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D ow nloaded from https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C TargetedDrugDelivery ochrane Germ any , W iley O nline L ibrary on [23/11/2022]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense D ow MethodsandPrinciplesinMedicinalChemistry nloaded from EREGdd..MFiittooeadlrkniabenrylhsB,ooHlda.,rTdHim.Bmusecrhmmaannnn,H,J..vHaonlednezWaterbeemd,J.BondoHansen https://onlinelibrary.wiley.com AFPllrzoeavw,iEoa.u(snEVddo.)MluimcreosorefathcetoSerrTieeschnology BInanchohvaavt,iYv.e(EdD.)osageFormsDesign /doi/ by ibrahim ragab - C inMedicinalChemistry andDevelopmentatEarlyStage ochrane G 2019 erm 2IS0B2N2:978-3-527-34689-9 ISBN:978-3-527-34396-6 any , W Vol.81 Vol.76 iley O R(NaGSP2IVES0oünrorBed2ulob.dN2lsws8isc.s:)d0aEe,9mD7MsmS8esr.t-uen3ia(n-E-rg5tSdgg2ec.D7i)ho-nD3eafg4eev3Pfve3Vf7h,eli-oH9alroup.r,pmsmaemnaesdcenBentuutfstocaihcrnmaKdlannonw,Hn. GBSSE2IV2ISS00ioeptiBBp11lorr.NN88ipvug7ml::a5c,e99sWto77inuo88l.e--,,er33FJtec--u55i.-ucn22Lb77gl.Da--,a,33SrMsr44pu23eS.61idgw(i54Em--o50dDDksuir,.s)luVac.got(EivDodensisr.)sycoinvery nline Library on [23/11/2022]. See the Terms and Conditions (https://onlinelibrary.w MSaoltlse,Ccouclreysstals,andPolymorphism GVoiol.r7d4anetto,F.(Ed.) iley.com/term PT2IVS0olaBo2lr.N1wg7:9re9ig7t8hD-t3,-i5As2.cT7o.-3(v4Ee6d3r.5)y-6andValidation E2IVS0oaB1l.rN87l:y397D8-r3u-5g27D-3e41v4e9-l8opment s-and-conditions) on Wiley Online L MD20i2es0tchoovdersyandStrategiesforDrug HD20ar1nu7dgleSr,eNle.,cBtuisvcihtymann,H.(Eds.) ibrary for rules of use; O A SNDIVSwoBiels.iNgnc7:8lno9ee7vcy8e,t-3Dre-y.5d,2aP7To-n3rld4ola5p2sD9tirc-e8ia,vMleD.lo(iEpsdemsa.)esenst Drug IVSoBl.N7:2978-3-527-33538-1 articles are governed by the applicable C 2IS0B1N9:978-3-527-34304-1 reative Com m Vol.77 ons L icense D ow nloaded from https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C Targeted Drug Delivery ochrane G erm any , W iley O EYSodegirtieeesdshbEwydairtoBraschhav nline Library on [23/11/2022]. See the T Raimund Mannhold erm Helmut Buschmann s and C Jörg Holenz onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense D ow nloaded from https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C EDdr.itYoorgeshwarBachhav ppArulolbdbliuoscohekedsr.pdNuoebnvloeisrthtwheedalrebrsaysn,WtaItuLhtEehYoi-nVrsfCo,Hremdairateotircosan,raenfudlly ochrane Germany , W B401,No126 containedinthesebooks,includingthisbook, iley O FTliolarkenNcaiogar tinobmeinfrdeethoaftesrtraotresm.Reneatsd,edrastaar,eilaludsvtirsaetdiotnosk,eep nline L 4ISPRn0eroodr0sifi0.eea8nDs9wrE.dMeRigatuoi7mmrsubnadiMannhold piLBAnirrbaioctrdaciasevtrhadeylrLuootirgefbaunCrlaetodlrnyyregetbCcraeeaoiltsrisasndloCaofrcagocrourdutitnhrhNgaeiot-srei.:nib.ta-oePpomupkbsliliemiscdaaatvfyioaorinlaDbaleta ibrary on [23/11/2022]. See the