pH responsive polycation inulin derivative for siRNA Delivery

siRNA-based therapeutics hold great potential for treatment of various cancers by targeting signalling pathways and oncogenes that promote cell proliferation, cell cycle progression, invasion/metastasis and resistance mechanisms in tumors. However, many challenges, including rapid nuclease degradation, poor cellular uptake and offtarget effects, need to be addressed in order to carry these molecules into clinical trials. Goal of the work The goal of the work was that to produce a new inulin derivative, Inulin-g-imidazole-g-diethylenetriamine (INU-IMI-DETA), bearing diethylentriamine chains (DETA) and imidazole groups (IMI) with good potential as polymeric complexing agent for siRNA. This because DETA and IMI groups able respectively to give strong polycation properties to resulting copolymer and to improve endosomal escaping exploiting the proton sponge effect. Moveover that polymer derivatives bearing 1,2-diaminoethane side chains exhibit a peculiar two-step protonation behavior that facilitates membrane destabilization at the acidic pH of late endosome or lysosome. The INU-IMIDETA derivative obtained was tested as siRNA complexing and delivering agent and a specific procedure was followed to obtain stable polyplex nanoaggregates. The in vitro silencing activity was also tested.