AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc....
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ADfortargetedsiRNAdelivery• JAmChemSoc.ArticleASAPDOI:
10.1021/jacs.8b10021PublicationDate(Web):October22,2018
• FurtherimprovementofAD-mediatedsiRNAdelivery– Activetargetingabilityforspecificcancer
celldeliverywithinthelesion• DualtargetingwarheadRGDKpeptide
– Targetstumorendotheliumbybindingtoανβ3integrin
– Bindstheneuropilin-1(Nrp-1)receptorpromotingcancercellpenetrationanduptake
• ThenewAD/RGDKsystemis10xmorepotentthantheADprecursor
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 1
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siRNA/AD/RGDKdesignandoptimization
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 2
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siRNA/AD/RGDKdesignandoptimization
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 3
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siRNA/AD/RGDKformation
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 4
NMsdiameter30-40nmΔG=-6.8kcal/molΔH=-5.0±0.2kcal/mol–TΔS=-1.9kcal/mol
Zetapotential+15mV(comparedto+25mVforsiRNA/AD)
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siRNA/AD/RGDK:stabilityandprotection
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 5
BindingofRGDKdoesnotalter
siRNA
Protectionfromdegradation
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siRNA/AD/RGDKuptakeismediatedbyintegrinandneuropilin-1
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 6
SuperioruptakewithrespecttoAD
cRGDcompetesforintegrinbinding
BlockingNrp-1withMabdrasticallydecreasessiRNA/AD/RGDKuptake
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siRNA/AD/RGDKquicklyandeffectivelyescapesendosomes
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 7
Endosomalescapealreadyinplay
Endosomalescapealmostfinished
Lyso-tracker
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siRNA/AD/RGDKissuperiortoADingenesilencinginvitro
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 8
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siRNA/AD/RGDKisnotcytotoxicincancerandhealthycells
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 9
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siRNA/AD/RGDKhasnohemolyticactivity
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 10
siRNA/AD/RGDKissubstantiallylesshaemolyticthansiRNA/AD
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siRNA/AD/RGDKishighlyeffectiveinvivo
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 11
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siRNA/AD/RGDKisnotcytotoxicinvivo
10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 12
