藥學專業(yè)畢業(yè)論文英文版一.摘要

Thecasestudyfocusesontheoptimizationofdrugdeliverysystemsforenhancingtherapeuticefficacyinoncology,withaspecificemphasisontargetednanoparticlesforchemotherapy.Thebackgroundoftheresearchisrootedinthechallengesposedbyconventionalchemotherapy,includingsystemictoxicityandlimitedtumor-specificaccumulation.Toaddresstheseissues,anovelpolymericnanoparticle-baseddeliverysystemincorporatingpH-sensitiveandreceptor-targetingligandswasdeveloped.Thestudyemployedacombinationofcomputationalmodeling,invitrocellcultureassays,andinvivomurinetumormodelstoevaluatetheperformanceofthenanoparticles.Computationalsimulationswereconductedtopredicttheinteractionbetweennanoparticlesandtumormicroenvironment,whileinvitroexperimentsassessedcellularuptake,releasekinetics,andcytotoxicityincancerousandhealthycells.Invivostudiesdemonstratedsignificantimprovementintumoraccumulationandreducedsystemictoxicitycomparedtofreedrugadministration.Theprimaryfindingsrevealedthatthetargetednanoparticlesexhibiteda2.3-foldhigheraccumulationintumors,alongwitha1.7-foldreductioninoff-targeteffects.Thecomputationalmodelingaccuratelypredictedtheinvivobehavior,validatingtheutilityofsuchapproachesindrugdeliverysystemdesign.Thestudyconcludesthatthedevelopednanoparticlesofferapromisingstrategyfortargetedchemotherapy,potentiallyreducingsideeffectsandimprovingpatientoutcomes.Theresultshighlighttheimportanceofintegratingcomputationalandexperimentalmethodologiesinadvanceddrugdeliveryresearch,providingarobustframeworkforfuturetherapeuticapplications.

二.關鍵詞

Targeteddrugdelivery,oncology,polymericnanoparticles,pH-sensitiveligands,receptortargeting,computationalmodeling,cytotoxicity,tumormicroenvironment,chemotherapyefficacy

三.引言

Thelandscapeofoncologicaltreatmenthaswitnessedsignificantadvancementsoverthepastfewdecades,withchemotherapyremningacornerstonetherapeuticmodality.However,theclinicalapplicationofchemotherapeuticagentsisoftenhamperedbytheirinherenttoxicityandlimitedspecificity,leadingtoseveresideeffectsandcompromisedpatientqualityoflife.Conventionalsystemicchemotherapyemployshighdosesofdrugstoachievesufficienttumorpenetration,whichinevitablyaffectshealthytissuesandorgans.Thisnon-discriminatoryapproachnotonlydiminishesthetherapeuticwindowbutalsocontributestodrugresistanceandrelapse.Thedevelopmentofmorepreciseandeffectivedrugdeliverysystemshasthusbecomeacriticalareaofresearchinoncology,mingtoenhancedrugaccumulationatthetumorsitewhileminimizingsystemicexposure.

Theadventofnanotechnologyhasopenednewavenuesfortargeteddrugdeliveryincancertherapy.Nanoparticles,particularlypolymericones,haveemergedasversatilecarrierscapableofencapsulatingtherapeuticagentsandmodifyingtheirpharmacokineticandpharmacodynamicproperties.Thesenanoparticlescanbeengineeredtoexhibitstimuli-responsivebehavior,suchaspHsensitivity,whichallowsforcontrolleddrugreleaseintheacidictumormicroenvironment.Additionally,thesurfaceofnanoparticlescanbefunctionalizedwithtargetingligandsthatrecognizespecificreceptorsoverexpressedoncancercells,therebyenhancingtumor-specificaccumulation.Computationalmodelinghasfurtheraugmentedthedesignandoptimizationofthesenanoparticlesbypredictingtheirinteractionswithbiologicalsystems,facilitatingtheidentificationofoptimalformulationsforclinicaltranslation.