Term 4GDS5GDB02prrIee..A40errHJ87rmmöLbe96rlgeaa–mDArnnHwPuaüyyotOceslBhsegRenue1Tlsznd5cEhoLmrfAan&nCA.,S.A. dfBDTpNdrunaiheoabtubbemtlaiitl.ooDdisactcng-rheahnreautaeebliaptboB.Nsvdhincbraaiehicliti>tilnieiioaosn.bNgnthfhrloaaeaLelrtbfimioiDbioenbarn;eltatiudaiohroletytbnesth.ciaIepbhinkulleeitboedltrihsnbheiebektldailoitbsgy<trsathhtpthethpisi:c// s and Conditions (https://onlinelibrary.wiley.com SãoMamedeCoronado ©2023WILEY-VCHGmbH,Boschstraße12, /term PC©oovSretcuriWgImahlaaglee:Design/Shutterstock 6Attrh9ali4lns6rsbi9lgoahWotitkosenimrneihasneyetriobmveoe,dtrhGe(epeinrrromclaldunaundgciyuenadggietnhs)oa.snNeyoofofpramrt–ofby s-and-conditions) on W photoprinting,microfilm,oranyother iley O mmftncrroooaeantdmacssehnipmdtisehne–acereirenfipkldaocusna,rubglentllurtiypscaahr.mngouesetarsmesrewc.kidttiReettidehdendgoabtiusohsyttrsielswutarrbcwerahodi.nt,otnseaklanra,emtepevnedeeosrni,mtntwtiooshsbaieeonn nline Library for rules of use; O A PeeoCTyPPoBripvuDoneebotFsrkIIeISDSStIBBSteBiNBNsnNiN:g:g:99:n9779:78S87S8-t-8C-3r33-aH--3-55i5-vU2252e7727L,--7-Z3C88-4282hG7727e8r878na1786nfi--5-09a2k-i5-,DInesdiigan articles are governed by the applicable C reative C om m ons L icense D ow nloaded from v https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C Contents ochrane Germ any , W iley O APersonalForeword xiii nline L 1 KPBrsaehsfaiacmsceaofAT.xaDvrogsehtiedDrugDelivery 1 ibrary on [23/11/2022]. See the T 1.1 Introduction 1 erm 1.1.1 ConceptofBioavailabilityandTherapeuticIndex 2 s and C 11111.....33323...111..12 PRETStaanersrtahgsitcaieevuntgeelciodeTeesdaDnrfPdorgueorergttDmhinDreeguleaiglabilvTi4lSeairytryysgteaetnmi2ndg(RReEt3eSn)tSiyosnte(mEPR4)Effect 4 onditions (https://onlinelibrary.w 11..33..12.3 LAocctiavleizTeadrDgeetliinvgery5 4 iley.com/term 1111....4333...333..12 TUMPhhlatyergsraniascepoateuilucnTtFdaicrifegoAledrptiTfpnoalgrircgTaeat5tiriongnegstionf6gTa6rgetedDrugDelivery 6 s-and-conditions) on W 1.4.1 DiabetesManagement 6 iley O 1.4.2 NeurologicalDiseases 7 nline L 1111....5444...345 CRCTaeaarsrngpdceiierotreavdtIaonsDrdcyuuicDglaa-itrDsieoDeanlisissveeesars9ye9Psro8ducts 10 ibrary for rules of use; O A 111111......689676..12 PCACRSCcaeuohcasftnraeslirelvcirelv-leeenuuennTtspTcgiaSeoaeartsnsrngagetdaeutn1itC1sni6d1nhggPa1lra4lo1ensn2dpgeEecsPtsR1E31ff5ect 12 articles are governed by the applicable C reative C om m ons L icense D ow nloaded from vi 2Contents ADdrudgre-DsseilnivgeUrynmSyestteMmesd:icEamlpNheaesdissoUnsiNnganToamrgeedteicdine-Based https://onlinelibrary.w AChpapnlidcraatkioanntssin2g1Pardeshi,RajuSonawane,andYogeshwarBachhav iley.com 22..12 ITnatrrgoedteudctDiornug-2D1eliverySystemsforUnmetMedicalNeeds 23 /doi/ by ibrahim 22..22..11.1 STmaragleltMingolLecigualnesdsasT2a5rgetingLigands 25 ragab - C 22..22..11..23 AApnttaibmoedrisesaassTTaargrgeteitninggLLigigaannddss 