Pharmaceutically active oligonucleotides (e.g siRNA) require adequate carriers for targeted and safe transport through the body, crossing membrane barriers and controlled release of their payload at the site of action. In contrast to lipoplex or polyplex formulations, cationic nanogels can serve as alternative oligonucleotide carriers. Usually they have pre-adjusted superstructures independent from their polyanionic cargo and show great stability, especially in presence of further polyanionic competitors. To this respect, we developed a novel concept for synthesizing polymeric cationic nanohydrogels,[1] which provides a safe and stable environment for siRNA, avoids carrier aggregation under physiologically relevant conditions and promotes size-dependent gene silencing in vitro. Via RAFT polymerization well-defined block copolymers of pentafluorophenyl methacrylate and tri(ethylene glycol) methyl ether methacrylate were synthesized that self-assemble in polar aprotic solvents (e.g. DMSO) into nm-sized polymer micelles. The resulting superstructures were used to generate cationic nanohydrogel particles by covalently cross-linking the reactive ester cores with spermine providing cationic moieties for stable siRNA complexation. Interestingly, the synthetic process offers possibilities to synthesize nanohydrogels of various sizes, which show a size-dependent gene silencing potential in vitro. Presently, we are working on the introduction of groups for active targetting and degradable cross-linkers for stimuli-responsive siRNA release.[2] Looking ahead, these novel cationic nanohydrogel particles can also serve as platform for advanced therapeutic oligonucleotide delivery strategies in the field of cancer immunotherapy.[3] [1] L. Nuhn, M. Hirsch, B. Krieg, K. Koynov, K. Fischer, M. Schmidt, M. Helm, M.; R. Zentel, ACS Nano 2012, 6, 2198. [2] L. Nuhn, L. Braun, I. Overhoff, A. Kelsch, D. Schaeffel, K. Koynov, R. Zentel, Macromol. Rapid Commun. 2014, 35, 2057−2064 [3] S. Hartmann, L. Nuhn, B. Paliztsch, M. Glaffig, N. Stergiou,B. Gerlitzki, E. Schmitt, H. Kunz, R. Zentel, Adv. Healthcare Mater. 2014, 4, 522 -527

Cationic nanohydrogel particles as carriers for therapeutic oligonucleotide delivery

251st National Meeting (2016)

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