposes.Theyhavehighthermalreversibilityandgood swellingratio.CopolymerizationandgraftingofPNIPAAmwithpolyethyleneglycol(PEG)andpolyethyleneoxide(PEO)haveestablishedarouteto obtainnewhydrogels.PNIPAAm-derivedhydrogelsfacepotentialdrawbackslikeincreasedcytotoxicityandlowbiodegradability.Becauseofthe applicabilityofthehydrogels,themodificationismadetothebackboneof PNIPAAmcopolymerstoincreasethebiodegradability.Theincorporation ofbiodegradablesegmentsusingcleavablebondshasimprovedbiodegradationandbiocompatibility.
Hydrogelshavingtransitiontemperaturenearphysiologicaltemperature areusedasnonsurgicaldrugdepotsandforsustaineddeliveryofdrugsand proteinstosusceptiblelivingcells.Transitiontemperaturecanbereadily tunedbycopolymerizationconditionsandbyvaryingthecontentofrepeatingunitsinthecopolymer,forexample,copolymerizationofacrylicacid (AAc)andNIPAAm.
Burstdrug-releasekineticsmaybesometimesobservedinthecaseof hydrogelsandporouscapsuleswithlowstrengththatiseasilyeroded.Additionally,hydrogelscansufferfrompoorencapsulationofhydrophobicdrugs duetothehydrophilicnatureofthehydrogel.Poloxamer-basedhydrogels andPLGA-PED-PLGAhydrogelsareexamplesofencapsulatedhydrogels withthesustaineddrug-releaseprofile.
Polymericmicelleswithspecificcore/shellarchitectureentraphydrophobicdrugsintheinnercoresurroundedbyanoutershellofhydrophilic polymers.Micelle-baseddrugdeliverysystemisusedforanticancerdrug deliveryduetoitseaseofadministration,reducedsystemtoxicity,highpayload,andtherapeuticefficiency.Thermostabilitydependsonthecloud pointofthethermosensitiveblockofthecopolymerformingthemicelle. Thereversiblephasetransitionisamechanismgenerallyemployedbythe thermosensitivemicelles.
Basedontheapplication,thetemperature-responsivedeliverysystems aredesigned.Multifunctionalanddualstimuli-responsivesystemshavebeen developedtoreleasethecargoinresponsetomorethanonestimulus.For example,temperature-pH-sensitivesystems,temperature-pHreductionsensitivepolymericmicelle,andmacromolecule-sensitivenanogelslike glucose-pH-thermo-responsivenanogelshavebeendeveloped.Thermoresponsivenanostructureshaveadvantageslikelowtoxicityandtarget specificity.
1.2.2Redox-responsivedrugdeliverysystem Redox-sensitivedrugdeliverysystemhasreceivedgreatattentionforits closeconnectionwithmanydiseasesandisextensivelystudied.Moreover, theredox-sensitivedeliverysystemhastheadvantageofintracellulardrug release.Thevariationintheredoxstatusoftissuesisexploitedinthedesigningofthissystem.Intracellularglutathione-dependentsystemsarethemajor redox-responsiveSDDS.TheconcentrationofGSH(glutathione)varies betweennormalandmalignantcells.Itrangesfrom2to20 μMinblood andnormalextracellularmatricesandfrom2to10 μMincancercells [4]. Otherdiseaseconditionslikeinflammation,theROS(reactiveoxygenspecies)levelincreases10-to100-foldcomparedwithnormalcounterparts.
Drugdeliverysystemswithdisulfidelinkageanddiselenidelinkagearethe twomajorreduction-basednano-drugdeliverysystems [4,5].Thedisulfide linkagescanbebrokenwithhighconcentrationsofGSH,resultinginaquick releaseofthecargoes.Thesedisulfidebondsaremainlyusedaslinkersand cross-linkingagents [4,6].Asalinker,thedisulfidelinkageconnects thepolymerbackbonewithdrugsorothercargoes.Inthebackbone, thedisulfidelinkagebreaksrapidlywithhighconcentrationsofGSHinthe surroundingenvironment.Thismakesthepolymerunstableundercertain situations.Inthebackbone,cystamine [7],cystine [8], N-succinimidyl-3(2-pyridyldithiol)propionate(SPDP) [9],disulfide-baseddimethacrylate (DSDMA) [10],etc.,areusedasdisulfide-containingfragments.Thedisulfide linkagespresentinthesidechainsareintendedtosupportthebackbone.The polymerswithdisulfidelinkagesinthesidechainsareeasytomodifyandcan havehighcargo-carryingcapacityandwouldbemorestablethanthedrug deliverysystemswithdisulfidelinkagesinthebackbone.Thislinkerdisulfide bondscanenrichthenanocarrierbyattachingmultiplegenes,drugs,and targetingmoleculestotheirsurface.Thesebondscanlinktwodifferent moietieswithdifferentfunctionsandcanactascross-linkingagents.
