Toxicity profile of RNAi nanomedicines

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1、ADR-12319;NoofPages8AdvancedDrugDeliveryReviewsxxx(2012)xxx–xxxContentslistsavailableatSciVerseScienceDirectAdvancedDrugDeliveryReviewsjournalhomepage:www.elsevier.com/locate/addrToxicityprofileofRNAinanomedicines☆ScottA.Barros⁎,JaredA.GollobAlnylamPharmaceuticals,300ThirdStreet,Cambridg

2、e,MA02142,USAarticleinfoabstractArticlehistory:TheemergingclassofRNAinterference(RNAi)therapeuticsisafundamentallynovelapproachtotreatingReceived19March2012humandiseasebyenablingthepursuitofmoleculartargetsconsidered“undruggable”bysmallmoleculesAccepted14June2012andtraditionalproteinthe

3、rapeutics.AkeychallengetowardrealizingthefullpotentialofthistechnologyAvailableonlinexxxxisthesafeandefficientdeliveryofsiRNAtotargettissues.ThephysicalchemicalpropertiesofsiRNAsprecludepassivediffusionacrossmostcellmembranes.Forsystemicadministration,noveldeliverysystemsarerequiredKeywo

4、rds:toconfer“drug-like”pharmacokineticandpharmacodynamicproperties.EngineerednanomaterialsandtheSmallinterferingRNANanotoxicologyemergingfieldofnanomedicineareimportantdriversofturningthepromiseofRNAitherapeuticsintoreality.SNALPThecurrentclinicalprogressofsystemicallyadministeredsiRNAth

5、erapeuticsisreviewed,withspecialattentionPreclinicaltoxicologytothetoxicityprofilesassociatedwithRNAinanomedicines.Asacasestudy,thepreclinicaldevelopmentofImmunostimulationALN-VSP,thefirstlipidnanoparticle(LNP)-formulatedsiRNAtherapeutictobetestedincancerpatients,isComplementactivationrev

6、iewedtobroadlyhighlightsomeofthepreclinicalsafetychallengesandareasofinvestigationfor“nextgeneration”LNPsystems.©2012ElsevierB.V.Allrightsreserved.Contents1.Introduction..............................................................02.ClinicalprogressofsiRNAnanomedicines.................

7、...............................02.1.SNALP-baseddelivery......................................................02.1.1.Hepatocellulartargeting.................................................02.1.2.Tumortissuetargeting..................................................02.2.RONDEL™a