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Page 1: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

ADfortargetedsiRNAdelivery•  JAmChemSoc.ArticleASAPDOI:

10.1021/jacs.8b10021PublicationDate(Web):October22,2018

•  FurtherimprovementofAD-mediatedsiRNAdelivery–  Activetargetingabilityforspecificcancer

celldeliverywithinthelesion•  DualtargetingwarheadRGDKpeptide

–  Targetstumorendotheliumbybindingtoανβ3integrin

–  Bindstheneuropilin-1(Nrp-1)receptorpromotingcancercellpenetrationanduptake

•  ThenewAD/RGDKsystemis10xmorepotentthantheADprecursor

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Page 2: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKdesignandoptimization

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Page 3: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKdesignandoptimization

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Page 4: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKformation

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NMsdiameter30-40nmΔG=-6.8kcal/molΔH=-5.0±0.2kcal/mol–TΔS=-1.9kcal/mol

Zetapotential+15mV(comparedto+25mVforsiRNA/AD)

Page 5: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDK:stabilityandprotection

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BindingofRGDKdoesnotalter

siRNA

Protectionfromdegradation

Page 6: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKuptakeismediatedbyintegrinandneuropilin-1

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SuperioruptakewithrespecttoAD

cRGDcompetesforintegrinbinding

BlockingNrp-1withMabdrasticallydecreasessiRNA/AD/RGDKuptake

Page 7: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKquicklyandeffectivelyescapesendosomes

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Endosomalescapealreadyinplay

Endosomalescapealmostfinished

Lyso-tracker

Page 8: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKissuperiortoADingenesilencinginvitro

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Page 9: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKisnotcytotoxicincancerandhealthycells

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Page 10: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKhasnohemolyticactivity

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siRNA/AD/RGDKissubstantiallylesshaemolyticthansiRNA/AD

Page 11: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKishighlyeffectiveinvivo

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Page 12: AD for targeted siRNA delivery - Nano2Clinic · AD for targeted siRNA delivery • J Am Chem Soc. Article ASAP DOI: 10.1021/jacs.8b10021 Publication Date (Web): October 22, 2018 •

siRNA/AD/RGDKisnotcytotoxicinvivo

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