Multifunctional, self-assembling anionic peptide-lipid nanocomplexes for targeted siRNA delivery

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Abstract

Formulations of cationic liposomes and polymers readily self-assemble by electrostatic interactions with siRNA to form cationic nanoparticles which achieve efficient transfection and silencing invitro. However, the utility of cationic formulations invivo is limited due to rapid clearance from the circulation, due to their association with serum proteins, as well as systemic and cellular toxicity. These problems may be overcome with anionic formulations but they provide challenges of self-assembly and transfection efficiency. We have developed anionic, siRNA nanocomplexes utilizing anionic PEGylated liposomes and cationic targeting peptides that overcome these problems. Biophysical measurements indicated that at optimal ratios of components, anionic PEGylated nanocomplexes formed spherical particles and that, unlike cationic nanocomplexes, were resistant to aggregation in the presence of serum, and achieved significant gene silencing although their non-PEGylated anionic counterparts were less efficient. We have evaluated the utility of anionic nanoparticles for the treatment of neuronal diseases by administration to rat brains of siRNA to BACE1, a key enzyme involved in the formation of amyloid plaques. Silencing of BACE1 was achieved invivo following a single injection of anionic nanoparticles by convection enhanced delivery and specificity of RNA interference verified by 5' RACE-PCR and Western blot analysis of protein. © 2014 The Authors.

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Tagalakis, A. D., Lee, D. H. D., Bienemann, A. S., Zhou, H., Munye, M. M., Saraiva, L., … Hart, S. L. (2014). Multifunctional, self-assembling anionic peptide-lipid nanocomplexes for targeted siRNA delivery. Biomaterials, 35(29), 8406–8415. https://doi.org/10.1016/j.biomaterials.2014.06.003

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