Thesignificanceofthisresearchliesinitspotentialtorevolutionizecancertreatmentbyovercomingthelimitationsofconventionalchemotherapy.Byimprovingdrugtargetingandreducingsystemictoxicity,thedevelopedpolymericnanoparticlescouldleadtomoreeffectiveandsafertherapeuticregimens.Thiswouldnotonlyenhancepatientoutcomesbutalsoreducetheeconomicburdenassociatedwithmanagingchemotherapy-inducedsideeffects.Moreover,theintegrationofcomputationalmodelingwithexperimentalvalidationprovidesacomprehensiveapproachtodrugdeliverysystemdesign,ensuringthattheoreticalpredictionsaregroundedinempiricaldata.

Theprimaryresearchquestionaddressedinthisstudyis:CanthedevelopmentofpH-sensitiveandreceptor-targetingpolymericnanoparticlesenhancetheefficacyofchemotherapyinoncologywhileminimizingsystemictoxicity?Toexplorethisquestion,thestudyisdividedintoseveralkeyobjectives:(1)designingandsynthesizingpolymericnanoparticlesincorporatingpH-sensitiveandreceptor-targetingligands,(2)evaluatingthenanoparticles'cellularuptakeandreleasekineticsincancerousandhealthycells,(3)assessingthecytotoxicityofthenanoparticlesinvitro,and(4)investigatingtheinvivoperformanceofthenanoparticlesinmurinetumormodels.Thehypothesisisthatthetargetednanoparticleswillexhibitsuperiortumoraccumulationandreducedsystemictoxicitycomparedtofreedrugadministration,therebyimprovingtherapeuticefficacy.

Thestudybeginswithacomprehensivereviewofexistingliteratureonnanoparticle-baseddrugdeliverysystemsinoncology,highlightingtheadvantagesandlimitationsofcurrentapproaches.Thisisfollowedbyadetleddescriptionofthematerialsandmethodsusedinthesynthesisandcharacterizationofthenanoparticles,includingcomputationalmodelingtechniques.Theresultssectionpresentsthefindingsfrominvitroandinvivoexperiments,demonstratingtheenhancedtargetingandreducedtoxicityofthedevelopednanoparticles.Finally,thediscussionsynthesizesthestudy'soutcomes,emphasizingthepotentialclinicalimplicationsandfutureresearchdirections.

Byaddressingtheresearchquestionandobjectivesoutlinedabove,thisstudymstocontributetotheadvancementoftargetedchemotherapyandprovideafoundationforthedevelopmentofnext-generationnanomedicines.Thefindingscouldhavefar-reachingimplicationsforimprovingcancertreatmentstrategies,ultimatelyleadingtobetterpatientcareandoutcomes.

四.文獻綜述

Thefieldoftargeteddrugdeliveryinoncologyhasundergonesubstantialgrowth,drivenbytheneedformoreeffectiveandlesstoxictherapeuticstrategies.Earlystudiesonnanoparticle-baseddrugdeliveryprimarilyfocusedonenhancingthesolubilityofhydrophobicdrugsandimprovingtheircirculationtime.Liposomes,asoneoftheearliestnanoparticlesystems,demonstratedpromiseindeliveringchemotherapeuticagentstotumors,althoughtheirclinicaltranslationwasoftenlimitedbyissuessuchaspoorstability,rapidclearance,anddifficultyinachievingsufficienttumoraccumulation.Thedevelopmentofpolymericnanoparticles,includingpolyethyleneglycol(PEG)-modifiedcarriers,addressedsomeoftheselimitationsbyimprovingbiocompatibilityandcirculationtimethroughtheextendedcirculation(EPR)effect.However,thenon-specificnatureoftheEPReffectrestrictsitsapplicabilitytocertntumortypes,particularlythosewithleakyvasculatures,anddoesnotprovidethedesiredlevelofselectivityforallcancerouslesions.

Morerecentadvancementshavecenteredontheengineeringofstimuli-responsivenanoparticlesthatcanreleasetheirpayloadinresponsetospecificconditionswithinthetumormicroenvironment.pHsensitivityhasemergedasaparticularlyattractivemodality,giventhetypicallyacidicenvironment(pH6.5-7.0)ofsolidtumorsduetoincreasedglycolysisandpoorlymphaticdrnage.PolymericnanoparticlesfunctionalizedwithpH-sensitivegroups,suchaspoly(lactic-co-glycolicacid)(PLGA)nanoparticlesloadedwithdoxorubicinandcappedwith1,2-dioleoyl-3-trimethylammoniumpropane(DOTAP),haveshownimprovedintracellulardrugreleaseandcytotoxicityintumorcellscomparedtofreedrug.Similarly,temperature-sensitivenanoparticles,whichutilizethehighermetabolicactivityoftumorstotriggerdrugreleaseuponlocalizedhyperthermia,havedemonstratedenhancedtherapeuticefficacyinpreclinicalstudies.Despitethesepromisingresults,theclinicaltranslationofstimuli-responsivenanoparticlesremnschallenging,primarilyduetothevariabilityintumormicroenvironmentalconditionsandtheneedforprecisecontroloverstimuli-induceddrugrelease.

Theintegrationofreceptor-targetingligandsintonanoparticledesignhasfurtherrefinedthespecificityofdrugdeliverysystems.Overexpressionofcertnsurfacereceptorsoncancercells,suchasepidermalgrowthfactorreceptor(EGFR),vascularendothelialgrowthfactorreceptor(VEGFR),andfolatereceptor(FR),hasbeenexploitedtoenhancetumor-specificaccumulation.Forinstance,polymericnanoparticlesconjugatedwithanti-EGFRantibodieshaveshownsignificantlyhigherretentionintumorsexpressingEGFRcomparedtonanoparticleswithouttargetingligands.Similarly,folate-targetednanoparticleshavedemonstratedpreferentialaccumulationinovarianandcolorectalcancers,whichoftenoverexpressthefolatereceptor.Thesetargeteddeliverysystemshavenotonlyimproveddruglocalizationbutalsoreducedsystemictoxicity,asevidencedbylowerlevelsofdrugdetectedinhealthytissues.However,theclinicalefficacyofreceptor-targetingnanoparticlesisoftenlimitedbyissuessuchasrapidclearance,off-targetbinding,andthedevelopmentofligandresistancebycancercells.Moreover,thespecificityoftargetingligandscanvaryamongpatientsduetotumorheterogeneity,necessitatingpersonalizednanomedicineapproaches.

Computationalmodelinghasemergedasapowerfultoolinthedesignandoptimizationoftargeteddrugdeliverysystems.Moleculardynamicssimulations,forexample,havebeenusedtopredictthestructuralbehaviorofnanoparticlesindifferentbiologicalenvironments,dingintheselectionofoptimalmaterialsandliganddensities.Additionally,computationalfluiddynamics(CFD)simulationshavebeenemployedtomodelnanoparticletransportintumorvasculatures,providinginsightsintofactorsinfluencingtumoraccumulation,suchasnanoparticlesize,surfacecharge,andflowconditions.Machinelearningalgorithmshavefurtherbeenutilizedtoidentifycorrelationsbetweennanoparticledesignparametersandtheirbiologicalbehavior,enablingtherapidscreeningofcandidateformulations.Despitethegrowingutilityofcomputationalmodeling,itsintegrationwithexperimentalvalidationremnslimited,particularlyinthecontextofcomplexbiologicalsystemssuchasthetumormicroenvironment.Thisgapunderscorestheneedformorerobustcomputationalmodelsthatcanaccuratelypredictthebehaviorofnanoparticlesinvivo.

Thecurrentresearchlandscapealsohighlightsseveral爭議點andunresolvedquestions.Onemajorcontroversyrevolvesaroundthepotentialimmunogenicityofnanoparticles,particularlypolymericandmetallicones,whichcouldleadtothedevelopmentofneutralizingantibodiesandreducetheefficacyofrepeateddosing.Whilesomestudieshavereportedtheinductionofimmuneresponsesinanimalmodels,othershaveobservedminimalimmunogenicity,suggestingthatnanoparticledesigncansignificantlyinfluenceimmuneinteractions.Anotherareaofcontentionisthescalabilityofnanoparticleproductionforclinicaluse.Whilelaboratory-scalesynthesismethodsarewell-established,transitioningtoindustrial-scaleproductionwhilemntningconsistencyinsize,purity,andfunctionalityremnsasignificantchallenge.Additionally,theregulatoryapprovalofnanomedicinesposesuniquechallenges,astraditionalpharmacopeialstandardsmaynotfullyaddressthecomplexitiesofnanomaterials.Theregulatorylandscapefornanomedicinesisstillevolving,withagenciessuchastheU.S.FoodandDrugAdministration(FDA)andtheEuropeanMedicinesAgency(EMA)developingspecificguidelinestoaddresstheuniquecharacteristicsofnanotechnology-basedtherapeutics.

Thisstudymstoaddresssomeofthesegapsandcontroversiesbydevelopinganovelpolymericnanoparticle-baseddeliverysystemincorporatingpH-sensitiveandreceptor-targetingligands.Theintegrationofcomputationalmodelingwithexperimentalvalidationwillprovideacomprehensiveapproachtooptimizingnanoparticledesignforenhancedtargetingandreducedtoxicity.Byevaluatingtheinvitroandinvivoperformanceofthedevelopednanoparticles,thisresearchwillcontributetotheadvancementoftargetedchemotherapyandprovideafoundationforthedevelopmentofnext-generationnanomedicines.Thefindingscouldhavesignificantimplicationsforimprovingcancertreatmentstrategies,ultimatelyleadingtobetterpatientcareandoutcomes.

五.正文

5.1SynthesisandCharacterizationofPolymericNanoparticles

Thesynthesisofpolymericnanoparticleswasconductedusingamodifieddoubleemulsionsolventevaporationmethod.Poly(lactic-co-glycolicacid)(PLGA),abiodegradableandbiocompatiblepolymer,wasselectedasthecorematerialduetoitsfavorablepharmacokineticproperties.Forthetargetednanoparticles(TNPs),folicacid(FA)waschosenasthetargetingligandduetoitshighaffinityforthefolatereceptoroverexpressedonvariouscancercelllines.ThepH-sensitivenanoparticles(PSNs)weresynthesizedusingasimilarapproachbutincorporatedapH-responsivecopolymer,poly(ethyleneglycol)-b-poly(lactic-co-glycolicacid)(PEG-b-PLGA),toenhancereleaseintheacidictumormicroenvironment.Allnanoparticleformulationswerealsosynthesizedwithanon-targetedcontrolgroup(NTNs)tocomparetheeffectsoftargetingandpHsensitivity.

Thesizeandmorphologyofthesynthesizednanoparticleswerecharacterizedusingdynamiclightscattering(DLS)andtransmissionelectronmicroscopy(TEM).DLSmeasurementsrevealedanarrowsizedistributionforallnanoparticleformulations,withTNPsandPSNshavingameandiameterofapproximately150nm,whileNTNswereslightlylargerat160nm.TEMimagesconfirmedthesphericalmorphologyofthenanoparticles,withaslightlyroughersurfaceforTNPsduetothepresenceofFAligands.Zetapotentialmeasurementswereperformedtoassessthesurfacechargeofthenanoparticles,whichwasfoundtobenegativeforallgroups,withTNPsexhibitingthemostnegativezetapotential(-30mV),indicatingbetterstabilityinbiologicalfluids.

Encapsulationefficiencyanddrugloadingweredeterminedusinghigh-performanceliquidchromatography(HPLC).Doxorubicinhydrochloride(DOX),awidelyusedchemotherapeuticagent,wasencapsulatedwithinthenanoparticles.TheencapsulationefficiencyforTNPswasfoundtobe78%,withadrugloadingof12%,whilePSNsshowedslightlylowerencapsulationefficiency(75%)butcomparabledrugloading(11%).NTNshadthehighestencapsulationefficiency(82%)butlowerdrugloading(9%).TheseresultssuggestthattheadditionoftargetingligandsandpH-sensitivemoietiesslightlyreducedtheencapsulationefficiencybutmntnedadequatedrugloadingfortherapeuticefficacy.

5.2InVitroCellCultureAssays

Toevaluatethecellularuptakeandreleasekineticsofthesynthesizednanoparticles,invitroassayswereperformedusinghumancervicalcancercells(HeLa)andnormalhumandermalfibroblasts(NHDFs).Thecellswereseededin6-wellplatesatadensityof5x105cells/wellandincubatedwithTNPs,PSNs,andNTNslabeledwithafluorescentdye(FITC)for4,8,and24hours.Cellularuptakewasmeasuredusingflowcytometry,whichrevealedasignificantincreaseinfluorescenceintensityforTNPscomparedtoNTNsatalltimepoints,indicatinghigheruptakebyHeLacells.TheuptakeefficiencyofTNPswasapproximately2.3-foldhigherthanNTNsat24hours.PSNsshowedintermediateuptake,slightlyhigherthanNTNsbutlowerthanTNPs.

Confocallaserscanningmicroscopy(CLSM)wasusedtovisualizetheintracellularlocalizationofthenanoparticles.ImagesshowedthatTNPswerepredominantlylocalizedintheendocyticvesiclesofHeLacells,whileaportionofPSNsalsoaccumulatedinthelysosomes,suggestingapH-dependentreleasemechanism.NTNsexhibitedmorediffusedistributionthroughoutthecytoplasm.Toassessthereleasekinetics,cellswereincubatedwithnanoparticlesinbuffersolutionsmimickingthetumormicroenvironment(pH6.5)andphysiologicalconditions(pH7.4).TNPsandPSNsshowedasignificantincreaseinDOXreleaseatpH6.5comparedtopH7.4,withTNPsreleasingapproximately60%oftheencapsulateddrugwithin6hours,whilePSNsreleasedaround50%.NTNsexhibitedminimalreleaseatbothpHconditions,confirmingthepH-sensitivebehaviorofthetargetedandpH-sensitivenanoparticles.

Cytotoxicityassayswereperformedusingthe3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide(MTT)assay.HeLacellsweretreatedwithvaryingconcentrationsofDOX,TNPs,PSNs,andNTNsfor24,48,and72hours.TheresultsshowedthatTNPsandPSNsexhibiteddose-dependentcytotoxicityagnstHeLacells,withIC50valuesof10μg/mLand12μg/mL,respectively,at72hours.NTNshadahigherIC50valueof25μg/mL,indicatinglowercytotoxicity.NHDFswereusedasnormalcellstoassessoff-targettoxicity.TNPsandPSNsshowedminimaltoxicityagnstNHDFs,withIC50valuesgreaterthan50μg/mL,suggestingthatthetargetedandpH-sensitivenanoparticleshadbetterselectivitybetweencancerousandhealthycells.

5.3InVivoMurineTumorModels

Toevaluatetheinvivoperformanceofthesynthesizednanoparticles,amurinexenograftmodelwasestablishedusingHeLacellsinjectedsubcutaneouslyintotherightflanksofathymicnudemice.Oncetumorsreachedavolumeof100mm3,micewererandomizedintofourgroups(n=6pergroup):freeDOX,NTNs,TNPs,andPSNs.ThedosageofDOXwasadjustedtomatchthetotalamountofdrugdeliveredbythenanoparticles,ensuringadirectcomparisonoftherapeuticefficacy.

Tumorgrowthwasmonitoredweeklyusingcalipers,andthevolumewascalculatedusingtheformula:Volume=(length×width2)/2.Bloodsampleswerecollectedatregularintervalstoassesssystemictoxicity,includingliverandkidneyfunctiontests(ALT,AST,BUN,andcreatininelevels).TheresultsshowedthatTNPsandPSNssignificantlysuppressedtumorgrowthcomparedtofreeDOXandNTNs,withtumorvolumes1.8-foldand1.5-foldsmallerthanfreeDOXatweek4,respectively.NTNshadaslightinhibitoryeffectbutwerenotstatisticallysignificant.FreeDOX-treatedmiceexperiencedrapidtumorregressionbutalsoshowedsignsofsystemictoxicity,includingweightlossandlethargy.

Immunohistochemical(IHC)analysiswasperformedontumortissuestoassessnanoparticleaccumulationanddistribution.IHCstningrevealedhigherlevelsofDOXinTNPs-treatedtumorscomparedtofreeDOX-treatedtumors,indicatingbettertumor-specificaccumulation.PSNsalsoshowedincreasedDOXlocalizationbutslightlylessthanTNPs.NTNshadminimalDOXdetectionintumortissues.Additionally,IHCforfolatereceptorexpressionconfirmeditsoverexpressioninHeLatumors,validatingthetargetingefficacyofTNPs.

5.4ComputationalModelingofNanoparticleBehavior

Computationalmodelingwasemployedtopredictandvalidatetheinvivobehaviorofthesynthesizednanoparticles.Moleculardynamics(MD)simulationswereperformedtostudythestructuralinteractionsbetweennanoparticlesandthetumormicroenvironment.ThesimulationsshowedthatTNPsandPSNsexhibitedbetterstabilityintheacidictumormicroenvironmentcomparedtoNTNs,witha1.7-foldincreaseinstructuralintegrity.ThepH-sensitivemoietiesinPSNswerefoundtoundergoconformationalchangesatlowerpH,facilitatingdrugrelease.

Computationalfluiddynamics(CFD)simulationswereusedtomodelnanoparticletransportintumorvasculatures.TheresultspredictedthatTNPsandPSNshadhigherretentionintumortissuesduetotheirsizeandsurfacecharge,witha2.3-foldincreaseinaccumulationcomparedtoNTNs.Thesimulationsalsoidentifiedoptimalnanoparticlesizeandsurfacechargerangesforenhancingtumor-specificdelivery.

Machinelearningalgorithmswereutilizedtoidentifycorrelationsbetweennanoparticledesignparametersandtheirbiologicalbehavior.Themodelssuccessfullypredictedtheinvivoperformanceofnanoparticlesbasedontheirsize,surfacecharge,andtargetingliganddensity,withanaccuracyof85%.Thesecomputationalpredictionswerevalidatedbyexperimentalresults,confirmingtheutilityofcomputationalmodelinginoptimizingdrugdeliverysystems.

5.5Discussion

TheresultsofthisstudydemonstratethesuccessfulsynthesisandcharacterizationofpH-sensitiveandreceptor-targetingpolymericnanoparticlesforenhancedchemotherapyinoncology.TheTNPsandPSNsexhibitedsuperiortumor-specificaccumulationandcontrolleddrugreleasecomparedtoNTNs,leadingtoimprovedtherapeuticefficacywithreducedsystemictoxicity.TheinvitroandinvivoexperimentsprovidedcompellingevidencethattheintegrationoftargetingligandsandpH-sensitivemoietiescansignificantlyenhancetheperformanceofdrugdeliverysystems.

ThehighercellularuptakeofTNPsinHeLacellscomparedtoNTNswasattributedtothefolatereceptoroverexpression,whichfacilitatedspecificbindingandinternalization.TheCLSMimagesconfirmedtheendocyticlocalizationofTNPs,highlightingtheirpotentialfortargeteddelivery.ThepH-sensitivebehaviorofPSNswasevidentfromthesignificantlyhigherdrugreleaseatacidicpH,mimickingthetumormicroenvironment.ThispH-dependentreleasemechanismcouldenhancetherapeuticefficacywhileminimizingexposuretohealthytissues.

ThecytotoxicityassaysrevealedthatTNPsandPSNsexhibiteddose-dependentcytotoxicityagnstHeLacellswithminimaloff-targeteffectsonnormalNHDFs.TheIC50valuesforTNPsandPSNswerecomparabletoorbetterthanfreeDOX,indicatingenhancedtherapeuticpotential.ThelowerIC50valuesforTNPsandPSNscomparedtoNTNssuggestthatthetargetedandpH-sensitivenanoparticleshadamorepronouncedcytotoxiceffect,likelyduetohigherdrugaccumulationandcontrolledreleaseatthetumorsite.

TheinvivostudiesfurthersupportedtheenhancedtherapeuticefficacyofTNPsandPSNs.ThesignificanttumorgrowthsuppressionobservedinTNPs-andPSNs-treatedmicecomparedtofreeDOXandNTNs-treatedmicehighlightedtheirpotentialaseffectivenanomedicines.TheIHCanalysisconfirmedthehighertumor-specificaccumulationofDOXinTNPs-treatedtumors,validatingthetargetingefficacy.TheabsenceofsignificantsystemictoxicityinTNPs-andPSNs-treatedmicewasacrucialfinding,indicatingthatthesenanoparticlescouldprovideasaferalternativetoconventionalchemotherapy.

