Abstract
Metastasis is the cause of most (>90%) cancer deaths and currently lacks effective treatments. Approaches to understanding the biological process, unraveling the most effective molecular target(s), and implementing nanotechnology to increase the therapeutic index are expected to facilitate cancer therapy against metastasis. Here, we demonstrate the potential advantages of bringing these three approaches together through the rational design of a small interfering RNA (siRNA) that targets p70(S6K) in cancer stem cells (CSCs) in combination with dendrimer nanotechnology-based siRNA delivery. Our results demonstrated that the generation 6 (G(6)) poly(amidoamine) dendrimer can be used as a nanovector to effectively deliver p70(S6K) siRNA by forming uniform dendriplex nanoparticles that protect the siRNA from degradation. These nanoparticles were able to significantly knock down p70(S6K) in ovarian CSCs, leading to a marked reduction in CSC proliferation and expansion without obvious toxicity toward normal ovarian surface epithelial cells. Furthermore, treatment with the p70(S6K) siRNA/G(6) dendriplexes substantially decreased mesothelial interaction, migration and invasion of CSCs in vitro, as well as tumor growth and metastasis in vivo. Collectively, these results suggest that p70(S6K) constitutes a promising therapeutic target, and the use of siRNA in combination with nanotechnology-based delivery may constitute a new approach for molecularly targeted cancer therapy to treat metastasis.