caa a22 4500 445313838 CHVBK 20180317142639.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s11095-010-0344-y doi (NATIONALLICENCE)springer-10.1007/s11095-010-0344-y Disulfide-Based Poly(amido amine)s for siRNA Delivery: Effects of Structure on siRNA Complexation, Cellular Uptake, Gene Silencing and Toxicity [Elektronische Daten] [Pieter Vader, Leonardus van der Aa, Johan Engbersen, Gert Storm, Raymond Schiffelers] ABSTRACT: Purpose: RNA interference (RNAi) is a process by which small interfering RNAs (siRNA) induce sequence-specific gene silencing. Therefore, siRNA is an emerging promise as a novel therapeutic. In order to realize the high expectations for therapeutic applications, efficient delivery systems for siRNA are necessary. Methods: In this study, a new series of biodegradable poly(amido amine)s with disulfide linkages in the backbone was synthesized out of N,N′-cystaminebisacrylamide (CBA), 4-amino-1-butanol (ABOL) and ethylene diamine (EDA). Effects of different percentages of butanolic side chains and protonatable fragments in the main chain on siRNA complexation, cellular uptake, gene silencing and toxicity were investigated. Results: Incorporation of EDA in the polymer resulted in increased siRNA condensation. Efficient siRNA condensation was shown to be necessary for cellular uptake; however, excess of polymer decreased siRNA uptake for polymers with high amounts of EDA. Silencing efficiency did not correlate with uptake, since silencing increased with increasing w/w ratio for all polymers. More than 80% knockdown was found for polyplexes formed with polymers containing 25% or 50% EDA, which was combined with low cytotoxicity. Conclusions: Poly(amido amine)s with minor fractions of protonatable fragments in the main chain are promising carriers for delivery of siRNA. The Author(s), 2010 delivery nationallicence disulfide bonds nationallicence poly(amido amine)s nationallicence quantitative uptake nationallicence siRNA nationallicence Vader Pieter Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box80082, 3508 TB, Utrecht, The Netherlands aut van der Aa Leonardus Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box217, 7500 AE, Enschede, The Netherlands aut Engbersen Johan Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box217, 7500 AE, Enschede, The Netherlands aut Storm Gert Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box80082, 3508 TB, Utrecht, The Netherlands aut Schiffelers Raymond Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box80082, 3508 TB, Utrecht, The Netherlands aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/5(2011-05-01), 1013-1022 0724-8741 28:5<1013 2011 28 11095 https://doi.org/10.1007/s11095-010-0344-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0344-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Vader Pieter Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box80082, 3508 TB, Utrecht, The Netherlands aut NATIONALLICENCE 700 1- van der Aa Leonardus Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box217, 7500 AE, Enschede, The Netherlands aut NATIONALLICENCE 700 1- Engbersen Johan Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box217, 7500 AE, Enschede, The Netherlands aut NATIONALLICENCE 700 1- Storm Gert Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box80082, 3508 TB, Utrecht, The Netherlands aut NATIONALLICENCE 700 1- Schiffelers Raymond Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box80082, 3508 TB, Utrecht, The Netherlands aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/5(2011-05-01), 1013-1022 0724-8741 28:5<1013 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer