siRNA Delivery Using a Cationic-Lipid-Based Highly Selective Human DNA Ligase I Inhibitor

The present article illustrates the serendipitous discovery of a cationic-lipid-based human DNA ligase (hLig) I inhibitor and the development of siRNA delivering, a hLigI-targeted cationic-lipid-based nonviral vector. We have tested a small in-house library of structurally similar cationic lipo-anisamides for antiligase activity, and amongst tested, N-dodecyl-N-(2-(4-methoxybenzamido)ethyl)-N-methyldodecan-1-ammonium iodide (C12M) selectively and efficiently inhibited the enzyme activity of hLigI, compared to other human ligases (hLigIIIβ and hLigIV/XRCC4) and bacterial T4 DNA ligase. Furthermore, upon hydration with equimolar cholesterol, C12M produced antiligase cationic liposomes, which transfected survivin siRNA and showed significant inhibition of tumor growth.