Polysaccharide functionalised span nanoparticles as gene delivery systems. Application in the treatment of colorectal liver metastasis

Résumé

The main objective of this work has been the design of a new polysaccharide functionalised nanosystem as a non-viral microRNA vector for the treatment of liver metastasis from colorectal cancer. For this purpose, we modified our previously developed span nanoparticles using polysaccharides with endothelial targeting properties. Thus, we have developed a xanthan gum-functionalised nanosystem able to associate, protect from degradation and deliver in vitro a model plasmid without compromising cell viability. Moreover, these nanoparticles showed a remarkable short- and long-term stability at different temperatures, both in suspension and as a lyophilised product. The xanthan gum cover targeted the nanoparticles, and therefore, the plasmid delivery to endothelial cells of liver, kidney and lung in vivo. In addition, span nanoparticles were functionalised with the glycosaminoglycans chondroitin sulfate and hyaluronic acid. The resulting systems were efficiently loaded with a model plasmid and characterised in terms of physicochemical, stability, DNA protection, cytotoxicity and transfection properties. Once selected the chondroitin sulfate-functionalised nanoparticles for further studies, we evaluated their clinical potential associating microRNA in the treatment of a murine model of colorectal cancer liver metastasis. First, these nanoparticles demonstrated to successfully target liver sinusoidal endothelial cells (LSECs) and deliver miR-20a, which has been found to be downregulated in tumour-activated LSECs. Finally, the administration of these miR-20a loaded nanoparticles demonstrated to reduce the tumour volume by 80% and the LSECs infiltration into tumour foci by 70% in a murine model of colorectal liver metastasis. Therefore, these results provide an in vivo proof-of-concept of the clinical potential of the developed nanoparticles as a novel microRNA-based therapeutic strategy for cancer treatment.