2278 ochrane Germ 2.2.1.4 LectinsasTargetingLigands 28 any , W 2.2.1.5 LactoferrinsasTargetingLigands 29 iley O 22222.....34222...222..12 RCLRTLDaioeeoissrcgfntgeeaucoaretllefitsauoineAtnsn-ocigBb-eorBbyasAnsraApeeasvdpens3ipdr9daToetTaFaciraotcugsrnhtegausetensirtneding3OC28gu9li2tnl93oi2coaklPe3r8spectives 35 nline Library on [23/11/2022]. See the T erm 333..21 PNNaPDnraaeaesdnlnssiohvoiMvceicteaaraaycrrTrrDraioieeerm4rsgrsa5seo-it(BlieNnacgasuenAldeopsmTpaerrod4gai5ecctihneedes)D–r5uO0gveDrevliievweraynSdysRtoelmesin:STmaraglletedDrug s and Conditions (https://onlinelibrary.w 3.2.1 EnhancedPermeabilityandRetention-Effect-BasedTargeting 50 iley.com 3.3 ActiveTargetingApproaches 52 /term 3333....4444...231 pESRtHneimdzSoyutmxilmiSeRtuiSmeltisimupRoleuinsRlpsieioRvsneepssoTipvnaoesrngiTvseaeitvreTgedaeTrNteagCdregtsNeedtCe5Nds4CNs5C6s5557 s-and-conditions) on W 3.4.4 TemperatureStimuliResponsiveTargetedNCs 58 iley O 3.4.5 UltrasoundStimuliResponsiveTargetedNCs 59 nline L 33..54.6 CMReoafngecnrleeuntsiciceoFsniealn6d0dSFtiumtuurleiRPerospspoencstisveT6a0rgetedNCs 59 ibrary for rules of use; O A 4444...123 ILILRALnmiajiipapptgpryooohoosssJadr.ooovtuKmmmaechnneeetoditssopCrCanaaoosdC8mneT0.s6maMi9rdeguerenrctdaieataidlrogLnDia,srNnuindgees-DDctiaekepavlieevTleaornp7yem2jSaey,nsJatteyamensdshkCuh6m9aarracJ.teHraizdaiati,oanndof articles are governed by the applicable C reative C om m ons L icense D ow nloaded from 44..33..21 DSerluegct:ioLnipoidfLRipatiidos 8810 Contents vii https://onlinelibrary.w 44..33..34 PLEigGanyldatAionncho8r2ing 83 iley.com 44..33..65 PDhruysgi-cLoocahdeimngicTaelcChhnairqaucetseriz8a4tion 85 /doi/ by ibrahim 44..33..78 MPraonduufcatcSttuarbinilgityPro8ce7ss 86 ragab - C 44..44.1 PTaasrgsievteedTaDregleitvienrgyof8L9iposomes 88 ochrane Germ 4.4.2 Active-TargetedDelivery 92 any , W 4.4.2.1 CancerCellTargeting 94 iley O 4444....7546.2.2 CRCSDFTyaueoaesccmnnltiteedcvoonmleirurdtsrssyaECIitnonleiflndsn11suo0i0ct8ea3ah1nnl0ecdT2liinrFuigumalttsuhTwreaeriCtgohlefitnPLiinricpogaoslpsToe9rcm8atnsessolfwaTtiitaohrngIeontfveLedsipLtioigpsaootismoonemasalfloL-rDipTeoalsirvogemertyeed nline Library on [23/11/2022]. See the T erm 5 LRAARGaainpesjufpteteitlsboraihceofmandAPtcySribeao–ibnsdnDrghserhavu1vnig1ia1,,2tM2CSi7oouennngsijhlunKgaa1.DtP1e0ausnb:deDeye,y,avSenilddodSphamacehnnitnhtDaHnuedbjmeyady,RajeevTaliyan, s and Conditions (https://onlinelibrary.w 5.1 Introduction 127 iley.com 5.2 DesignofADCs 128 /term 5555....3222...123 MALPainneytckliohbeaaordndiys1m31031o22f9Action 133 s-and-conditions) on W 5.4 PharmacokineticConsiderationsforADCs 134 iley O 5.4.1 HeterogeneityofADCs 134 nline L 5555....4444....2333..21 DBPAhibiosastarornmirbapaultycitotoiionkcnainle1Ct13oi36cn6PsiadrearmateitoenrssfoofrAADDCCss 113365 ibrary for rules of use; O