Redox-sensitivedeliverysystemcontainingdiselenidebondsarealso sensitivetothereductionandshowsimilarpropertieslikedisulfidelinkages. Theselenidebondshowsbondenergy(diselenidebond,172kJmol 1 and carbon-seleniumbond,244kJmol 1)lowerthandisulfidebonds,making themsuitablefordevelopingmoresensitivedeliverysystems.Themajor challengeusingdiselenidebondcontainingpolymeristhedifficultyin theincorporationofselenidebond.
Oxidation-responsivedrugdeliverysystemsisanothermajorgroupof drugdeliverysystemsinredox-sensitivesystemsandmainlyrelyonthe
ROS,mainlyH2O2 and –OHradicals.ROSareomnipresentintissuesand areassociatedwithpathologicalconditionslikearteriosclerosis,heartand nerveinjuriesandinflammations.Thesegroupsofdrugdeliverysystems includethesulfide-containingsystemssuchaspoly(propylenesulfide), selenium-containingsystems,ferrocene-containingsystems,boronicester groups,etc. [11–14].
1.2.3pH-responsivesystems Inmostoftheapplicationsrelatedtodiseases,thedrugsneedtobedelivered tospecificsitesinordertodeciphermaximumefficacywithminimumtoxicity.pH-responsivesystemsareabetterchoiceforthisandarecommonly usedSDDSduetothechangeinpHamongtheorgans,organelles,andtissues.Thissystemalsoconfersprecisedeliveryoptionsandpredetermined releaserates.AllpH-responsivepolymersusedcontainapendantacidic (carbonicandsulfonicacids)orbasic(ammoniumsalt)groupsasaproton acceptorordonor.ThesecarrierscantracedelicatechangesinthepHof inflammatoryorothermalignantsites.Generally,thetumormicroenvironmenthaslesspH(7.0)comparedtotheirnormalcounterparts(pH7.4).The changeinenvironmentalpHcausestheionizationofpendantacidicorbasic groupsresultinginthecross-linkingandchangesintheswellingproperties ofthepolymer.TheprecisionandaccuracyofpH-responsivesystemsare increasedbycombiningthemwithotherstimulisuchastemperatureor redoxstimuliasmultifactor-responsivedrug-releasesystem [2].
ThenatureofthedrugreleaseisdesignedbythepHofthesolutionto whichthepolymerisexposed.ThealterationinpHcausesthepolymerto shrinkorswell.Forexample,polyacidicpolymerswillshrinkatlowpHand swellathighpHbecauseoftheprotonationofacidicgroups.Inthecaseof polybasicpolymers,ionizationofbasicgroupsincreaseswithincreaseinpH.
AAcandcellulosederivativesarethemostwidelyusedpH-sensitivepolymers.Morethantwophasescanoccurincopolymerswithrandomlydistributedpositiveandnegativechargedgroups.Inthesecopolymers,the interactionofsegmentswitheachotheroccursthroughelectrostaticinteractionsandhydrogenbonding.Theexistenceoftheseinteractionshelpsthe polymertoshrinkandswellaccordingtothechangesintheenvironmental conditionsandadoptastableconformation.
Polyacrylicacid(PAAc)andpolymethacrylicacid(PMAAc)aretheexamplesofthepolyacidicpH-responsivesystem.PMAAcgraftedwithPEGshow uniquepHsensitivity.HydrogelsmadefromPAAcorPMAAccanbe
employedfortargetedreleaseofdrugsatneutralpH.Forcolon-specificdrug delivery,polyanionscross-linkedwithazoaromaticcross-linkerswereused. SulfonamidecontainspolyacidpolymerswithpKa intherange3–11andthe hydrogenatomoftheamidenitrogenisreadilyionizedtoformpolyacids. TheaminogroupisprotonatedathighpHandpositivelyneutralizedand ionizedatlowpHcontrollingtheswellingandshrinkingnatureofhydrogels. Polybaseswiththeaminogrouparethemostrepresentativepolybasicgroup.
