Jornal de Toxicologia Clínica
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Optimizing Structure and Activity of the Squalenoyl-siRNA Nanoparticles

Suzan Boutary*, Guy Khalaf, Marie Caillaud, Didier Desmaele, Semen Yesylevskyy, Christophe Ramseyer, Liliane Massaad-Massade

siRNA is a promising tool for targeted therapy. Previously we conjugated the siRNA to Squalene (SQ) by copper- free click chemistry, which has been proven to successfully deliver siRNA to tumors with fusion oncogenes and Schwann cells. To go further for future human application, this study aims to optimize the synthesis and the nanoprecipitation of siRNA-SQ conjugates while conserving their physicochemical characteristics and efficiency. We succeeded in increasing the yield of the siRNA-SQ conjugation reaction making it scalable up to 50-times. The size, the polydispersity index and the ζ-potential of the nanoparticles obtained are strongly dependent on the solvent used. Moreover, the molecular dynamics simulations reveal the physical mechanisms of nanoparticle formation at the early stage of their growth. However, these parameters do not influence the activity of the nanoparticles both in vitro and in vivo. Established protocols of efficient and reliable siRNA-SQ nanoparticles production open up the perspective of their therapeutic usage in humans.