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Polymers for siRNA Delivery Combining precision with multifunctionality


*Corresponding author
Ludwig-Maximilians-University Munich, Pharmaceutical Biotechnology, Center for System-based Drug Researchand Center for Nanoscience (CeNS), Butenandtsstrasse 5-13, D-81377 Munich, Germany


The different tasks in therapeutic siRNA delivery at the extra- and intracellular locations call for dynamic carriers. These carriers have to be bioresponsive, sensing their microenvironment and facilitating the next delivery step. Amongst other carriers, cationic oligomers can complex and compact siRNA into nanosized complexes called polyplexes. Different functions have to be incorporated into polyplexes, such as shielding moieties for protecting nanoparticles in the patient’s blood circulation, targeting ligands for specific binding to receptors at the target cell surface and endocytosis into endosomes, and membrane-destabilizing agents for intracellular release into the cytosol, where RNA interference takes place. As outlined here, solid phase supported synthesis using artificial oligoamino acids provides a powerful basis for the design of multifunctional and precise cationic oligomers. These form polyplexes with high siRNA delivery activity and low toxicity.


RNA interference (RNAi) with small synthetic 21-23 nucleotide interfering RNA (siRNA) as its key mediator has attracted much attention due to its ability to tackle a number of human genetic disorders and infectious diseases by inhibiting targeted gene expression and function in a sequence-specific manner (1, 2) (Figure 1). For capitalizing the enormous therapeutic potential of siRNA, the design of suitable synthetic dynamic vectors overcoming the extracellular and intracellular barriers is of utmost importance. Apart from liposomal systems, polymers like polylysine (PLL), polyamidoamine (PAMAM) and polyethylenimine (PEI) were the most widely investigated carriers in earlier studies for plasmid DNA (pDNA) based gene delivery (3). Such polymeric carriers can easily be produced and functionalised with active domains required for various delivery steps (Figure 1); however, they still bear numerous limitations. They often display significant cytotoxicity which generally increases with polymer molecular weight. Several polymer classes such as PEI are also not biodegradable. Most critical are the still limited efficiency of polymeric formulations a ...