Abstract
8-Hydroxyoctanoic acid (8-HOA) produced through cyclooxygenase-2 (COX-2) catalyzed dihomo-γ-linolenic acid (DGLA) peroxidation in delta-5-desaturase inhibitory (D5D siRNA) condition showed an inhibitory effect on breast cancer cell proliferation and migration. However, in vivo use of naked D5D siRNA was limited by off-target silencing and degradation by endonucleases. To overcome the limitation and deliver the D5D siRNA in vivo, we designed an epithelia cell adhesion molecule targeted three-way junctional nanoparticle having D5D siRNA. In this study, we have hypothesized that 3WJ-EpCAM-D5D siRNA will target and inhibit the D5D enzyme in cancer cells leading to peroxidation of supplemented DGLA to 8-HOA resulting in growth inhibitory effect in the orthotopic breast cancer model developed by injecting 4T1 cells. On analysis, we observed a significant reduction in tumor size and metastatic lung nodules in animals treated with a combination of 3WJ-EpCAM-D5D siRNA and DGLA through activating intrinsic apoptotic signaling pathway and by reducing endothelial–mesenchymal damage.
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