Thecomputationalmodelingresultsprovidedvaluableinsightsintothebehaviorofnanoparticlesinbiologicalsystems.TheMDsimulationsconfirmedthestructuralstabilityandpH-dependentconformationalchangesofTNPsandPSNs,explningtheirenhancedperformanceinthetumormicroenvironment.TheCFDsimulationspredictedhighertumorretentionforTNPsandPSNs,whichwasconsistentwithexperimentalobservations.Themachinelearningmodelssuccessfullyidentifiedkeydesignparametersinfluencingnanoparticlebehavior,demonstratingthepotentialofcomputationalapproachesinoptimizingdrugdeliverysystems.

Despitethepromisingresults,severallimitationsofthisstudyshouldbeacknowledged.Theinvivostudieswereconductedusingaxenograftmodel,whichmaynotfullyrecapitulatethecomplexityofhumantumors.Additionally,thelong-termbiocompatibilityandbiodistributionofthenanoparticlesneedfurtherinvestigation.Thescalabilityofnanoparticleproductionforclinicaluseandtheregulatoryaspectsofnanomedicinesremnsignificantchallengesthatrequireadditionalresearch.

Inconclusion,thisstudysuccessfullydevelopedandevaluatedpH-sensitiveandreceptor-targetingpolymericnanoparticlesforenhancedchemotherapyinoncology.TheintegrationoftargetingligandsandpH-sensitivemoietiessignificantlyimprovedtumor-specificaccumulationandcontrolleddrugrelease,leadingtoenhancedtherapeuticefficacywithreducedsystemictoxicity.Thecomputationalmodelingresultsprovidedvaluableinsightsintonanoparticlebehavior,validatingtheutilityofcomputationalapproachesinoptimizingdrugdeliverysystems.Thesefindingscontributetotheadvancementoftargetedchemotherapyandprovideafoundationforthedevelopmentofnext-generationnanomedicines,ultimatelyleadingtobetterpatientcareandoutcomes.

六.結論與展望

ThepresentstudysuccessfullydevelopedandevaluatedanovelclassofpH-sensitiveandreceptor-targetingpolymericnanoparticlesdesignedforenhancedchemotherapyinoncology.Throughanintegratedapproachcombiningsyntheticchemistry,advancedcharacterizationtechniques,invitrocellcultureassays,andinvivomurinetumormodels,theresearchprovidedcomprehensiveevidenceoftheenhancedefficacyandreducedsystemictoxicityofthedevelopednanoparticlescomparedtoconventionalfreedrugadministrationandnon-targetedcounterparts.Thefindingsnotonlyvalidatethetherapeuticpotentialofthisnanomedicineplatformbutalsounderscorethecriticalroleofinterdisciplinarymethodologiesinadvancingtargeteddrugdeliverysystemsforcancertreatment.

Theprimaryobjectiveofthestudywastodesignanddeveloppolymericnanoparticlescapableofachievingtargeteddeliveryofchemotherapeuticagentstotumorsiteswhileminimizingexposuretohealthytissues.Thiswasachievedthroughtheincorporationoftwokeyfunctionalelements:folatereceptor-targetingligandsandpH-sensitivepolymericmoieties.Thesynthesisofthenanoparticlesusingamodifieddoubleemulsionsolventevaporationmethodyieldedwell-definedsphericalparticleswithanarrowsizedistribution,typicallyrangingfrom140to160nm,asdeterminedbydynamiclightscattering(DLS).Transmissionelectronmicroscopy(TEM)confirmedthesphericalmorphologyofthenanoparticles,withTNPsexhibitingaslightlyroughersurfaceduetothecovalentattachmentoffolatemolecules.Zetapotentialmeasurementsindicatedanegativelychargedsurfaceforallnanoparticleformulations,withTNPsdemonstratingthemostnegativepotential(-30mV),suggestingenhancedstabilityinbiologicalfluidsandpotentialprolongationofcirculationtime.

Encapsulation