Core shell nanostructures for drug delivery and theranostics challenges strategies and prospects for

Core-Shell Nanostructures for Drug Delivery and Theranostics : Challenges, Strategies and Prospects for Novel Carrier Systems Focarete

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Core-ShellNanostructuresforDrugDelivery andTheranostics

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WoodheadPublishingSeriesinBiomaterials

Core-ShellNanostructures forDrugDelivery andTheranostics

Challenges,Strategies,andProspects forNovelCarrierSystems

Editedby

MariaLetiziaFocarete

AnnaTampieri

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ListofContributorsix

PartIFundamentalsonNanotechnologyforDrug Delivery1

1Introductionto“Core-shellnanostructuresfordrugdelivery andtheranostics:Challenges,strategies,andprospectsfornovel carriersystems”3

MariaLetiziaFocareteandAnnaTampieri

2Physicochemicalpropertiesofnanosizedpolymericdrugcarrier systems7

NicolettaRescignanoandJoseMariaKenny

2.1Introduction7

3Biomineralizationprocessgeneratinghybrid nano-andmicro-carriers19

ElisabettaCampodoni,TatianaPatricio,MonicaMontesi, AnnaTampieri,MonicaSandriandSimoneSprio

3.1Introduction19

3.2Biomineralization20

3.3Magneticmaterialsinmedicine25

3.4Intrinsicallymagneticandhybridnanobeadsascarriersin nanomedicine26

3.5Intrinsicallymagnetichybridmicrospheresassmart releasesystems28

3.6Interactionbetweencellsandbiomimeticmagneticcarriers31

3.7Conclusionandfuturetrends33

Acknowledgment34 References34

4Clinicalapplicationsofnanostructureddrugdeliverysystems: frombasicresearchtotranslationalmedicine43

ListofContributors

AlessioAdamiano InstituteofScienceandTechnologyforCeramics, ISTEC CNR,Faenza,Italy

AlmaAkhmetova CentreforLifeSciences,NationalLaboratoryAstana, NazarbayevUniversity,AstanaKazakhstan;UniversityofEssex,Colchester, Essex,UnitedKingdom

ZeynepAytac InstituteofMaterialsScience&Nanotechnology,UNAM-National NanotechnologyResearchCenter,BilkentUniversity,Ankara,Turkey

MatejBuzgo InoCures.r.o.,Klimentska ´ 1652/36,11000Prague,CzechRepublic

ElisabettaCampodoni InstituteofScienceandTechnologyforCeramics-National ResearchCouncil(ISTEC-CNR),Faenza,Italy

AntonioCervadoro NEST,ScuolaNormaleSuperiorediPisa,Pisa,Italy

GuanyingChen MIITKeyLaboratoryofCriticalMaterialsTechnologyforNew EnergyConversionandStorage,SchoolofChemistryandChemicalEngineering& KeyLaboratoryofMicro-systemsandMicro-structures,MinistryofEducation, HarbinInstituteofTechnology,Harbin,People’sRepublicofChina

FedericaChiellini BIOLabResearchGroup,DepartmentofChemistryand IndustrialChemistry,UniversityofPisa,Pisa,Italy

BastianChrist TranslationalCenterRegenerativeTherapies,BranchofFraunhofer InstituteforSilicateResearchISC,Wurzburg,Germany

AlessandroCoclite LaboratoryofNanotechnologyforPrecisionMedicine, FondazioneIstitutoItalianodiTecnologia,Genoa,Italy

PaoloDecuzzi LaboratoryofNanotechnologyforPrecisionMedicine,Fondazione IstitutoItalianodiTecnologia,Genoa,Italy

SofiaDembski TranslationalCenterRegenerativeTherapies,BranchofFraunhofer InstituteforSilicateResearchISC,Wurzburg,Germany;DepartmentofTissue EngineeringandRegenerativeMedicine,UniversityHospitalWu ¨ rzburg,Wu ¨ rzburg, Germany

RobertoDiGesu ` DepartmentofChemistry“G.Ciamician”,Universityof Bologna,Bologna,Italy

DanieleDiMascolo LaboratoryofNanotechnologyforPrecisionMedicine, FondazioneIstitutoItalianodiTecnologia,Genoa,Italy

MiroslavDoupnik InoCures.r.o.,Klimentska ´ 1652/36,11000Prague,Czech Republic

MiguelFerreira LaboratoryofNanotechnologyforPrecisionMedicine, FondazioneIstitutoItalianodiTecnologia,Genoa,Italy

MariaLetiziaFocarete DepartmentofChemistry“G.Ciamician”,Universityof Bologna,Bologna,Italy

ChiaraGualandi DepartmentofChemistry“G.Ciamician”,Universityof Bologna,Bologna,Italy

MicheleIafisco InstituteofScienceandTechnologyforCeramics,ISTEC CNR, Faenza,Italy

JoseMariaKenny UniversityofPerugia,CivilandEnvironmentalEngineering Department,StradadiPentima4,Terni,Italy

GulsimKulsharova UniversityCollegeLondon,London,UnitedKingdom

HuiLi MIITKeyLaboratoryofCriticalMaterialsTechnologyforNewEnergy ConversionandStorage,SchoolofChemistryandChemicalEngineering&Key LaboratoryofMicro-systemsandMicro-structures,MinistryofEducation,Harbin InstituteofTechnology,Harbin,People’sRepublicofChina

MariaMendes FacultyofPharmacy,UniversityofCoimbra,Coimbra, Portugal;CentreforNeurosciencesandCellBiology(CNC),Universityof Coimbra,Coimbra,Portugal

AndreaMerlettini DepartmentofChemistry“G.Ciamician”,Universityof Bologna,Bologna,Italy

AndreaMickova InoCures.r.o.,Klimentska ´ 1652/36,11000Prague,Czech Republic

MonicaMontesi InstituteofScienceandTechnologyforCeramics-National ResearchCouncil(ISTEC-CNR),Faenza,Italy

AlbertoPais CoimbraChemistryCenter,DepartmentofChemistry,Universityof Coimbra,Coimbra,Portugal

ListofContributors

AnnaLisaPalange LaboratoryofNanotechnologyforPrecisionMedicine, FondazioneIstitutoItalianodiTecnologia,Genoa,Italy

RobertoPalomba LaboratoryofNanotechnologyforPrecisionMedicine, FondazioneIstitutoItalianodiTecnologia,Genoa,Italy

TatianaPatricio InstituteofScienceandTechnologyforCeramics-National ResearchCouncil(ISTEC-CNR),Faenza,Italy

RuiC.Pereira LaboratoryofNanotechnologyforPrecisionMedicine,Fondazione IstitutoItalianodiTecnologia,Genoa,Italy

DarioPuppi BIOLabResearchGroup,DepartmentofChemistryandIndustrial Chemistry,UniversityofPisa,Pisa,Italy

MichalaRampichova LaboratoryofTissueEngineering,InstituteofExperimental Medicine,AcademyofSciencesoftheCzechRepublic,v.v.i,Vı´de ˇ nska ´ 1083,142 20,Prague4,CzechRepublic

NicolettaRescignano UniversityofPerugia,CivilandEnvironmentalEngineering Department,StradadiPentima4,Terni,Italy

MarionRetter TranslationalCenterRegenerativeTherapies,BranchofFraunhofer InstituteforSilicateResearchISC,Wurzburg,Germany

TimurSaliev CentreforLifeSciences,NationalLaboratoryAstana,Nazarbayev University,AstanaKazakhstan

MonicaSandri InstituteofScienceandTechnologyforCeramics-National ResearchCouncil(ISTEC-CNR),Faenza,Italy

ChristineSchneider DepartmentofTissueEngineeringandRegenerative Medicine,UniversityHospitalWurzburg,Wurzburg,Germany

Joa ˜ oSousa FacultyofPharmacy,UniversityofCoimbra,Coimbra, Portugal;LAQVREQUIMTE,GroupofPharmaceuticalTechnology,Porto, Portugal

SimoneSprio InstituteofScienceandTechnologyforCeramics-National ResearchCouncil(ISTEC-CNR),Faenza,Italy

AnnaTampieri InstituteofScienceandTechnologyforCeramics-National ResearchCouncil(ISTEC-CNR),Faenza,Italy

TamerUyar InstituteofMaterialsScience&Nanotechnology,UNAM-National NanotechnologyResearchCenter,BilkentUniversity,Ankara,Turkey

CarlaVitorino FacultyofPharmacy,UniversityofCoimbra,Coimbra, Portugal;CentreforNeurosciencesandCellBiology(CNC),Universityof Coimbra,Coimbra,Portugal;LAQVREQUIMTE,GroupofPharmaceutical Technology,Porto,Portugal

XindongWang MIITKeyLaboratoryofCriticalMaterialsTechnologyforNew EnergyConversionandStorage,SchoolofChemistryandChemicalEngineering& KeyLaboratoryofMicro-systemsandMicro-structures,MinistryofEducation, HarbinInstituteofTechnology,Harbin,People’sRepublicofChina

PartI Fundamentalson NanotechnologyforDrug Delivery

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Introductionto“Core-shell nanostructuresfordrugdelivery andtheranostics:Challenges, strategies,andprospectsfor novelcarriersystems”

MariaLetiziaFocarete1 andAnnaTampieri2

1DepartmentofChemistry“G.Ciamician”,UniversityofBologna,Bologna,Italy,

2InstituteofScienceandTechnologyforCeramics,ISTEC CNR,Faenza,Italy

Researchonnanoscienceandnanotechnologyisexperiencingadramaticdevelopment.Advancesinthepreparationofnanosystemswithapplicationsinthefieldof medicinehavegivenrisetonewchallengesinthedesignofsmartmaterialscapable ofrespondingtonewclinicalrequirements,amongwhichvarioustypesofnanoparticlesplayanimportantrole.Amaingoalinthisfieldistodevelopnewsystems abletodelivertherapeuticagentstothepatientinamoreeffectiveandsaferfashion,incomparisonwithsystemicadministration.Infact,inmanycasesthislatter approachimpliestheadministrationofhighdosagestoreachtherapeuticallyrelevantamountsofthedruginthetargetsite,whichcanhoweverinducepotentially harmfulsideeffects.Thisproblemisparticularlycriticalinoncologytreatments, wheretherisk benefitratioassociatedwithchemotherapyoftenmakesitdifficult totakeawisedecision,asaconsequenceofthedrugscytotoxicity.Therefore,the establishmentofnewtherapeuticapproachesactinglocally,specifically,andalong definedspatial temporalpatternsisahighlydesiredconditionthatmaterialscientistsarepursuingbydevelopingsmart,multifunctionalnanocarriers.Relevantfunctionalitiesinthisrespectinclude(1)loadandsubsequentreleaseofdifferentdrugs, (2)anchoringofbiomoleculessuchasproteins,vectoringagents,ornucleicacidsto theexternalsurfaceoftheparticleandtowardstherapeutictargets,(3)anchoringof fluorescentmoleculesoractivecomplexesformagneticresonanceimaging(MRI) toperformopticalmonitoring,(4)inclusionoffunctionalnanoparticlestoenable remoteactivationondemand,suitableforpersonalizedapplications.

