Her-2-directed systemic delivery of fatty acid synthase (FASN) siRNA with novel liposomal carrier systems in the breast cancer mouse model

Abstract

Despite the current advancements in the gene silencing therapy in vitro, the systemic delivery of siRNA still remains a challenging task for its transition into clinics. We have previously developed the Her2-targeted fatty acid synthase (FASN) siRNA-encapsulating immunoliposomes (ILs) with a great stability in the presence of serum. We report here the therapeutic potential of the lipid-based novel formulations in the breast cancer mouse model. The growth inhibitory and gene silencing effects of various formulations were determined by measuring the size of the tumour, cell proliferation, apoptotic index and immunoassays against Her2-overexpressed tumour xenografts in nude mice. The pegylated DSPC/Chol and DOPE/CHEMS ILs containing FASN-siRNA significantly decreased the tumour growth relative to non-targeted liposomes. They induced the 1.5-fold increase in cellular apoptosis and several fold decrease in proliferation as compared to non-targeted liposomal formulations of FASN-siRNA. Moreover, FASN-siRNA-ILs produced several fold increase in the ratios of p53/p21 and Bax/Bcl-2. The gene silencing effects of targeted FASN-liposomes were found to be significantly superior, resulting in 30–40% downregulation in FASN as compared to non-targeted similar formulations. Both types of FASN ILs provided a highly efficient approach for targeted delivery in Her-2-expressed breast cancer and thus offered a promising anticancer strategy in the clinical therapy.