Poly(N,N-dimethylaminoethylmethacrylate)(PDEAEMA)hasbeenthemost frequentlyusedpH-responsivepolymericbase.Polycationichydrogelsshow minimumswellingintheneutralpH,minimizingthereleaseofdrugcargo. Thispropertyofpolycationichydrogelshasbeenusedtodevelopcarriers forfoul-tastingdrugs,topreventthemfromreleasingintotheneutralpHenvironmentofthemouth.
ThepHresponsivenessofpolyelectrolytehydrogelscanbemodulatedby usingneutralcomonomers.VariouscomonomersshowdifferenthydrophobicityandhencedifferentpHresponsiveness.2-Hydroxyethylmethacrylate, methylmethacrylatemaleicanhydride,etc.,aretheexamplesofcomonomersusedinpolyelectrolytehydrogels.
pH-sensitivebioerodiblepolymersuseenzyme-substratereaction.An enzyme-substratereactionproducesachangeinpHandthischangein pHisutilizedfortheerosionofapH-sensitivepolymercontainingadrug cargo.Inadditiontothebioerodiblepolymers,rDNAmethodsandprotein engineeringwereemployedtodevelopsyntheticproteinsthatcanundergo reversiblegelationinresponsetopHchanges.pH-sensitivenanoparticles enhancedrugavailabilitythroughefficientabsorptionmechanisms.Polymerssuchashydroxypropylmethylcellulosephthalateandcelluloseacetate phthalatewereusedtoencapsulatethedrugload.Ionicgelation,solvent evaporation,solventdiffusion,supercriticalfluidtechnology,saltingout, polymerization,etc.,canbeemployedtoproducepH-sensitivepolymeric nanoparticles.
1.2.4Enzyme-responsivedrugdeliverysystems Enzymeactivateddrugdeliverysystemisanewclassofdeliverysystem wherethedrugreleaseiscontrolledbyenzymereactions.Severalnanomaterialsandpolymersarebeingusedforthedevelopmentofenzymeresponsivedrugdeliverysystems.Thissystemhastheadvantageofahigh degreeofspecificity.Mostofthephysiologicalandmetabolicprocesses arerelatedwithenzymessuchasglycosidase,lipase,phospholipase,and
protease.Theseenzymesareexploitedtoachieveenzyme-mediateddrug cargoreleasethroughbiocatalyticactionatinflammatoryormalignantsites. Thenanocarrierscarryingpayloadattachedwiththemthroughencapsulationorcovalentbondingwillreleasethedrugsatthetargetsitesthrough site-specificenzymaticcleavage.Multipleenzymesareusedtotriggerthe drug-releasesystem [15].Differentclassesofproteaseareinvolvedinvarious physiologicalandpathophysiologicalconditionslikewoundhealing,tumor invasion,andtissueremodeling.ProteinkinaseC-alpha,uPA(urokinasetypeplasminogenactivator),andMMPs(matrixmetalloproteinases)are thecommonlyusedproteaseenzymesinthecontrolleddrugrelease [16–18].Themajorchallengeinenzyme-responsivedrugdeliverysystem istopreciselycontroltheinitialresponsetimeofthesystem.Phospholipases areanotherimportantgroupofenzymesinvolvedininfections,neurodegenerations,malignancies,andinflammations.PhospholipaseA2(PLA2) enzymeisutilizedtoreleasedrugsorexposetargetligandsfromliposome orsmallunilamellarvesicle(SUV)-mediateddrugdeliverysystems [19,20].Glucoseoxidaseofoxidoreductasefamily,involvedinglucose metabolism,hasitsapplicationinthediagnosisanddrugdeliveryinresponse toglucoselevels [21].
