Studiesonthedevelopmentofhybridnanoparticlefortheinhibitionofprostatecancer-derivedexosomerelease

Abstract

Alltypesofcellssecreteexosomes,whichcarryvariousbioactivemoleculessuchasnucleicacid,proteinsandmetabolites.Exosomesplaykeyrolesincell-cellcommunicationbytransferringthecargotoothercells.Especially,cancercell-derivedexosomescontributetotumorprogressionbyinducingpolarizationofmacrophagestowardananti-inflammatoryM2phenotype.Accordingly,itisimportanttoreducecancer-derivedexosomethatcanmaketumorgrowth.GW4869isthemostcommonlyusedpharmacologicalagentforblockingexosomegeneration.GW4869isloadedinthecoreoflipid-polymerhybridnanoparticleduetoshieldanddeliverthehydrophobicdrug.Prostatecancerisoneofthemostcommoncancersamongmales.Prostate-SpecificMembraneAntigen(PSMA)ishighlyexpressedonthesurfaceofprostatecancercells.Inthisstudy,anti-PSMAscFvantibodywasnon-covalentlyconjugatedwithhybridnanoparticleviaavidin-biotinaffinity.Anti-PSMAscFvmodifiedhybridnanoparticlescantargetactivelytoprostatecancercells(PSMA+)andtargetpassivelytotumorassociatedmacrophageinthetumormicroenvironment.Itwasdemonstratedthathybridnanoparticlestargetedprostatecancercellatinvitrolevelandblockedcancer-derivedexosomereleasesuccessfullyfortreatmentforprostatecancer.Collectively,lipid-polymerhybridnanoparticleisloadedwithGW4869,anexosomesecretioninhibitor,andmodifiednon-covalentlywithananti-PSMAscFvforprostatecancercell-targeteddelivery.|모든세포는핵산,단백질,대사산물과같은다양한생체활성분자를가지는엑소좀을분비한다.엑소좀은가지고있는내용물을다른세포로전달함으로써세포-세포상호작용에서중요한역할을한다.특히암세포에서유래한엑소좀은대식세포의분화를항염증M2형으로유도해종양진행에기여한다.따라서종양성장을촉진하는암세포유래엑소좀을줄이는것이중요하다.GW4869는엑소좀생성을억제하는데가장많이사용되는약제이다.소수성약물인GW4869는지질-폴리머하이브리드나노입자의코어에함입되어안전하게운반될수있다.전립선암은남성에게가장흔하게발생하는암중하나로전립선세포특이막항원(PSMA)은전립선암세포의표면에많이발현된다.본연구에서anti-PSMAscFv항체를아비딘과바이오틴의상호작용을통해하이브리드나노입자와비공유결합시켰다.anti-PSMAscFv를붙인하이브리드나노입자는전립선암세포(PSMA+)를직접적으로표적할수있고종양미세환경에서간접적으로종양관련대식세포를표적하여엑소좀방출을억제할수있다.시험관내수준에서하이브리드나노입자가전립선암세포유래엑소좀을성공적으로억제하고전립선암치료에효과가있음을입증하였다.결과적으로지질-폴리머하이브리드나노입자에엑소좀분비억제제인GW4869를함입하고anti-PSMAscFv를결합함으로써전립선암세포유래엑소좀의방출을억제하고종양성장을억제하였다.