title: Retracted: Inhibition of hepatitis C virus replication by intracellular delivery of multiple siRNAs by nanosomes.
abstract: Sustained antiviral responses of chronic hepatitis C virus (HCV) infection have improved recently by the use of direct-acting antiviral agents along with interferon (IFN)-α and ribavirin. However, the emergence of drug-resistant variants is expected to be a major problem. We describe here a novel combinatorial small interfering RNA (siRNA) nanosome-based antiviral approach to clear HCV infection. Multiple siRNAs targeted to the highly conserved 5'-untranslated region (UTR) of the HCV genome were synthesized and encapsulated into lipid nanoparticles called nanosomes. We show that siRNA can be repeatedly delivered to 100% of cells in culture using nanosomes without toxicity. Six siRNAs dramatically reduced HCV replication in both the replicon and infectious cell culture model. Repeated treatments with two siRNAs were better than a single siRNA treatment in minimizing the development of an escape mutant, resulting in rapid inhibition of viral replication. Systemic administration of combinatorial siRNA-nanosomes is well tolerated in BALB/c mice without liver injury or histological toxicity. As a proof-of-principle, we showed that systemic injections of siRNA nanosomes significantly reduced HCV replication in a liver tumor-xenotransplant mouse model of HCV. Our results indicate that systemic delivery of combinatorial siRNA nanosomes can be used to minimize the development of escape mutants and inhibition of HCV infection.
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Partha K
authors.initials: PK
authors.lastname: Chandra
authors.affiliation: Center for Nanomedicine and Drug Delivery, College of Pharmacy, Xavier University of Louisiana, New Orleans, Louisiana, USA.
authors.forename: Anup K
authors.initials: AK
authors.lastname: Kundu
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Hazari
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Chandra
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Bao
authors.affiliation: Department of Comparative Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Ooms
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Gilbert F
authors.initials: GF
authors.lastname: Morris
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.affiliation: Center for Nanomedicine and Drug Delivery, College of Pharmacy, Xavier University of Louisiana, New Orleans, Louisiana, USA.
authors.forename: Tarun K
authors.initials: TK
authors.lastname: Mandal
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA. Electronic address: sdash@tulane.edu.
authors.forename: Srikanta
authors.initials: S
authors.lastname: Dash
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000628:therapy* / Q000821:virology; D008081:Liposomes / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000473:pathology / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009368:Neoplasm Transplantation; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics*; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics; D012093:Replicon; D014162:Transfection; D014779:Virus Replication
chemical_list: D020121:5' Untranslated Regions; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D012367:RNA, Viral; D002784:Cholesterol; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane