Zheng, Mengyao and Pavan, Giovanni Maria and Neeb, Manuel and Schaper, Andreas K and Danani, Andrea and Klebe, Gerhard and Merkel, Olivia M and Kissel, Thomas (2012) Targeting the blind spot of polycationic nanocarrier-based siRNA delivery. ACS nano, 6 (11). pp. 9447-9454. ISSN 1936-0851
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Abstract
Polycationic nanocarriers attract increasing attention to the field of siRNA delivery. We investigated the self-assembly of siRNA vs pDNA with polycations, which are broadly used for nonviral gene and siRNA delivery. Although polyethyleneimine (PEI) was routinely adopted as siRNA carrier based on its efficacy in delivering pDNA, it has not been investigated yet why PEI efficiently delivers pDNA to cells but is controversially discussed in terms of efficacy for siRNA delivery. We are the first to investigate the self-assembly of PEI/siRNA vs PEI/pDNA and the steps of complexation and aggregation through different levels of hierarchy on the atomic and molecular scale with the novel synergistic use of molecular modeling, molecular dynamics simulation, isothermal titration calorimetry, and other characterization techniques. We are also the fist to elucidate atomic interactions, size, shape, stoichiometry, and association dynamics for polyplexes containing siRNA vs pDNA. Our investigation highlights differences in the hierarchical mechanism of formation of related polycation-siRNA and polycation-pDNA complexes. The results of fluorescence quenching assays indicated a biphasic behavior of siRNA binding with polycations where molecular reorganization of the siRNA within the polycations occurred at lower N/P ratios (nitrogen/phosphorus). Our results, for the first time, emphasize a biphasic behavior in siRNA complexation and the importance of low N/P ratios, which allow for excellent siRNA delivery efficiency. Our investigation highlights the formulation of siRNA complexes from a thermodynamic point of view and opens new perspectives to advance the rational design of new siRNA delivery systems.
| Item Type: | Scientific journal article, Newspaper article or Magazine article |
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| Uncontrolled Keywords: | siRNA delivery; DNA delivery; polyethyleneimine; molecular modeling; isothermal titration calorimetry; RT-PCR; supramolecular complexation |
| Subjects: | Physical sciences > Physics > Computational physics |
| Department/unit: | Dipartimento tecnologie innovative > Istituto di ingegneria meccanica e tecnologia dei materiali |
| Depositing User: | Andrea Danani |
| Date Deposited: | 03 Mar 2015 13:52 |
| Last Modified: | 08 Jul 2016 09:20 |
| URI: | http://repository.supsi.ch/id/eprint/6217 |
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