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Abstract
Drug resistance acquired by cancer cells is a significant challenge in the clinic and requires impairing the responsible pathological pathway. Administering chemotherapeutics along with silencing resistance-basis activity using RNA interference (RNAi) is expected to restore the activity of the chemotherapeutic and generate synergistic cancer eradication. 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 implies that combined gene silencing and chemotherapy is a promising strategy to overcoming a significant challenge in cancer therapy.
Highlights
One of the immediate utilities of RNA interference (RNAi) in biomedical applications is to sensitize target cells to therapy by silencing an antagonistic pathological pathway or resistance against chemotherapeutic agents [1,2,3]
The limited extracellular stability and intracellular siRNA release capability of siRNA/ PAMAM dendriplexes were addressed by grafting an acid-degradable PK shell around the dendriplex core via surface-initiated photo-polymerization (Figure 2a)
In order to ensure the formation of PK shell around siRNA/PAMAM dedriplexes without generating empty PK particles, photo-initiator eosin was conjugated only onto PAMAM
Summary
One of the immediate utilities of RNAi in biomedical applications is to sensitize target cells to therapy by silencing an antagonistic pathological pathway or resistance against chemotherapeutic agents [1,2,3]. TAM engages mitochondrial estrogen receptor (ER)-β as an antagonist, inducing the intrinsic apoptotic program that damages mitochondrial DNA of breast cancer cells by stimulating reactive oxygen species (ROS) (i.e., superoxide) formation [5]. This cytotoxic effect is offset when the expression of manganese superoxide dismutase (MnSOD) is up-regulated in TAM-resistant breast cancer cells and superoxide is catalyzed to less harmful hydrogen peroxide [6, 7]. Re-sensitizing cancer cells to chemotherapy by silencing the pathological pathway may result in a lower necessary dose of chemotherapeutic agents administered, reducing adverse side effects
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