Antitumor effects of retargeted AAV2 virus on ovarian cancer in vivo

Abstract

Adeno-associatedvirus(AAV)isapromisingvectorforsystemicdeliveryofsiRNAduetoitslong-termexpressionabilitywithoutimmunogenicityandpathogenicity.However,itsbroadhosttropismandlackoftissuespecificityhaslimitedclinicalapplicationssuchascancertherapy.Therefore,redirectingthenaturaltropismofAAVvectorstouniquecellsurfaceantigensisanimportantrequirementforinvivoRNAi-basedcancertherapy.Toexploittheoverexpressionpropertyofepithelialcelladhesionmolecule(EpCAM)inspecificcancertypes,weherecreatedanti-EpCAManitibody-conjugatedAAVserotype2(AAV2)vectorsthroughastreptavidin-biotinbridge.Uponintravenousinjection,anti-EpCAM-conjugatedAAV2vectorsshowedprominenttumor-specificaccumulationinEpCAM-positivetumor-bearingmicewithoutundesirablesequestrationinliver.Inaddition,whenloadedwithtransgenestoexpressshRNAagainstepidermalgrowthfactorreceptor(EGFR),systemicallyinjectedanti-EpCAM-conjugatedAAV2/shEGFRvectorsinducedsignificantdownregulationofEGFRexpressionintumors,andeventuallysuppressedtumorgrowthevenatthelongdosingintervaloftwoweeks.Thisinvivoantitumoreffectrepresentstheincreasedinfectionefficacyoftropism-modifiedAAV2vectorsandprolongedexpressionofEGFRshRNAintumortissues.Thus,thisstudysuggeststhegreatpotentialofanti-EpCAM-conjugatedAAV2/shEGFRvectorsasRNAi-basedcancertherapeutics.