1.2.5Magnetic-responsivedrugdeliverysystems Magnetic-responsivedrugdeliverysystemsprovideanoninvasiveapproach tospatiotemporalcontrolofthecarrierstothetargets.Thishelpsthesystem toreleasethepayloadsunderprogrammableexposureofexternalmagnetic fields.Themostcommonlyusedcore/shellmagneticnanoparticleexhibitsa varietyofuniquemagneticproperties.Thecomplexconsistsofthedrugand pharmaceuticallystableferromagneticcarrier.Basedonthefabrication methodthesurface-to-volumeratioofMNPs(magneticnanoparticles) canbeadjusted.Increasedsurface-to-volumeratioprovidesnumerous activesitesfortheconjugationofbiomolecules.Thisallowsprecisionin designandengineeringtoachievetheirsmartfunctionslikeelevatedblood half-life,releasesitespecificity,andincreaseddeliverybyapplyingalocalized externalmagneticfield [22]
Furthermore,whenthesenano-scaledMNPswereencapsulatedincolloidalcarriers,suchasmicelles,liposomes(Magnetoliposomes),andsolid nanoparticles,theybecomemoresensitivetoanexternalmagneticfield. Thesemagneticnanoparticlesalsoenabletheengineeringofmultistimuli-responsivedrugdeliverysystemswhichcanactonpH,redox,
andenzymes [23,24].Forexample,cystamine-modifiedgelatinencapsulatednanocarriercontainingdoxorubicinasthepayloadshowedincreased drugtargetspecificity,EPR,andgoodbiocompatibility [25].
1.3Conclusion Thedevelopmentofsmartdrugdeliverysystemoffersgreatpotentialto engineerpathologyspecificdrugdesignanddeliveryapproachessuiting totheclinicalrequirement.However,thefieldfurtherrequiresincreased attentiontoaddressthechallengesofclinicalacceptabilityandclinicaltranslations.Thedevelopmentofmorenano-drugcarriersisunderwaytoeven increasethesmallerphysicochemicalchangesinpathologicandnormaltissues.Morecombinationsandmultifactorialreleasesystemsareattractive becauseoftheiradvanceinselectivityandspecificitytherebyincreasing theoverallefficacyofthedrugs.
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Nanofiber-basedanticancer drugdeliveryplatform ArathyramRamachandraKurupSasikalaa,b,c,AfeeshRajan Unnithana,b,d,ChanHeeParka,b,CheolSangKima,b
aDepartmentofBionanosystemEngineering,GraduateSchool,ChonbukNationalUniversity,Jeonju, RepublicofKorea
bDivisionofMechanicalDesignEngineering,ChonbukNationalUniversity,Jeonju,RepublicofKorea cCollegeofMedicalandDentalSciences,UniversityofBirmingham,Birmingham,UnitedKingdom dInstituteofTranslationalMedicine,ChemicalEngineeringDepartment,UniversityofBirmingham, Birmingham,UnitedKingdom
2.1
Canceristhesecondforemostcausesofdeathongloballyjustbehindthe cardiovasculardiseasedemandingvitalattentiontosignificantlyreduce theglobalcancerburden. [1] Cancerisahighlyheterogeneousandmultifaceteddisease.Incancer,thecellsundergomutationintheirgeneticmaterialandresultinuncontrolledgrowth.Thereforethesystemicdeliveryof antineoplasticagentssuchaschemotherapyorantiangiogenicdrugs,radiotherapy,andsurgeryhavebeenthetraditionalmethodsoftreatingcancerfor alongtime.Thoughitissuccessfulforsometypesofcancer,themainproblemassociatedwithsuchtreatmentisthepoortargetabilityandhighlyinvasivenature [2].Henceanextensiveresearchisgoingoninsearchofan improvedornoveltreatmenttocombatthisdeadlydiseasebydeveloping newdrugdeliveryplatformsthathaveextremetumortargetabilityandminimaltoxicitytowardnormalcells.
Withthedevelopmentofnanotechnology,cancernanomedicine,the applicationofnanomedicineforthetreatmentofcancer,hasseenenormous progressinrecentyears [3,4].Todateseveraltypesoforganicandinorganic nanomaterialsintheformofnanoparticles,microparticles,liposomes,dendrimers,nanotubes,etc.,wereengineeredtofunctionaseffectivecancer theranosticagents [5–9].Themainadvantagesofthenanoengineeredmaterialsincludethecapabilitytoincreasethesolubilityofwater-insolubledrugs, long-termbloodcirculation,andtheeaseoffunctionalization [10–12] However,evenwiththesetechnologies,therestillremainmanyshortcomingsassociatedwiththesenanocarriers.Thenanocarrierscouldtideover numerousbarriersstartingfromtheinjectionsitetothetargetcell,such asmucosalbarriersandnonspecificuptake [13,14].Theintravenouslydeliverednanosystemsdisplayoverrelianceontheenhancedpermeationand retention(EPR)effecttodeliverthenanocarriersintothetumor [15] aswell astheysufferrapidclearancefromthebloodstreamwithsubsequentoveraccumulationinnontargetorgans [16,17].
