alexa pH-responsive Multi-PEGylated dual cationic nanoparticles enable charge modulations for safe gene delivery.
Materials Science

Materials Science

Journal of Nanomedicine & Nanotechnology

Author(s): Xiong MP, Bae Y, Fukushima S, Forrest ML, Nishiyama N,

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Abstract In gene therapy, the cytotoxicity of many polycations is undesirable and has been attributed to nonspecific membrane destabilizing effects and intracellular polyplex-mediated toxicity. To help prolong the pharmacokinetic profile of nonviral vehicles for gene delivery, the cationic surface charge of current systems is typically shielded through the conjugation of polyethylene glycol (PEG) chains to the particle surface. However, the design of an intelligent polycation with environment-sensing charge modulations is essential to minimize cytotoxicity and enhance gene expression. We have designed a novel di-cationic block copolymer, poly(aspartate-hydrazide)-block-poly(L-lysine), capable of pH-mediated endosomal membrane disruption based on charge interactions, which has negligible toxicity elsewhere to the cell. The poly(L-lysine) segment, with a high pK(a) value of approximately 9.4, preferentially forms a poly-ion complex with the negative phosphate groups of pDNA, whereas the pH-responsive poly(aspartate-hydrazide) segment, with the comparatively lower pK(a) approximately 5.0, is characterized by a substantial fraction of unprotonated amino groups at physiological pH. As a consequence, complexation between such a polymer and pDNA leads to the formation of a two-layered nanoparticle. In particular, the nanoparticle possesses an unprotonated pH-responsive segment to serve as both a scaffold for acid-labile linkages of various moieties such as aldehyde-PEG and to transition from neutral to charged for disrupting endosomal membranes, and safely enhancing gene expression. Our system supports an endosomal escape mechanism based on charge interactions rather than the proton-sponge effect, and may be an important step towards engineering new classes of intelligent nonviral vectors. This article was published in ChemMedChem and referenced in Journal of Nanomedicine & Nanotechnology

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