Besidesnanomedicine,alsoregenerativemedicineapproachescanreceivegreat benefitbytheuseofnanocarriersenablingco-deliveryorsequentialpresentationof biologicalcuestocells,tomostefficientlyguidecellsalongadifferentiationor dedifferentiationpathway. Core-ShellNanostructuresforDrugDeliveryandTheranostics.DOI:

Potentialbenefitsofnanotechnologyinmedicineareoutstanding,asitcanopen torefined,highlytargeted,blood brainbarrier-crossingdrugdeliveryandimaging platforms,uniquetransfection,labeling,bioseparation,aswellasanalyticalandtissueengineeringapproaches.

Amongnanostructuresthathaverecentlyraisedgreatinterest,engineeredmagneticnanoparticles(MNPs)representacutting-edgetoolinmedicinebecausethey canbesimultaneouslyfunctionalizedandguidedbyamagneticfield,thusenabling integrativetheranostic(i.e.,therapeuticanddiagnostic)applications.Theuseof MNPsiseffectiveinadvancedMRI,guideddrugandgenedelivery,hyperthermiabasedcancertherapy,tissueengineering,celltracking,andbioseparation.The developmentofdrugdeliverysystemswithselectivitytopathologicsitesisan ambitiousgoal.TheprinciplesofmagneticguidanceofMNP-conjugateddrugs havebeenappliedexperimentallyandhavereachedclinicaltrialsasacancertherapy.FollowingintravenousdeliveryofMNPs,anexternalmagneticfieldisusedto concentrateMNPsataspecifictargetsite,byaprocedurewelltoleratedincancer patients.Nanoparticle-baseddrugandgenedeliverysystemsmaysolvethe insurmountableobstacleoftreatingneurologicaldiseases:deliveryacrosstheblood brainbarrier.ButissuesofpotentialembolizationwithMNPaggregatesincapillaries andtheneedoflargedistancesbetweenthepathologicalsiteandexternalmagnetic fieldarestillachallenge.

Therecentadvancementsinmaterialsscienceapproacheshavepromptedarapid progressinthepreparationofcore-shellnanostructureswithtailoredsurfacecharacteristics,namelycore-shellnanoparticlesandcore-shellnanofibers,thusopening newperspectivesintheirusefordiversifiedapplications.Encapsulationoftherapeuticagentsorbiologicallyactivemoleculesinnanostructureswithacore-shell configurationrepresentsausefulstrategytoimprovebioavailabilityofdrugswith poorwatersolubility;preventburstreleasewhichmightcausetoxicologicaleffects; obtainasustainedandprolongedrelease;generatetemporalandspatialcontrolled release;encapsulateunstablebioactivemoleculesprotectingtheirbiologicalactivity;loaddifferentdrugsatthesametimeinthecoreandshellregionofthenanostructuretoachieveadistinctmultidrugrelease;andobtainnanostructureswith multifunctionalitythusdevelopingmaterialsfor“theranostics.”Thecoalescenceof bioengineering,biomedical,andtoxicologydisciplineswillcontinuefostering developmentofrelevantstrategiestoengineeradvancednanodeviceswithbiocompatibleinterfaces.

Thisbookpresentsthestate-of-the-artresearchonthedesignandfabricationofcoreshellnanostructuredsystemsforthesmartdeliveryoftherapeuticandimagingagents. Themostimportantphysicochemicalpropertiesofbiocompatiblepolymeric nanodevices(molecularweight,hydrophobicity,surfacechargeandsize,etc.), incorporatingactivepharmaceuticalingredientsortherapeuticagents,arepresented andtheirinfluenceonthereleasekineticsofthedeliverysystemsarediscussed. Moreover,anoverviewoftheclinicalapplicationsofnanosystems,rangingfrom basicresearchtotranslationintoclinicalpracticeispresented,takingintoaccount regulatoryissues,includingthoseaddressingsafetyconcerns,aswellasquestions relatedtotheup-scalingprocessesandreproducibility.

Novelbiocompatibleandbioresorbablemagneticmaterials,promisingfornew therapeuticapproachesandtoovercometheuseofcytotoxicsuperparamagnetic carriers,arepresented.Suchinnovativematerialsareobtainedthroughabiomineralizationprocessabletogeneratehybridnano-andmicro-carrierswithsuperparamagneticpropertiesforapplicationinnanomedicineasnoveldiagnosticnano-tools orassmartdrugdeliverysystems.

Thedifferenttechniquesusedforthepreparationofnanoparticleswithacoreshellstructure,aswellasstimuliresponsivecore-shellnanoparticles,areillustrated andnanoparticlepropertiesarediscussed.Inaddition,theuseofcore-shellnanoparticlesinmanyadvancedmedicalapplications,suchastheranostics,cancerimaging andtherapy,andcardiovasculardiseases,isthoroughlydescribed.

Thelastpartofthebookisrelatedtocore-shellnanofibersfordrugdelivery applicationsintissueengineering,woundhealing,anticancertherapy,etc. Electrospunfiberscanbeloadedwithdifferentagents,rangingfromsmallmoleculestogrowthfactorsandproteins.Variousloadingmethods,suchasblendelectrospinning,coaxialelectrospinning,andemulsionelectrospinningtechniquesare described.Moreover,anextensiveoverviewofdrugreleasekineticsinrelevant invitro and invivo environmentsisreported.Severalapplicationsofcore-shell nanofibersfordrugandbiomoleculerelease,aswellasforgenetherapy,arepresented,includingcutting-edgeapplicationssuchascontrolledmultidrugdelivery anddrugreleaseondemandbyexternaltriggering.

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Physicochemicalpropertiesof nanosizedpolymericdrugcarrier systems

NicolettaRescignanoandJoseMariaKenny UniversityofPerugia,CivilandEnvironmentalEngineeringDepartment,Stradadi Pentima4,Terni,Italy

2.1Introduction

Theadventofnanomedicinemarksanunparalleledopportunitytoadvancethetreatmentofvariousdiseases,includingcancer.Theuniquepropertiesofnanoparticles (NPs),suchaslargesurface-to-volumeratio,smallsize,theabilitytoencapsulate variousdrugs,andtunablesurfacechemistry,givethemmanyadvantagesovertheir bulkcounterparts.Thisincludesmultivalentsurfacemodificationwithtargeting ligands,efficientnavigationofthecomplex invivo environment,increasedintracellulartrafficking,andsustainedreleaseofdrugpayload.TheseadvantagesmakeNPs amodeoftreatmentpotentiallysuperiortoconventionalcancertherapies [1]

NPs,suchasliposomesorpolymericNPs,haveprovenadvantageousatsolubilizingtherapeuticcargos,substantiallyprolongingthecirculationlifetimesofdrugs [2].Evenso,itwasMaedaandco-workers [3] who,withtheirdiscoveryofthe enhancedpermeabilityandretention(EPR)effect,demonstratedthepotentialfor heightenedaccumulationoflong-circulatingmacromoleculesbyextravasation throughfenestratedbloodvesselsintumorsandopenedseveralexcitingavenues forsite-specificlocalizationofchemotherapeutics.Consequently,overthepasttwo decades,thischaracteristicofsolidtumorshasbeenamajorimpetusforextensive researcheffortsaimedatapplyingNPstochemotherapy.Withgrowingevidenceof theEPRphenomenoninpathologies,rangingfrominfection [4] toheartfailure [5], NP-baseddrugdeliveryisemergingasapowerfulstrategyinseveraldistinctdiseaseconditions,asdemonstratedbyclinicalapprovalofNPformulationsforfungal infections,hepatitisA,multiplesclerosis,andend-stagerenaldisease [6].Their longcirculationlifetimesandabilitytoextravasatetodiseasesiteslargelyimproved thesafetyandtolerabilityofNP-formulateddrugs,bestshownbythereducedcardiotoxicityobservedinpatientsafteradministrationofliposomaldoxorubicin(DOX) comparedwiththatinthoseundergoingtreatmentwiththeconventionalformulation [7].TheseimprovementsinpatientmorbidityledtotheUSFoodandDrug Administration(FDA)approvalofliposomalDOX(Doxil)forthetreatmentof Kaposi’ssarcomain1995 [8],aswellasapprovalofNPalbumin-boundpaclitaxel (Abraxane)10yearslater,whichsimilarlyreduceddetrimentalsideeffects Core-ShellNanostructuresforDrugDeliveryandTheranostics.DOI: https://doi.org/10.1016/B978-0-08-102198-9.00002-8

8Core-ShellNanostructuresforDrugDeliveryandTheranostics

associatedwiththeconventionalpaclitaxelformulationbyeliminatingtheexcipient CremophorEL [9].

Althoughimprovementsinpatientsafetyandmorbidityledtoclinicalapproval ofNPplatforms,suchasDOXandpaclitaxel,efficaciouspatientresponsesremain modest;currently,theseplatformsofferonlymarginalimprovementsoverconventionalformulations [10].Despitetheirpotentialforincreaseddrughalf-livesand improvingadrug’spropensitytoaccumulateatsitesofinjury,theplatformsfacea complexseriesofbiologicalbarriersthatseverelylimitsite-specificbioavailability, preventingachievementofpropertherapeuticoutcomes.Theseobstaclesinclude opsonizationandsubsequentsequestrationbythemononuclearphagocytesystem, nonspecificdistribution,hemorheological/bloodvesselflowlimitations,pressure gradients,cellularinternalization,escapefromendosomalandlysosomalcompartments,anddrugeffluxpump [11].Inadditiontothesubstantialchallengespresentedbyeachindividualbiologicalbarrier,itisimportanttonotethatthesevary incomplexitydependingonfactors,suchasadministrationroute(oralversusintravenous),diseasetype(cancerversusinfection),andstateofdiseaseprogression (early-versuslate-stagecancers).

TheminimaltherapeuticimpactobservedfollowingNPdeliveryisadirectconsequenceoftheNP’sinabilitytoovercomemanyofthesebarriers.Avastamount ofresearchandresourcesarecontinuallyinvestedintheincorporationofinnovative designfeatureswithintraditionalnanocarrierconstructsforpropernegotiationof biologicalbarriers,resultinginthecreationofmultifunctionalNPs.Oftentimes, thesefeaturesincludeincorporationofactivetargetingmoietiesforenhanced uptakeinspecificcells [12] orconstituentcomponentsforstimulus-responsive release(e.g.,pH-sensitive,thermosensitive,andultrasound) [13].Althoughthese modificationshighlighttheimpressiveversatilityandpreclinicalpotentialofnanomedicine,veryfewNPsthatsimplyaddressoneorafewbiologicalbarriersprogresstotheclinicalarena.Thisrealizationhasledmanyexpertstoprovocatively question,andchallenge,thefieldofNP-baseddrugdeliveryinhopesoftransitioningthedisciplinefromplatformswithmerepotentialtothosecapableofdelivering positiveclinicaloutcomes.

2.2Polymericnanocarriersystems

2.2.1PolymerNPs(nanospheres,nanocapsules,andmicelles)

NP-baseddrugdeliveryplatformshaveemergedassuitablevehiclesforovercomingpharmacokineticlimitationsassociat edwithconventionaldrugformulations. Translationalresearchinpolymertherapeuticshasalreadytransferredproducts intothemarket [14] .Theseincludepolymericdrugs(e.g.,Copaxonefor multiplesclerosisandtheorallyadminist eredsequestrantsRenagelandWelchol), polymer proteinconjugates(e.g.,PEGylated interferons(Pegasys;Peg-Intron)), andpolymer aptamerconjugates(Macugenformaculardegeneration)currently inroutineclinicaluse [15].ImprovementonPEGchemistryandconjugation

strategies,e.g.,enzyme-mediatedaswellasrecombinanttechniques,hasimportantlycontributedtothissuccess.Althoughpolymer-drugconjugatesarenowin advancedclinicaltrials,progresshasbeenslowduetoclinicalfailuresresulting frompoorrationaldesignorcommercialiss ues.Lackofsuitabilityofthespecific polymersfromaclinicalviewpoint(safety),poorreproducibilityofmanufacture, andlackofvalidatedcharacterizationmethodsforsuchcomplexconjugatesand architectureshavelimitedthisprogress [16].

Polymerspreparedfrompolyesters:poly(lactic-co-glycolicacid)(PLGA)andits homopolymerspoly(lactide)(PLA)andpoly(glycolide)havebeenselecteddueto theirbiocompatibility,biodegradability,andhighstabilityinbiologicalfluidsand duringstorage [17].ThesepolymershavebeenapprovedbytheFDAfordrug delivery;theycandegradebynonenzymatichydrolysisoftheesterbackbonein bodyfluid.Thedegradationproducts(i.e.,lacticandglycolicacids)aremetabolic compoundsandreadilyeliminatedfromthebodythroughKrebscycle [18]

Polymersomes:Polymermicellesandpolymervesicles,asknownaspolymersomes,arestableandrobustpolymer-basedNPsthatcanbedesignedtodegrade, thusallowingthesecarrierstobeclearedfromthehumanbodyandavoidlong-term toxicitysideeffects [19].Furthermore,theversatilityofpolymerchemistryallows topreciselytunethepropertiesofthesepolymersomes,suchasmembranethickness andstimulussensitivity,andenablestheintroductionoffunctionalgroupsthatcan beusedtoattachtargetingligands(eitherbeforeassemblyofthepolymersintothe NPoronthefinalpolymerNPs).Particularexpertisehasbeendevelopedinpolypeptidedesign,conjugationofpolypeptidesandpolysaccharides,ringopeningpolymerizationofpolyesters,polycarbonate,andpolypeptides,andrecombinant productionofelastin-likepolymers [20].Severalmethodshavebeendevelopedto preparedrug-loadedNPswithdesiredreleasecharacteristicsfrombiodegradable polymers.Theseincludeemulsificationsolventevaporation,nanoprecipitation, microfluidics,emulsificationsolventdiffusionmethod,phaseinversion,sonication, andsaltingout. Invitro and invivo responsesfromtheNPsareinfluencedbytheir variousproperties,suchastheparticlesizeandsizedistribution,surfacemorphology,porosity,surfacechemistry,surfaceadhesion,zeta-potential,drugstability, drugencapsulationefficiency,surface/bulkerosion/degradation,diffusionofthe drug,kineticsofdrugrelease,andthethermodynamicpropertiesoftheNPs.

2.2.2Liposomes

Despitethefactthatliposomesaredevelopedandproducedfordecades,thereare stillmanyunresolvedissuesincluding:

● therearenopredictivetoolsallowingfortherationaldesignoftheliposomeformulation [21];

● thereareonlybrief,imprecise,indicationsprovidedbyauthorities(FDI,EMA)howthe liposomeformulationshouldbecharacterized [8];

● thereareonlylimitednumberofvalidatedinvitrotestsfortheevaluationliposomeperformance [22];and

● theproductionprocessesareonlyqualitativelydescribed.

10Core-ShellNanostructuresforDrugDeliveryandTheranostics

Whereasliposomescanbeeffectivelyusedforamphiphilicmolecules,thereare currentlynoeffectiveproductionprocessesforencapsulationofhighlyhydrophilic compounds.Encapsulationofbiologicalmacromolecules(proteins,nucleicacids, andsugars)isstillveryinefficientornonexisting [23].

2.2.3Dendrimers

Dendrimersweresynthesizedforthefirsttimeduring1978

90.Theyareunique tree-likebranchedpolymersassociatedwithbiomolecules-likeproperties,lowpolydispersityandhighdegreeofversatilityintermsofstructure(easilyphysicochemicallycustomizable),administration(enteralparenteral,andtopicalroutes),and application(drugdeliveryagents,diagnosis,therapy,anddetection).Forallthese reasons,theyemergedasanewappealingclassofparticlesfornanomedicine [24].

Theabilityofdendrimerstoencapsulateandbindtheguestmoleculecanbeused forsolubilityenhancement,sustainedrelease,anddrugdeliverapplications [25].In the20thcentury,theadvancesinthedesign,aswellastheinnovationsindendrimerssynthesis,haveprovidedalargenumberofpublicationsaccordingtotheISI webofknowledge,WebofScience(18.459),contributingtothecreationofa strongproofofconceptforbiomedicalapplications(suchasdrugcarriersandgene deliverysystems).Nevertheless,theapplicationsofdendrimersinbiologicalsystemswereforlongtimelimitedbecauseoftheirintrinsictoxicity.Theadverse effectsweremainlyattributedtogenerationnumberandcationicsurface,andother minorparameterswerealsotakenintoconsideration [26].Theseaspectshave encouragedthesearchfornewbiocompatibledendrimerfamilies,andithasbeen demonstratedthatsurfacemodificationalmostcompletelyabolishedtheintrinsic toxicityofdendrimers [27].Inthisrespect,themoststudieddendrimershavebeen Polyamidoamine(PAMAM)dendrimers invitro and invivo, [28] (i.e.,2657publicationsonPAMAMdendrimersbetween2000and2015).Altogether,duetotheir outstandingphysicochemicalpropertiesandtheenhancedbiocompatibility,dendrimersguaranteeaninnovative,highlycustomizabledrugdeliverysystemableto improvethepharmacokinetics,andconsequentlytheefficacyofthedrug,compared totheunconjugatedone.Dendrimernanocarriersofferthepotentialtoenhancethe bioavailabilityofdrugsthatarepoorlysolubleand/orsubstratesforeffluxtransporters [29].Starpharmahasmadethemostsignificantcontributiontodendrimertherapeuticswiththevirucide(Vivagel) [30] andaparentalanticancerdendrimer (DEP) docetaxelconjugate.

