Lipid Encapsulation of Cationic Polymers in Hybrid Nanocarriers Reduces Their Non-Specific Toxicity to Breast Epithelial Cells

ABSTRACT Purpose 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