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WIREs Nanomed Nanobiotechnol
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Polyethylenimines for siRNA and miRNA delivery in vivo

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The discovery of RNA interference (RNAi) as a naturally occurring mechanism for gene knockdown has attracted considerable attention toward the use of small interfering RNAs (siRNAs) for therapeutic purposes. Likewise, microRNAs (miRNAs) have emerged as important cellular regulators of gene expression, and their pathological underexpression allows for novel therapeutic strategies (‘miRNA replacement therapy’). To address issues related to the instability, charge, and molecular weight of small RNA molecules, nanoparticle formulations have been explored for their in vivo application. Polyethylenimines (PEIs) are positively charged, linear, or branched polymers that are able to form nanoscale complexes with small RNAs, leading to RNA protection, cellular delivery, and intracellular release. This review highlights the important properties of various PEIs with regard to their use for in vivo RNA delivery. PEI modifications for increased efficacy, altered pharmacokinetic properties, improved biocompatibility and, upon covalent coupling of ligands, targeted delivery are described. An overview of various modified PEIs and a comprehensive list of representative studies using PEI‐based siRNA or miRNA delivery in vivo are given. WIREs Nanomed Nanobiotechnol 2013. doi: 10.1002/wnan.1228 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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Polyethylenimine (PEI) structures, complex formation, and chemical modifications. Linear and branched PEIs over a broad range of molecular weights are available for efficient complexation of small RNAs (e.g., siRNAs, pre‐miRNAs, miRNAs), leading to the formation of nanoscale PEI‐based complexes (‘polyplexes’; lower panel: atomic force microscopy). Various PEI modifications can be introduced in terms of shielding and coupling of cell‐specific ligands (e.g., antibodies) for targeted delivery (right).
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Parameters influencing the physical and biological properties of polyethylenimine (PEI)‐based polyplexes. Various parameters can affect the biological activity of PEI‐based polyplexes at different levels. The complexation components, namely molecular weight, degree of branching, and modifications of PEI as well as molecular weight and modifications of the nucleic acids, the ionic strength of the complexation buffer, and the PEI/nucleic acid ratio (N/P ratio) strongly influence the characteristics of the polyplexes. Their stability, size, and surface charge determine the biological activity of the nanoplexes in vitro and in vivo. Complex interactions between the polyplexes and the organism affect the pharmacokinetic and pharmacodynamic behavior of PEI‐based complexes and their utility for in vivo applications.
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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