Optimization Of Transforming Growth Factor-Beta 1 Sirna Loaded Chitosan-Tripolyphosphate Nanoparticles For The Treatment Of Colorectal Cancer Hepatic Metastasis In A Mouse Model

Metastatic liver disease is the most frequent complication of colorectal cancer (CRC), and the development of liver-targeted nanoparticles for drug delivery is a promising therapeutic approach. However, to improve the efficacy of passive drug delivery, its release rate at the sites of liver metastases should be maximized while minimizing drug uptake in non-targeted cells. Herein, we report the development and use of tripolyphosphate (TPP) modified chitosan (CS) nanoparticles loaded with small interfering RNA (siRNA) directed against transforming growth factor beta 1 (TGF-beta 1), which promotes tumorigenesis in advanced CRC. The nanoparticles efficiently inhibited CRC hepatic metastasis in an animal model. Particles of 300 nm in size and zeta potential at 20 mV showed a more striking liver-targeting effect. A weight ratio of CS/TPP of 8:1 for particles with TGF-beta 1 siRNA loaded at a concentration of 20 mu M at pH 7.5 showed good pH-responsive drug release when exposed to a CRC homogenate at pH 6.5. In vivo, CS-TPP/TGF-beta 1 siRNA nanoparticles significantly reduced the volume and number of CRC metastatic foci. This was accompanied by the downregulation of TGF-beta 1 expression in the tumor microenvironment, inhibition of tumor associated macrophage formation, and improvement of the immune microenvironment. These results indicate that it is possible to achieve effective passive liver targeting by optimizing the processing parameters. The design of nanoparticles carrying siRNA against overexpressed oncogenes provides an excellent platform for the development of an efficient liver cancer therapy.