Title : Potential of siRNA-bearing nanoparticles in the treatment of hepatocellular carcinoma in the model animals
Therapeutics based on small interfering RNA (siRNA) have demonstrated tremendous potential for treating cancer. However, non-specific targeting, premature degradation, and intrinsic toxicity of the siRNAs have to be solved before applying them in translational medicines. To address these challenges, nanotechnology-based tools might help shield siRNA and ensure its specific delivery to the target site. Besides playing a crucial role in prostaglandin synthesis, the cyclo-oxygenase-2 (COX-2) enzyme has been reported to mediate carcinogenesis in various types of cancer, including hepatocellular carcinoma (HCC). Similarly, another regulatory enzyme polo like kinase-1 (Plk-1) has been found to be crucial for cancer cells to propagate and survive in the patients. We encapsulated COX-2 specific siRNA in Bacillus subtilis membrane lipid-based liposomes (subtilosomes) and evaluated their potential in the treatment of di-ethyl nitrosamine (DEN)-induced hepato-carcinoma. We also developed Plk-1 specific siRNA-bearing lipid-based nanocarriers. Our findings corroborated that the nanoparticle-based formulation was stable, releasing specific siRNA in a sustained manner. For example, the subtilosome-based formulation was successful in inhibiting TNF-α expression in the experimental animals, while Plk-1 specific siRNA inhibited target enzyme. The apoptosis study indicated that the subtilosomized siRNA inhibits DEN-induced carcinogenesis more effectively than free siRNA. The as-developed formulation also suppressed COX-2 expression, which in turn up-regulated expression of p53 wild-type and Bax on the one hand and downregulated Bcl-2 expression on the other. Histopathological studies also revealed better tumor regression in liver cells with standard cellular architecture. The survival data established increased efficacy of subtilosome-encapsulated COX-2 siRNA against hepatocellular carcinoma.