Thelimitedsuccessandtoxicityassociatedwithcurrentsystemicadministrationofdrugshasmotivatedresearcherstosearchfor“localtherapysystems(LTSs),”adirectapproachtodeliveragentsforcancertherapy.LTScan beconsideredasapromisingalternativetosystemicdeliverybysupplying thedrugsdirectlytothetargetedsiteofinterestviaanimplantablesystem [18] whichresultsnotonlyinhighertherapeuticefficacyandlowertoxicity [19,20] butalsoreducestheneedforrepeatedchemotherapyapplication [21].TheLTSsaretypicallydesignedtobeimplantedimmediatelyaftera tumorresectingsurgery,whichsparetherequirementforanadditionalsurgerytoplacethetherapeuticmaterialinthepatient [18] andenablethe on-sitedeliveryofdrugbysidesteppingtheharshenvironmentandlonger journeythatthedrughastotaketoreachthesiteofinterestwhendelivered systematically.ThusLTScanberegardedasanintelligentstrategyto improvethequalityoflifeandtoenhancethepatientcompliancebyrepurposingpromisingdrugsforcancertreatment.
Recently,electrospunpolymerfibershavegainedagreatattentionas implantableanticancerdrugdeliverydevicesduetotheiruniquearchitecturalfeaturesandrobustdrugloadingcapabilitywithveryencouraging preliminaryresults [22–27].Nanofiberscanberegardedasaversatileonedimensionalnanomaterialforawiderangeofapplicationsnotonlyinthe fieldofresearchbutalsoincommercialarenas [28].Amongthebroadspectrumofintriguingnanomaterialswithgreatpotentialapplications,nanofibersstandpreeminentduetotheiroutstandingphysicalandchemical
properties [29].Themainadvantagesofthenanofibersaretheirexceptionallyhighsurfacearea-to-volumeratio,uniqueporositywithinterconnected pore,andbiomimeticextracellularmaterial(ECM)-likestructuremake themanattractivecandidateformanyadvancedapplicationssuchasmusculoskeletaltissueengineering(includingbone,cartilage,ligament,andskeletalmuscle),skinengineering,vasculartissueengineering,neuraltissue engineering,andascarriersforcontrolleddeliveryofdrugs,proteins,and DNA [28,29].Thischapteraimsatsummarizinganddiscussingthestateof-the-artnanofiber-basedanticancerdrugdeliveryplatformstoprovidea comprehensiveandsignificantscientificbasesupportingfuturestrategic directionincancertherapies.
2.2State-of-the-artnanofiberfabrication Electrospinningisconsideredasoneofthesimplesttop-downapproaches usedtogeneratenanofibers [30].Electrospinningcanbeperformedusing awidevarietyofmaterialssuchaspolymers,sol-gel,suspension,andmelts [31].Theaccessibilityofawiderangeofnaturalandsyntheticbiomaterials hasextendedthescopeofdevelopingnanofibrousscaffolds [29].Byvarying thematerialselectionandchemicalcompositions,thenanofibersobtaintunablematerialpropertiessuchasmechanicalstrength,biodegradability, wettability,andsoon [28,32]
Theconventionalelectrospinningsetupisshownin Fig.2.1.Ingeneral, theelectrospinningsetupconsistsofthreebasicparts:(1)high-voltagesupply,(2)aneedleconnectedtosyringeandpump,and(3)thecollector,which isusuallygroundedornegativelybiased.Duringelectrospinningprocess highvoltageisappliedtocreateanelectricallychargedjetofpolymersolution.Whenthischargedpolymersolutionispumpedoutthroughthespinneret,itformsasphericaldropletduetotheinternmentofsurfacetension. Mutualchargerepulsionandthecontractionofthesurfacechargestothe counterelectrodecauseaforcedirectlyoppositetothesurfacetension.If theintensityoftheelectricfieldescalates,thesphericalsurfaceofthepolymeratthetipofthecapillarytubeextendstoformaconicalshapetermedas theTaylercone [33].Astheelectrostaticforceactingonthesurfaceofthe liquidovercomesthesurfacetension,thechargeliquidjetispulledfromthe Taylorconeandejecteddirectlytowardthetargetcollector.Thechargedjet undergoesinstabilityandelongationprocesswhichcausethepolymerfiber tobecomelongandthin.Asthesolventevaporatesthepolymerfiberswere formedonthecollector.Therequiredmodificationstotheconventional