A 5555555.......5554555......111311.....34312 AAIMGBAnrdppeeoemoppttna-urlTttibozuucrvouaxzaeltmuisiidmstomumaAnabzasbDuabOonmVCOfzdesaoAzdEbigoDonalgEtimCiatmmnhmsiiectniaiMcan1n1it3n3saio9i7rn1nke3e19t3(T71-31D63M71) 139 articles are governed by the applicable C reative C om m ons L icense D ow nloaded from viii 55Co..55n..t11en..56ts PEonlfaotrutzuummaabbVVeeddootitnin-p1i4iq0 140 https://onlinelibrary.w 55..55..21.7 TUrsaestoufzAuDmCasbiDneRruhxetuemcaantoid14A0rthritis 141 iley.com 55..55..34 UUsseeooffAADDCCssiinnBOapchttehriaallmInolfoegctyion1s41141 /doi/ by ibrahim 55..76 RReegsiusltaatnocreyoAfsApDecCtsfo1r4A2DCs 143 ragab - C 55..77..12 RRoolleeooffOONBPDQA144143 ochrane Germ 5.8 ConclusionandFutureDirection 144 any , W References 145 iley O 6666...122.1 HIGGGPnreeDiatgnnrsEhoeehP-d-aTGDTunhirctrfeatoeSidrocr.aetnKpDeGyhdiffialMiE1rokc5nomau5zdrlyaatams-lnti(otedHy-–TAfGProteGruroalsCtdL)aCr.nuJacga1ned5Tcrh9ehTarervseraapt1my59e(GnDtEP1T5)5asaSuicide nline Library on [23/11/2022]. See the T erm 66667....2324..23 TNOCRTareootirhfnpvgeeeclererlletu-eECnNsdcnaieeonzPgsnycarsmeotirdv1esre6s1u56Bfgo15rs6rei2aGnsDtOCEraPalnTDcerur1g(6T4DNeBliCve)ry161169 s and Conditions (https://onlinelibrary.w MilicaMarkovic,ShimonBen-Shabat,andArikDahan iley.com 7.1 Introduction 169 /term 7777....2122...111.1 VCMPralooaladsdsceriyurccngvl,oAsTv.paiMrrpagorseodetae-eMcrdhneP-TPdraoiraordtgdreeurdtugiPngArgAopEdppnrpruzorgoyaamcAchechstiv1a171t71i70o1n 172 s-and-conditions) on W 77..22..11..32 APhnotisbpohdoyl,ipGaesneeA,a2-nMdeVdiirautes-dDPirreocdtreudgEAncztyivmaeti–oPnrod1r7u3g iley Online L 777...222...222..12 PTPMerhoopendtrioradupcegayTrAbraop1nxp7ysr5ploaoatrcetheTrTra1anrgspe1to7irn7tgerTTraynpsep1orte1r7s9 176 ibrary for rules of use; O A 77777.....45623.2.3 DFCRCBuieooilsftnmeceucurAprleesuucnsisPticdiaoreotnoTsniosrpanen11a1c88sl8tp24As3oparnptedrrosCaclihn1e8isc0ainlATpaprgliectaetdioPnrsodr1u8g3Design 181 articles are governed by the applicable C reative C om m ons L icense D ow nloaded from 8 ECxaordsioamceInsdfiocratDiorungsDe1l9iv3eryApplicationsinCancerand Contents ix https://onlinelibrary.w 8.1 EAnxjtaralicPeallnudlayra,VSerseiecrlaens:jiAninPOulvaekrkvaite,wand1V9a3ndanaPatravale iley.com 88..11..21 EEvxoolsuotmioensoafsEDxeolsivoemryesVeh1i9c4lesforTherapeutics 195 /doi/ by ibrahim 88..11..22..12 EEnxodgoegneonuosuLsoLaodaidnigngMMetehtohdosds 191898 ragab - C 88..22.1 EInxflousoemnceesoafsDCoannocrerCTehllserap2e0u2tics 199 ochrane Germ 8.2.2 DifferentTherapeuticCargoExploredinCancerTherapy 202 any , W 8.2.2.1 DeliveryofProteinsandPeptides 203 iley O 8888888.......3234532....1222..32 DDECCEDxxloeeeioonlllniiissvvcvioocleeeummarrrlsyyyeeiEoooosBvnfffMaaCRClsouNahe2dardeA1ditmfiiD1iooeornpdut2srh0gwoae4tDniretadhceptlFiieCvvuuaeettrriuRdycriNeCfaoAcaArrTssCgapoarerg2cde0ti2ts7oi0nv4ga2sP1c0euplatirdDesisea2s0e8s 