Chapter21TargetedDrugDeliverySystem(TDDS)掌握靶向給藥系統(tǒng)的概念、分類、特點。熟悉靶向制劑的體內(nèi)外質(zhì)量評價。了解分子藥劑學(xué)和細(xì)胞生物學(xué)技術(shù)，了解靶向制劑的藥動學(xué)基礎(chǔ)。熟悉被動靶向制劑中脂質(zhì)體、納米粒、微乳等的特點、組成、靶向原理及制備方法、質(zhì)量評價。了解主動靶向制劑和物理化學(xué)靶向制劑的類型、特點.Drugdeliverysystem(DDS)給藥系統(tǒng)Adrugdeliverysystem(DDS)isdefinedasaformulationoradevicethatenablestheintroductionofatherapeuticsubstance

治療物質(zhì)inthebodyandimprovesitsefficacyandsafetybycontrollingtherate,time,andplaceofreleaseofdrugsinthebody.Thisprocessincludestheadministrationofthetherapeuticproduct,thereleaseoftheactiveingredientsbytheproduct,andthesubsequenttransportoftheactiveingredientsacrossthebiologicalmembranestothesiteofaction.DefinitionDrugdeliverysystemisaninterfacebetweenthepatientandthedrug.Itmaybeaformulationofthedrugtoadministeritforatherapeuticpurposeoradeviceusedtodeliverthedrug.Targeteddrugdeliverysystem(TDDS)DefinitionTheselectivedeliveryofadrugtoaspecificregion(tissue,celltype)ofthebody經(jīng)某種途徑給藥后，藥物通過特殊載體的作用，特異性地濃集在靶部位的給藥系統(tǒng)。Theaimoftargeteddrugdeliveryistoimprovethetherapeuticeffectivenessofadrug(ortreatment)whileatthesametimeimprovingitssafety.Therefore,theaimistoincreasethetherapeuticindexofadrug.6SuperioritiesofTDDSTraditionaldrugdeliverysystems:Medicationisdistributedthroughoutthebodythroughthesystemicbloodcirculation;Asmallportionofthemedicationreachestheorgantobeaffected.SuperioritiesofTDDSTargeteddrugdelivery:Concentratethemedicationinthetissuesofinterest;ReducingtherelativeconcentrationofthemedicationintheremainingtissuesSIDEEFFECTSEFFICACYTargetposition:anorganortissueaparticularcelltypeaspecificintracellularcompartment.特定細(xì)胞器內(nèi)ClassificationofTDDS

分類Passivetargeteddrugdelivery被動靶向Activetargeteddrugdelivery主動靶向Physicochemicaltargeteddrugdelivery物理化學(xué)靶向ClassificationofTDDS體內(nèi)靶向性評價(1)Relativeuptakerate

相對攝取率

Re=(AUCi)p/(AUCi)s

(2)Peakconcentrationratio

峰濃度比

Ce=(Cmax)p/(Cmax)s(3)Targetingefficiency

靶向效率

Te=(AUC)target/(AUC)non-target

傳統(tǒng)的隔室藥動學(xué)模型不適于評價靶向制劑MolecularPharmaceutics從分子水平和細(xì)胞水平研究劑型因素對藥物療效的影響的科學(xué)。藥物分子與DDS的體內(nèi)外轉(zhuǎn)運與代謝藥物分子與載體的相互作用靶向給藥的分子機制分子水平的藥代動力學(xué)研究12Particulatedrugcarriers微粒類載體Liposome脂質(zhì)體Nanoparticles/macroparticles納米粒/微球Micelles膠束Emulsion乳劑Dendrimers樹突狀物L(fēng)IPOSOMES脂質(zhì)體WhatareLiposomesAdvantagesofLiposomesClassesofLiposomesPreparationofLiposomesLiposomesarephospholipidbasedvesiclescomprisingofaqueousandlipidcompartments.