2.3Maintherapeuticagentsencapsulated

NanospheresbasedonPLGAhavebeenextensivelyinvestigatedforsustainedand targetedreleaseofdrugssuchasanticancerdrugs [31],antibiotics [32],peptideand proteindrugsnamelyhumangrowthhormone [33],lysozyme [34],bovineserum albumin, [35] andinsulin [36]

2.3.1Anticancerdrugs

SmallanticancerdrugshavebeenencapsulatedinPLGA-basedNPsinthelast yearsandtheirefficacytotreatvariouscancershasbeenevaluated invitro and invivo.Differentexamplesarepresentinliterature.Long-termclinicaluseof DOX,ahighlypotentanthracyclineapprovedagainstawidespectrumoftumorsis compromisedbytoxicities,cardiomyopathies,andsubsequentcongestiveheartfailures [37].PEGylatedPLGANPsencapsulatingDOXenhanceantitumoralefficacy comparedwiththefreedrug [38].Moreover,theseNPswereshowntodecrease drasticallysideeffects,inparticularcardiomyopathiescomparedtoDoxil,aliposomalformulationofDOXcurrentlyavailableonthemarket [39].Chemotherapy ofglioblastomaislargelyineffectiveastheblood brainbarrierpreventsentryof mostanticanceragentsinthebrain.NontargetedDOX-loadedPLGANPscoated withpoloxamer188werefoundtocrosstheblood brainbarrierandtoeffectively decreasethetumorgrowthinratmodel [40].Paclitaxel(PTX),amitoticinhibitor usedinthetreatmentofvariouscancers,presentsalowtherapeuticindexandalow aqueoussolubility.TheencapsulationofPTXintoPLGANPsstronglyenhances thecytotoxiceffectofthedrugascomparedtoTaxol [41].9-nitrocamptothecin(9NC)isananticancerdrugwhichtargetsthetopoisomeraseInuclearenzyme. BecauseofinstabilityatbiologicalpHandlowwatersolubility,thedeliveryofthis drugisquitechallenging.9-NC-loadedPLGANPs,preparedbynanoprecipitation, haveshownasustainedreleaseupto160hoursindicatingthesuitabilityofPLGA NPsincontrolled9-NCrelease [42].PLGA-basedNPstargetingthetumorcellsor tumorendotheliumhavebeenshowntobeusuallymoreactiveinpreclinicalstudies thannontargetedNPs.Someexamplesarepresentinliterature.Acyclicpeptide, Cyclo-(1,12)-penITDGEATDSGC(cLABL),hasbeenshowntoinhibitLFA-1/ ICAM-1viathebindingtoICAM-1.Inaddition,cLABLhasbeenshowntobe internalizedafterbindingtoICAM-1 [43].Thiscyclicpeptidewasconjugatedto PLGANPscarryingDOX.ThesenanovectorswereshowntobemorerapidlyuptakenbyA549lungepithelialcellsthannontargetedNPs.Folate-decoratedDOXloadedPLGANPsinducedacellularuptake1.5timeshigherbyMCF-7cellsthan nontargetedNPs [44].Recently,otherfolate-decoratedPTX-loadedPLGA-PEG NPsshowedagreatercytotoxicityagainstHEC-1Acancercellsboth invitro and invivo

2.4Physicalproperties

2.4.1Dimensionandsurfacecharge

Inthecontextofbiomedicalapplicationsofengineerednanomaterials,theforemost distinctivefeatureistheirsize,whichfallin-betweenindividualatomsormolecules andcorrespondingbulkmaterial.Thereducedsizeofnanomaterialswillnotonly provideanopportunityforincreaseduptakebutalsowillbuildchancestointeract withbiologicaltissuestoagreatermagnitudetoachievedesiredtypeofselective

12Core-ShellNanostructuresforDrugDeliveryandTheranostics

biologicalactionfortherapeuticpurposes [45].Furthermore,intherecenttimes,it hasbeenestablishedthatparticlesizeisparticularlydomineeringwhileotherphysicochemicalparametersarecontrolled.Toconfirmthis,systematicassessmentof size-dependentbiologicalprofileandbiodistributionofthreemonodisperse drug silicananoconjugatesof20,50,and200nmhavebeenevaluated.Thisevaluationwasperformedthroughlaboratoryexperimentsinconjugationwithmathematicalmodelingtoestablishtheoptimalsizeforthemosteffectiveantitumordrug deliverysystem.Itwasrevealedthatthe50nmsizeddrugnanoconjugateparticles hadhighestcancertissueretentionovertimeleadingtodeepertissuepenetration andeffectiveinternalizationwithinthecancercellsalongwithslowerclearance [46].Additionally,nanomaterialsareanticipatedtocrossbiologicalobstacles,gainingentrancetothebody,andsubsequentlynanosizemaygoverntheirkinetics, absorption,distribution,metabolism,andexcretionthatwouldnotbepossibleotherwisewiththebulkmaterialofakincomposition [47]

Thesurfacechargeofapolymerisanimportantparameterwhichhelpstodeterminetheirefficiencyforsurfacemodification [48].Theeffectofsurfacechargecan beusedtoimprovethedrugabsorptionviatheoralrouteeitherbyincreasingthe proximityofformulationtotheepitheliumorhigherparticleuptakeviaPayer’s patchesorboth.

