AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc....

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AD for targeted siRNA delivery J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 Further improvement of AD-mediated siRNA delivery Active targeting ability for specific cancer cell delivery within the lesion Dual targeting warhead RGDK peptide Targets tumor endothelium by binding to α ν β 3 integrin Binds the neuropilin-1 (Nrp-1) receptor promoting cancer cell penetration and uptake The new AD/RGDK system is 10x more potent than the AD precursor 10/04/19 1st CA17140 TS, University of Trieste, April 8-11 2019 1

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Transcript of AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc....

  • 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

  • siRNA/AD/RGDKdesignandoptimization

    10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 2

  • siRNA/AD/RGDKdesignandoptimization

    10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 3

  • 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)

  • siRNA/AD/RGDK:stabilityandprotection

    10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 5

    BindingofRGDKdoesnotalter

    siRNA

    Protectionfromdegradation

  • siRNA/AD/RGDKuptakeismediatedbyintegrinandneuropilin-1

    10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 6

    SuperioruptakewithrespecttoAD

    cRGDcompetesforintegrinbinding

    BlockingNrp-1withMabdrasticallydecreasessiRNA/AD/RGDKuptake

  • siRNA/AD/RGDKquicklyandeffectivelyescapesendosomes

    10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 7

    Endosomalescapealreadyinplay

    Endosomalescapealmostfinished

    Lyso-tracker

  • siRNA/AD/RGDKissuperiortoADingenesilencinginvitro

    10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 8

  • siRNA/AD/RGDKisnotcytotoxicincancerandhealthycells

    10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 9

  • siRNA/AD/RGDKhasnohemolyticactivity

    10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 10

    siRNA/AD/RGDKissubstantiallylesshaemolyticthansiRNA/AD

  • siRNA/AD/RGDKishighlyeffectiveinvivo

    10/04/19 1stCA17140TS,UniversityofTrieste,April8-112019 11

  • siRNA/AD/RGDKisnotcytotoxicinvivo

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