Design and Synthesis of Piperazine-Based Compounds Conjugated to Humanized Ferritin as Delivery System of siRNA in Cancer Cells

Gene expression regulation by small interfering RNA (siRNA) holds promise in treating a wide range of diseases through selective gene silencing. However, successful clinical application nucleic acid-based therapy requires novel delivery options. Herein, to achieve efficient negatively charged siRNA duplexes, the internal cavity “humanized” chimeric Archaeal ferritin (HumAfFt) was specifically decorated with cationic piperazine-based compounds (PAs). By coupling these rigid-rod-like amines thiol-reactive reagents, chemoselective conjugation efficiently afforded on topologically selected cysteine residues properly located inside HumAfFt. The capability PAs-HumAfFt host and deliver molecules human transferrin receptor (TfR1), overexpressed many cancer cells, explored. These systems allowed into HeLa, HepG2, MCF-7 cells improved silencing effect glyceraldehyde-3-phosphate dehydrogenase (GAPDH) respect traditional transfection methodologies provided promising TfR1-targeting system for multifunctional therapeutic applications.