脂質(zhì)體是利用磷脂雙分子層膜所形成的囊泡。

Basedonthesolubility,adrugcanbeencapsulatedeitherintheaqueouscompartmentorinthelipidbilayer.藥物分子可被包裹在水相或脂質(zhì)雙層中。HydrophilicHydrophobic

Phospholipidsareamphiphathicinnature,containingahydro-phobictailandhydrophilichead.磷脂為兩性物質(zhì)，膽固醇亦屬兩親物質(zhì)，有疏水親水兩種基團.TypesoftheLiposomesImmunoCationicLongCirculating

Conventional

TargetedDoxil?-FDA批準(zhǔn)的第一個納米藥物通用名：DoxorubicinLiposomal；阿霉素脂質(zhì)體商品名：Doxil（多喜）,Caelyx(楷萊)公司：SequusPharmaceuticals應(yīng)用：最初用于治療卡波氏肉瘤，后被批準(zhǔn)用于卵巢癌治療

AmphotericinBLiposome1）Targetingability

靶向性和淋巴定向性

2）Extendedcirculationtime長效性

3）Goodbioacceptabilityandbiocompatibility

細(xì)胞親和性與組織相容性

4）Reducethetoxicityofcrudedrug降低藥物毒性5）Increasethestabilityofdrug提高藥物穩(wěn)定性

物理和化學(xué)穩(wěn)定性較差（磷脂分子的氧化)脂質(zhì)體的劑型特點磷脂+膽固醇a、磷脂類卵磷脂、腦磷脂、大豆磷脂和人工合成磷脂

中性磷脂、負(fù)電荷磷脂、正電荷磷脂、長循環(huán)磷脂b、膽固醇脂質(zhì)體“流動性緩沖劑”(fluiditybuffer)

調(diào)節(jié)膜流動性

制備脂質(zhì)體的材料Materials:Phospholipids+cholesterolPreparationofliposomeNeutral:PC,DPPC,DMPC,DOPENegatively-charged:PA,OG,DCPPositively-charged:SA,DDABCholesterol:fluiditybufferPhospholipidsCommoncomponentsoftheliposomesCholesterolCholesterolactsasa“fluiditybuffer”.膽固醇擦入磷脂雙分子層中，改變磷脂中疏水鏈的流動性。Thisaddsrigidity剛性

tothelipidbilayers.

PreparationmethodFilmdispersionmethod薄膜法High-pressurehomogenizermethod高壓乳勻法Reversephaseevaporationvesiclemethod

逆向蒸發(fā)法Injectionmethod注入法Freeze-thawingmethod凍融法FilmdispersionmethodPhospholipidsandcholesterolweredissolvedinorganicsolventsRemoveorganicsolventsbyrotaryevaporation，toformuniformfilmAddwaterandkeepstirringInjectionmethodDissolvephospholipidsandcholesterolinorganicsolventsInjectthesolventintophosphatebuffer（50-60℃）keepstirringuntiltheorganicsolventisremoved1、Morphology,particlesizeanddistribution

形態(tài)、粒徑及其分布2、Entrapmentefficiencyandloadingcapacity

載藥量和包封率包封率=〔脂質(zhì)體中的藥量/（介質(zhì)中的藥量+脂質(zhì)體中的藥量）〕×100%3、Leakagerate滲漏率滲漏率=（儲存一定時間后滲漏到介質(zhì)中的藥量/儲存前包封的藥量）×100%4．Distributioninvivo

藥物體內(nèi)分布

脂質(zhì)體制劑的質(zhì)量評價Nanoparticles納米粒Colloidalparticlesranginginsizebetween1and1000nmareknownasnanoparticles由天然或合成的高分子載體材料制成的、粒度在納米數(shù)量級（1-1000nm）的固態(tài)膠體微粒

