Acid-degradable core-shell nanoparticles for reversed tamoxifen-resistance in breast cancer by silencing manganese superoxide dismutase (MnSOD).

This study attempted to reverse tamoxifen (TAM)-resistance in breast cancer by silencing a mitochondrial enzyme, manganese superoxide dismutase (MnSOD), which dismutates TAM-induced reactive oxygen species (ROS) (i.e., superoxide) to less harmful hydrogen peroxide and hampers therapeutic effects. Breast cancer cells were co-treated with TAM and MnSOD siRNA-delivering nanoparticles (NPs) made of a siRNA/poly(amidoamine) (PAMAM) dendriplex core and an acid-degradable polyketal (PK) shell. The (siRNA/PAMAM)-PK NPs were designed for the PK shell to shield siRNA from nucleases, minimize detrimental aggregation in serum, and facilitate cytosolic release of siRNA from endosomal compartments. This method of forming the PK shell around the siRNA/PAMAM core via surface-initiated photo-polymerization enables ease of tuning NPs' size for readily controlled siRNA release kinetics. The resulting NPs were notably homogenous in size, resistant to aggregation in serum, and invulnerable to heparan sulfate-mediated disassembly, compared to siRNA/PAMAM dendriplexes. Gel electrophoresis and confocal microscopy confirmed efficient siRNA release from the (siRNA/PAMAM)-PK NPs upon stimuli-responsive hydrolysis of the PK shell. Sensitization of TAM-resistant MCF7-BK-TR breast cancer cells with (MnSOD siRNA/PAMAM)-PK NPs restored TAM-induced cellular apoptosis in vitro and significantly suppressed tumor growth in vivo, as confirmed by biochemical assays and histological observations. This study impl...
Source: Biomaterials - Category: Materials Science Authors: Tags: Biomaterials Source Type: research