ComparedwithNPswithaneutralornegativecharge,positivelychargedNPs aretakenupatafasterrate.Ithasbeensuggestedthatthecellmembranepossesses aslightnegativechargeandcelluptakeisdrivenbyelectrostaticattractions.A recentstudydemonstratedthatthiselectrostaticattractionbetweenmembraneand positivelychargedNPsfavorsadhesionontothecell’ssurface,leadingtouptake. BindingofnegativelychargedNPstoalipidbilayercauseslocalgelation,whereas bindingofpositivelychargedNPsinducesfluidity.Severalstudieshaveconfirmed thepivotalrolesurfacechargeplaysindownstreambiologicalresponsestoNPs [49].

2.4.2Physicalstate

Thedegradationrateisoftenconsideredtobeanimportantselectioncriterionfor biomedicalapplications.Thedegradationratedependsalsoonthecrystallinityof polymermatrix.Thestereochemistryandthermalhistoryhavedirectinfluenceon PLAcrystallinity,andtherefore,onitspropertiesingeneral.Averyimportantpropertyofpolymersistherateofcrystallinitywherecrystallinityistheindicationof amountofcrystallineregioninthepolymerwithrespecttoamorphouscontent. Crystallinityinfluencesmanypolymerpropertiesincludinghardness,modulus,tensilestrength,stiffness,crease,andmeltingpoints.So,whileselectingapolymerfor arequiredapplication,itscrystallinityplaystheforemostrole.Physicalcharacteristicssuchasdensity,heatcapacity,andmechanicalandrheologicalpropertiesof polymeraredependentonitsTg.ForamorphousPLA,theTgisoneofthemost importantparametersbecausedramaticchangesinpolymerchainmobilitytake placeatandaboveTg.ForsemicrystallinePLA,bothTgandTmareimportant physicalparametersforpredictingPLAbehavior [50]

2.5Chemicalproperties

2.5.1Hydrophobicity/hydrophilicity

Thehydrophobicityofthepolymeristhesecondmostimportantpropertywhich affectsthe invitro and invivo fateofpolymericsystemandrepresentsitsaffinity towardstheorganicaswellastheaqueousphase.However,themolecularweight ofthepolymerisdependentuponthechainlengthoftheoligomer,anditpossesses directrelationwiththehydrophobicity [51].Hydrophobicityofpolymersgreatly determinestheabsorptionpatternanddegradationkineticsofadeliverysystem [52]

Thedegradationkineticsdictatestherateanddurationofdrugrelease,thatis,the slowerthedegradation,themoreprolongedwillbetherelease.OwingtothehydrophobicnatureofPLGA,orPLAforexample,nano/microparticleswithcore-shell structuresarepreparedthroughvariousemulsificationprocessesandhydrophilic drugscouldbeencapsulatedinthehydrophiliccoreoftheparticles,whereas hydrophobicdrugstendtodistributeinthehydrophobicshell.Thetypicalrelease profileforPLGAparticulatedeliverysystemsistheinitialburstphasefollowedby anear-zeroorderphase.Variousintramuscularorsubcutaneouscontrolleddelivery systemsintheformofimplantsormicroparticleshavebeendevelopedusingbiodegradablepolyesterssuchasPLAandPLGA [52].

2.5.2Molecularweight

Themolecularweightofthepolymerisoneofthemostimportantfactorsthat affectthepharmacokineticandpharmacologicalefficiencyofadeliverysystem.It significantlyaffectsreleasekineticsofdrugbyinfluencingpolymerdegradation behavior.Thehighermolecularweight(HMw)ofthepolymerisattributedtowards alongerchainlengthmonomers/oligomers,whichreducesitsinitialbursteffect anddegradationrate,andhence,thesustainedreleaseofthedrug [53].Theuseof HMwpolymersincreasesthebioavailability [54] anddrugloading [54],whereas theyexertanoppositeeffectontheencapsulationefficiency(EE)andparticlesize ofthedeliverysystem.TheeffectofmolecularweightofPLGA/PLANPsoftwo hydrophobicmodeldrugs(dexamethasoneandflutamide)suggestedthatthedrug loadingcapacityandparticlesizeofcarriersincreasewithHMwpolymeralong withreductioninpercentagecumulativerelease.ThePLGANPsofRivastigmine alsodemonstratedslowerreleasethanpoly-(butylcyanoacrylate)NPs.Thiseffect wasalsoattributedtoHMwofPLGA [55].Anenormousincreaseinbioavailability andEEofcurcuminisreportedwhenencapsulatedinHMwpolymers,thatis, PLGAandPCL-PEG-PCLco-polymers,respectively.Apartfromthese,sustained effect,higherEEanddrugloading,increasedbioavailability,bettertherapeutic response,lowinitialbursteffect,andbetterintestinalabsorptionwithincreasein themolecularweightofthepolymerisseenirrespectiveofthepolymerandthe drugused.TheseeffectslikeincreaseinEEareattributedtoanincreaseinviscosity oftheorganicphasewithincreasingmolecularweightoftheincorporatedpolymer whichreducesthediffusionofthedrugintheexternalaqueousphasebefore

14Core-ShellNanostructuresforDrugDeliveryandTheranostics

colloidalhardening [56].Inbrief,lowermolecularweightpolymeryieldssmaller sizeparticlesalongwithreductionintheirEE [54].Nevertheless,thisisnotalways true:fornorcantharidin,betterabsorptioncharacteristicswereseenwithlowmolecularweightchitosanascomparedtoveryHMwpolymerwhichmayyieldporous particlesduetotheformationoflargeparticlesthataggregatethemselvesandthus reduceabsorption [57].Thiscouldbeexplainedonthebasisofthethermoplastic natureandinherenttackinessoftheHMwpolymer.

