The effect of guanidinylation of PEGylated poly(2-aminoethyl methacrylate) on the systemic delivery of siRNA

abstract Small interfering RNA (siRNA) has a huge potential for the treatment or prevention of various diseases.However, to realize the therapeutic potential of siRNA drugs, efficient, tissue-specific and safe deliverytechnologies must be developed. Here we synthesized two kinds of polymers (PEGylated poly(2-aminoethyl methacrylate) labeled as PEG-b-PAEM or PEA, and guanidinylated PEGylated poly(2-aminoethyl methacrylate) marked as PEG-b-PAEM-co-PGEM or PEAG) using atom transfer radical pol-ymerization and evaluated their capability of mediating siRNA delivery invitro and invivo. Both polymerspresented excellent siRNA encapsulation ability, formed regular nanostructures with siRNA, robustlymediated cellular internalization and cytoplasmic localization of siRNA, and resulted in targeted geneknockdown efficiently. However, PEAG showed much more outstanding abilities referring to aboveevaluating indicators compared with PEA. Both PEA/siRNA and PEAG/siRNA polyplexes displayed strongliver, lung and spleen accumulation in mice for a long time after intravenous administration. PEAG/siApoB polyplexes (single dose at 1 mg/kg) further repressed ApoB expression in liver and resulted inblock of lipid transportation. In addition, both polymers delivered high amounts of siRNA into tumortissue in the Hela-Luc xenograft murine model. More siRNA accumulated in tumor with the increase of N/P ratio and PEAG/siRNA polyplexes showed higher siRNA accumulation than PEA/siRNA polyplexes at thesame N/P ratio. These findings set the stage for further studies of structuralefunctional mechanisms anddevelopments of siRNA therapeutics. 2013 Elsevier Ltd. All rights reserved.