206 nline Library on [23/11/2022]. See the T erm 9 ARASDCaoneecnmafkleignnvprhyeeolaarenwmyxPcleoaieFtstdfrotagNnrmmaPu2iac1euktl2n,liea,StitascwinoAadnrc2nsSi1daa2spn,a2gSr2rau1abcmhhaKaP.sSasaniRmy,NaAAl.Sa.nSdamnkReNt,ASu,UdispitnegeDas, s and Conditions (https://onlinelibrary.w 9.1 Introduction 221 iley.com 9.2 NA-BasedComplexDeliverySystem 228 /term 9999....2222....1111...132 PPLCoeilpaplyistdmsidi-cBeear-alB-sBNeaadsAseCe-dBdoCamNsoeApmdl-epCCxloeoNxmmANpplADleexexDlDiDevleeeilvlriiyvevreeSyrryyySstSySeysymtssettmeemm232023221299 s-and-conditions) on W 9.2.2 AdvancedNA-BasedComplexDeliverySystems 232 iley O 9.2.2.1 InorganicandHybridNPs 232 nline L 9999....2323...221..23 SAGEexpelonfp-solAoimcmsaseteeimEsondabnsiltediondfNgNNaAAn2o-N3CC5oaenmllospslter2xu3cD3tuelrievsery2S3y3stems 234 ibrary for rules of use; O A 9999....4335..23 FCPCARrueaocofnktnetunccerrelieoeunrnwsPTcTilreoehhosndeesgrpramae2pp2c4ey4yt0ni0vtes223378224309 articles are governed by the applicable C reative C om m ons L icense D ow nloaded from x 1Co0ntents PArpapslhicaanttioSn.KohfaPrkRaOrTaAnCdTAetcuhlnLo.lJoagdhyainv DrugDevelopment 247 https://onlinelibrary.w 1100..21 DInetsriogdnuocftiPoRnOT2A47CS:ABriefOverview 252 iley.com 1100..33.1 TChanercaepreu2ti5c5ApplicationsofPROTACs 254 /doi/ by ibrahim 1100..33..23 NImeumruondeogloegniecraaltDivieseDaisseosrde2r6s3 261 ragab - C 1100..34.4 VChiraallleInnfgeecstiaonndsLi2m6i4tationsintheDevelopmentPROTACs 265 ochrane Germ 10.5 FuturePerspectives 266 any , W References 266 iley O 11 MetalComplexesastheMeansortheEndofTargeted nline L 111111...122.1 CICTDnrehletalvarsioovpsdree1urrW:yocC.ntfHioheoarsanmpUthebnarl2moet7nyPe1etrsoNteece2t7dD2sru2g7s1 273 ibrary on [23/11/2022]. See the T 11.2.2 DeliverytotheCellsorEnvironmentstoBeTargeted 275 erm 11.2.3 ReleasefromtheMetalWhereandWhenRequired 276 s and C 1111111111.....34553..11 CCTHTaallyaarrpggssosseextt23eii::nadADgPcuSl2tatai8rvlta-1ieTnteMhugrmieeetasaAt:lgTMCeheonetmtasClphClee2oxm7me7ispcalel2xa7en6sdP2h7y9sicalEnvironment 280 onditions (https://onlinelibrary.w 1111..55..32 TpHhe-BEaPsRedETffaercgtetin2g83 282 iley.com 11111111....9786 COTTaaotrrhnggeceerlttuiiTnnsaiggrogSSnettstrriaanttee2ggg8Sii8eetrssa::tTEergnaizenyssmpoe2rA8te7crtsiva2ti8o4n 286 /terms-and-conditions) on W References 289 iley O 12 FormulationofPeptidesforTargetedDelivery 299 nline L 1122..12 IPPannaetpdnrtkoPitddiraueGjscaatUkniotasanterDdaa,i2nKn9daC9ereaknnarcSearisTwhaenria,pNyikit3a0N2air,AvinashGunjal,RatneshJain, ibrary for rules of use; O A 11111112222222.......2222322......356142 BLPLBPMeaeurreaepnunlaitckagnisrnedteCCmeoCaa-matTianinaacnaccrceCegerr3ear31tn0i2nc343e3g00r037B9a3se0d6onSiteofAction 315 articles are governed by the applicable Creative C om m ons L icense