title: Lipid encapsulation of cationic polymers in hybrid nanocarriers reduces their non-specific toxicity to breast epithelial cells.
abstract: OBJECTIVE
  Clinical application of cationic polymers for delivery of nucleic acids has been limited by their toxicity. The purpose of this study is to evaluate whether the polymer-in-lipid hybrid nanotechnology recently developed for controlled siRNA delivery can tackle this toxicity issue by reducing exposure of the cellular components to free cationic polymers.
  
  
  METHODS
  Lipid-polymer hybrid nanocarriers (LPNs) encapsulating complexes of hexadecylated polyethylenimine (H-PEI) and biologically inactive siRNA in lipids were prepared at different lipid-polymer ratios. Comparative toxicity of these LPNs and unencapsulated cationic materials on breast epithelial cell lines MDA-MB-231 and MCF-10a was evaluated.
  
  
  RESULTS
  Even at a low lipid-polymer ratio (3:1 w/w), encapsulation of H-PEI improved its LC(50) values measured within hours by 3-5 fold, and caused less reduction in the colony-formation rates in 10-14 days. The observed reductions in the acute and delayed carrier toxicity were associated with significantly less membrane damages, improved mitochondrial functions, reduced reactive oxidative species production, and lower caspase-3 activity (all p < 0.05) without sacrificing the siRNA transfection efficiency.
  
  
  CONCLUSIONS
  This study has validated the hybrid nanotechnology for controlled RNA delivery from a toxicological perspective. This is especially valuable if local or long-term RNA therapy is intended for which low carrier toxicity is essential.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Hui Yi
authors.initials: HY
authors.lastname: Xue
authors.forename: Mayuri
authors.initials: M
authors.lastname: Narvikar
authors.forename: Juan-Bao
authors.initials: JB
authors.lastname: Zhao
authors.forename: Ho Lun
authors.initials: HL
authors.lastname: Wong
mesh_terms: D001940:Breast / Q000166:cytology; D053148:Caspase 3 / Q000378:metabolism; D002412:Cations / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry / Q000633:toxicity*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008055:Lipids / Q000737:chemistry / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D049329:Nanostructures / Q000737:chemistry / Q000633:toxicity*; D011094:Polyethyleneimine / Q000737:chemistry / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002412:Cations; D004337:Drug Carriers; D008055:Lipids; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011094:Polyethyleneimine; D053148:Caspase 3