Nanocapsule納米囊屬藥庫膜殼型，由聚合材料外殼和液狀核構(gòu)成，藥物主要溶解在液狀核中，這種納米囊主要適于包裹脂溶性藥物。

Nanosphere納米球?qū)倩|(zhì)骨架型，屬于實心的球或微粒，藥物吸附在其表面或包裹、溶解在其內(nèi)部。AdvantagesofNPdeliveryPhysicalstability物理穩(wěn)定性好Belongstocolloidsystem屬膠體系統(tǒng)，較混懸型微球制劑容易給藥Extendedtherapeutictime長效UptakebyRES被動到達(dá)肝臟、脾臟和骨髓Ligand-modifiednanoparticle可主動靶向分布于其他器官Enhancedpermeability改變藥物對生物膜的透過性，有利于藥物的胞內(nèi)靶向傳輸白蛋白納米粒Hydrophobicdrugs,e.g.,Paclitaxel,docetaxel,rapamycinetc.AlbuminMeansize=50-150nmcryo-TEMConcentrationdependentdissociationintoindividualdrug-boundalbuminmoleculesActivedruginnanoparticleisinnon-crystalline,amorphous,readily

bioavailablestateTaxolAbraxane(nab-paclitaxel)isasolvent-free‘nano’versionofTaxol(cremophor-basedpaclitaxel)Contents:Paclitaxel6mg/mlCremophor537mg/mlEthanol396mg/mlContents:100mgpaclitaxel900mgalbuminNoSurfactants/SolventsAbraxanereceivedFDAApprovalJanuary,2005formetastaticbreastcancerAbraxaneNanomaterials納米粒的載體材料Biodegradable生物可降解Biocompatible生物相容性Lowtoxicity

天然高分子材料半合成高分子材料合成高分子材料殼聚糖Chitoson一種天然的聚陽離子多糖具有優(yōu)良的生物相容性和生物降解性已經(jīng)廣泛的應(yīng)用于醫(yī)療領(lǐng)域甲殼類動物甲殼素殼聚糖34聚乳酸聚乳酸-乙醇酸PLAPLGA乳酸丙交酯乙醇酸乙交酯36Polymerizationmethod

聚合法

Dispersionmethod

分散法

NPpreparation：物理分散法/化學(xué)反應(yīng)法micellepolymerizationemulsionpolymerizationinterfacialpolymerization

emulsiondispersionsalting-outdispersionsolventevaporationSonicationPreparationofNanoparticlesEvaporation乳化-溶劑蒸發(fā)法38Result39AppearanceofINS-PLC-NPsbeforeandafterlyophilization凍干前凍干品凍干后CharacterizationofINS-PLC-NPsbeforeandafterlyophilization40Therapeuticeffectindiabeticratsafters.c.injection(n=5)3Days41界面縮聚法Interfacialpolymerization如氰基丙烯酸酯的單體在OH-離子的作用下，發(fā)生聚合反應(yīng)，可生成聚氰基丙烯酸酯納米粒。

米托蒽醌聚氰基丙烯酸正丁酯毫微粒nanoparticledrugmoleculeNPloadedwithdrugMitoxantronepolybutylcyanoacrylatenanoparticles圖米托蒽醌毫微粒的掃描電鏡照片TumorinhibitioneffectsOverallsurvivalofHCCpatientstreatedwithDHAD-PBCA-NPorDHADinjection

治療108例原發(fā)性肝癌效果（華西醫(yī)院、四川省腫瘤醫(yī)院、重慶市腫瘤醫(yī)院、廣西醫(yī)科大學(xué)腫瘤醫(yī)院）InvivodistributionofNPNanoparticleswillusuallybetakenupbytheliver,spleenandotherpartsoftheRESdependingontheirsurfacecharacteristicsNanoparticleswithmorehydrophobicsurfaceswillpreferentiallybetakenupbytheliver,followedbythespleenandlungsParticleswithlongercirculationtimes,andhencegreaterabilitytotargettothesiteofinterest,shouldbe100nmorlessindiameterandhaveahydrophilicsurfaceinordertoreduceclearancebymacrophages.Microemulsion微乳Microemulsionsareclear,stable,isotropicliquidmixturesofoil,waterandsurfactant,frequentlyincombinationwithaco-surfactant.由適當(dāng)比例的表面活性劑，助表面活性劑，水和油自發(fā)形成的各向同性、外觀透明或半透明、熱力學(xué)穩(wěn)定的分散體系Incontrasttoordinaryemulsions,microemulsionsformuponsimplemixingofthecomponentsanddonotrequirethehighshearconditionsgenerallyusedintheformationofordinaryemulsions.Thetwobasictypesofmicroemulsionsaredirect(oildispersedinwater,o/w)andreversed(waterdispersedinoil,w/o).DifferencebetweenMicroemulsionsandemulsions50Advantagesofmicroemulsionbaseddrugdeliveryspontaneousformation自發(fā)形成，不需外界提供能量easeofmanufacturingandscale-upthermodynamicstability熱力學(xué)穩(wěn)定，長期放置或離心不分層improveddrugsolubilizationandbioavailability提高難溶性藥物的溶解度，促進(jìn)藥物吸收，提高其生物利用度OilFormulatingMicroemulsionsCo-surfactantWaterO/WmicroemulsionW/Omicroemulsion52MethodofmicroemulsionpreparationMicrofluidization加水滴定法加油滴定法加乳化劑滴定法交替加入法微乳的形成不需要外界做功，是體系內(nèi)各組分達(dá)到適當(dāng)?shù)呐浔葧r自發(fā)形成的。LiposomePolymericnanoparticles/macroparticlesBlockcopolymermicellesEmulsionDendrimersClassesofparticulatedrugcarriersPassivetargeteddrugdelivery被動靶向Activetargeteddrugdelivery主動靶向Physicochemicaltargeteddrugdelivery物理化學(xué)靶向ClassificationofTDDSPassivetargeteddrugdelivery

Passivetargetingreliesonthenaturaldistributionpatternofthedrugordrug-carriersystemParticlesize,Surfacecharacters粒徑大小表面特征Lessthan7μm:removedfromthebloodbymacrophages

巨噬細(xì)胞oftheRES

網(wǎng)狀內(nèi)皮系統(tǒng)whenadministeredsystemicallyLargerthan7μm:targetdrugtolungNanoparticleslessthan50nm:accumulateinbonemarrow

骨髓slowly廣泛應(yīng)用于腫瘤靶向治療中的一種靶向機制：EPReffect(enhancedpermeabilityandretention)增強的血管通透性和存留量

increasedpermeabilityofendothelialbarriersintumorbloodvessels;thelackofeffectivelymphaticdrainagefromthetumor.血管壁間隙較寬，結(jié)構(gòu)完整性較差，淋巴回流缺失實體瘤組織血管豐富EPR效應(yīng)（大分子物質(zhì)和微粒在腫瘤組織具有的高通透性和滯留效應(yīng)）Smoothmusclelayer內(nèi)皮間隙致密、結(jié)構(gòu)完整

被動靶向Passivetargeteddrugdelivery被動靶向Activetargeteddrugdelivery主動靶向Physicochemicaltargeteddrugdelivery物理化學(xué)靶向ClassificationofTDDSActivetargeteddrugdelivery

Activetargetingemploysadeliberatelymodifieddrugordrugcarriermoleculecapableofrecognizingandinteractingwithaspecificcelltissueororganinthebody經(jīng)特殊分子修飾的藥物或藥物載體，可將藥物定向地運送到靶區(qū)濃集發(fā)揮藥效。Modificationofthecarriersystemmayincludeincorporationofantigen-specificantibodies抗體,orattachmentofcellreceptor-specificligands配體ActiveparticulateDrugCarriersMechanismforactivetargetdeliveryofdrug-loadedparticulatesOnbindingtothereceptors,theligand–particlecomplexcouldbeinternalizedintothecell.Majortargetingligandsfordrugdelivery根據(jù)肝細(xì)胞表面過量表達(dá)去唾液酸糖蛋白受體，能夠特異性地結(jié)合半乳糖殘基，對膽固醇分子進(jìn)行半乳糖修飾。半乳糖修飾的膽固醇脂質(zhì)體不同半乳糖密度的膽固醇衍生物不同鏈長的膽固醇衍生物XunSun,etal.JofDrugTargeting.2005,13:121-128.JofDrugTargeting.2010,18:520-535

A549cellsHepG2cells配體分子結(jié)構(gòu)對Gal-LPD轉(zhuǎn)染率的影響TargetingMoietyAntigenbindingfragments66ProdrugDefinition:Apharmacologicallyinactivechemicalentitythatwhenmetabolizedorchemicallytransformedbyamammaliansystemisconvertedintoapharmacologicallyactivesubstance.母體藥物經(jīng)化學(xué)衍生而成的物質(zhì)，在體內(nèi)經(jīng)酶或化學(xué)反應(yīng)再生成母體藥物，發(fā)揮治療作用Improvepatientacceptability(decreasepainoninjection)AlterandimproveabsorptionAlterbiodistributionAltermetabolismAltereliminationWhyuseprodrugs?Metabolism(enzymedependant)ChemicalMethods(non-dependant):Hydrolysis水解

Decarboxylation脫羧

NOTpatientdependant!Stability/StorageissuesConversionofProdrugsPrincipalsforthedesignofprodrugProdrugshouldbe:InactiveandnontoxicEasilysynthesizableChemicallystableoutsidesiteofactionBioreversible(parentdrugmustberegeneratedinvivo)TargetmechanismofprodrugErythromycin紅霉素

isaverybittersubstanceeasilydestroyedatacidicpHPropionateesteristoincreaselipidsolubilityforimprovedabsorption

Estermustbehydrolyzedforantibacterialactivity

Laurylsulfatesalt十二烷基硫酸鹽–absorptionnotaffectedbyfood,lessbitteraftertasteandisacidstableFunctionalGroupsinProdrugsAzoProdrugs偶氮前體藥物Bacterialreductases

reductivecleavageOccursincolon

discouragessmallintestinesystemicabsorptionConcentratesthedrugatthedesiredsiteofaction柳氮磺胺吡啶

73KeyLabofDrugTargetinganddrugdeliverysystems,SichuanUniversity靶向藥物及釋藥系統(tǒng)教育部重點實驗室四川大學(xué)華西藥學(xué)院14-Succinatelysozymeconjugatefortherenaldeliveryoftriptolide(雷公藤）Renaldiseaseandsystemicdiseasecausedbyrenaldiseasearefrequentlyoccurredanddifficulttotreatallovertheworld.It’sreportedthattheincidenceofkidneydiseasewasupto9.6%inChina,andmorethan90%ofpatientsknowverylittleabouttheirdisease.TheincidenceofEndStageRenalDisease(ESRD)inChina:1/10000in19943/10000in2002

RenalDiseaseTriptolide:ApotentC3suppressantandimmunosuppresantwithseveretoxicity雷公藤TripterygiumTilfordiiHookF.TripterygiumTilfordiiHookF.衛(wèi)茅科療效明確制劑以多甙片為主副作用大主要有效成分：

雷公藤內(nèi)酯醇溶菌酶作為腎靶向的藥物載體Thecharacteristicsoflysozymeascarrierforrenaldrugtargeting

SelectivedispositioninkidneyBiodegradableContainingreactivefunctionalgroupsNone-antigenicAdministratedFITC+TPbyi.v.AdministratedTPS-LZMlabeledFITCbyi.v.TPTPS-LZM雷公藤內(nèi)酯醇和前體藥物給藥半小時后的體內(nèi)分布Mechanismforrenaltargeting-megalinmediatedsitespecificdeliveryPassivetargeteddrugdelivery被動靶向Activetargeteddrugdelivery主動靶向Physicochemicaltargeteddrugdelivery物理化學(xué)靶向ClassificationofTDDSPhysicochemicaltargetedpreparationsPhysicochemicaltargetingreferstodeliverysystemsthatreleaseadrugonlywhe