Naphthalimide‐modified dendrimers as efficient and low cytotoxic nucleic acid delivery vectors

Abstract

AbstractPoly(amidoamine) (PAMAM) dendrimers have been widely used as nucleic acid delivery vectors. To improve the transfection efficacy, ligands such as amino acid, peptide and lipid are conjugated to the periphery of dendrimers. However, the structures of these ligands are generally flexible, and few reports about rigid‐ligand‐modified dendrimers are reported. In this work, three novel PAMAM dendrimers (G5‐1, G5‐2 and G5‐3) modified with rigid naphthalimide were synthesized as nucleic acid delivery vectors. Magnetic resonance spectroscopy showed that the average numbers of naphthalimide molecules conjugated on the PAMAM periphery in compounds G5‐1, G5‐2 and G5‐3 are 8, 30 and 50, respectively. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay revealed good cytocompatibility of these vectors in multiple cell lines, including MG63, HeLa, HEK293 and MC3T3‐E1 cells, with a cell survival rate of more than 90% in most cases. Among the three dendrimers, G5‐1 with fewer naphthalimide molecules showed stronger RNA binding ability than G5‐2 and G5‐3. G5‐1 also exhibited the best gene silencing efficacy at a dendrimer to miRNA weight ratio of 1:2 in MC3T3‐E1 cells, which is much higher than the commercial transfection agent Lipofectamine 2000 tested under the same conditions. In addition, G5‐1 showed high transfection efficacy in plasmid DNA‐mediated luciferase expression experiments. These results suggest that rigid ligand modification can be developed as a new strategy to design safe and highly efficient nucleic acid delivery vectors. © 2021 Society of Industrial Chemistry.