2.6Conclusion

Thephysicochemicalpropertiesofapolymerhavevitaleffectsonefficiencyofa deliverysystem,whichhelpresearchersintheselectionofanoptimizedpolymer withrequiredpropertyforspecificpurpose.Likewise,hydrophilicpolymersorsurfactantscanbecoatedonthepolymericdrugparticletoimprovethecirculation half-lifeofthedrugbyavoidingreticulo-endothelialsystemuptake.Thedrug releasecanbemodified,thatisextendedandcontrolled,fromhourstomonthswith theselectionofpropermolecularweightandthenatureofthepolymer.Anamorphous,hydrophilicpolymerisrecommendedforrapidrelease,upto1month, whereasahighlycrystallinepolymerisconsideredbestforslowrelease,lasting morethan6months.Targetingcanalsobeachievedincancerouscells,macrophagesofliverandspleen(incaseoffatalinfections),byusingahydrophobicpolymer.Therefore,thephysiochemicalpropertiesofapolymerareessentialbecause theyplayaprominentpartinmatrixdegradation,drugreleasemechanism,drug loading,andmostimportantlyfordrugtargetingataspecificsite.

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Biomineralizationprocess generatinghybridnano-and micro-carriers

ElisabettaCampodoni,TatianaPatricio,MonicaMontesi, AnnaTampieri,MonicaSandriandSimoneSprio

InstituteofScienceandTechnologyforCeramics-NationalResearchCouncil(ISTEC-CNR), Faenza,Italy

3.1Introduction

Biomaterialsplayanengagingroleinthefieldofregenerativemedicinewhere biomimicryhastodaybecomeadrivingconcept.Infact,theclosereproductionof thephysicochemical,morphological,andmechanicalfeaturesoftargetedtissues providebiomaterialswithabilitytoexchangeinformationwithcellsandtriggerthe boneregenerativecascade [1].Tothispurpose,nature-inspiredapproachesfor nanomaterialsdevelopmentarerapidlygaininggroundtoobtainmaterialswith unusualperformance.Infact,organicmacromoleculesatthebaseofbiologicstructuresstorecomplexinformationthatcanbeexploitedtogenerate3Dconstructs exhibitinghighmimicryoflivingtissues.Thisconceptisperfectlyrepresentedby biomineralization,anaturalassembling/mineralizationprocessthathasbeensuccessfullyreproducedinlaboratorytoinduceheterogeneousnucleationofinorganic nanophasesontotheorganicmatrix,drivenbycontrolmechanismsinherentinthe organicmatrixitself,andtoproducehybridscaffoldswithbone-mimickingcompositional,morphological,andstructuralfeatures [2 8].Thechemicalinteraction betweentheorganicandinorganiccomponentconfersuniquepropertiestosuch hybridmaterials.Biomineralizationprocessesarealsoeffectiveintheproductionof nano-sizedstructuresthatcanbeusedasnano-andmicro-carrierswithenhanced bioactivityandbiodegradability [9 11].Inthebroadfieldofnanomedicine,nanoparticles(NPs)arewidelystudiedbecausetheirapplicationisexpectedtochange thesceneryofpharmaceuticalandbiotechnologicalindustries [12].Infactthe clinicalapplicationofnewerandmoreeffectivedrugsisstillconstraineddueto thepresenceofseveralbarriersandblocksbetweenthesiteofintroductionandthe targetsitesuchasreticulo-endothelialsystem,membranebarriersandblood brain barrier,orthepossibilitytobeinactivatedordegraded [13].Besides,systemicdrug deliverylimitsthetherapeuticeffectivenessandmoreeasilyprovokeundesired secondaryeffects.Today,thedevelopmentofcarrierswithsmartmultifunctional propertiesandabilityofreleasealongdefinedspatial temporalprofilesisa particularlyhottopicinmaterialsresearch.Ontheonehand,chemicaldopingof Core-ShellNanostructuresforDrugDeliveryandTheranostics.DOI: https://doi.org/10.1016/B978-0-08-102198-9.00003-X

20Core-ShellNanostructuresforDrugDeliveryandTheranostics

mineralphasesallowstotailorrelevantpropertiesofthefinalcompositematerials suchasspecificaffinitywithtargetedcells,antibacterial,andmagnetism [14 16].

Inparticular,thedopingwithironionsintroducedinacertainratiointhehydroxyapatitecrystalbestowsuperparamagneticpropertiesusefulforvariousfrontier applicationsinnanomedicinesuchason-demandactivationanddrugdelivery, imaging,cellstimulationbymeansofexternalmagneticfield [17].

Thischapterdescribesthebiomineralizationprocessandrelatedapplicationsto generatenovelbiocompatibleandbioresorbablemagneticmaterialspossiblyopening tonewtherapeuticapproachesandovercometheuseofcytotoxicsuperparamagnetic carriers.Particularly,thechapterwillillustratetworecentapproachesbywhich differentorganicmacromoleculeswereusedastemplateforbiomineralizationprocess thusgeneratinghybridnano-andmicro-carrierswithsuperparamagneticproperties, exhibitingsuitablepropertiesforapplicationinnanomedicineasnoveldiagnostic nano-toolsorsmartdrugdeliverysystems.

3.2Biomineralization

Recentresearchonmaterialscienceisincreasinglytakinginspirationfromnature withthepurposetoobtainnewmaterialswithabilityofsmartresponsivenessto environmentalstimuli.Inparticular,biomineralizationreferstoprocessesbywhich organismsformmineralsandconsistinacomplexcascadeofphenomenageneratinghybridnanostructuredmaterialshierarchicallyorganizedfromthenanoscaleto themacroscopicscale.Thisprocessisatthebasisofload-bearingstructuressuch

Figure3.1 Exampleswherethebiomineralizationprocesstakesplaceinnature:a)sea

sponge;b)bone;c)tooth;d)exoskeletonofcrayfish;e)diatom;f)shell.