Pavan, Giovanni Maria and Posocco, Paola and Tagliabue, Aaron and Maly, Marek and Malek, Anastasia and Danani, Andrea and Ragg, Enzio and Catapano, Carlo V and Pricl, Sabrina (2010) PAMAM dendrimers for siRNA delivery: computational and experimental insights. Chemistry-A European Journal, 16 (26). pp. 7781-7795. ISSN 1521-3765
Full text not available from this repository.Abstract
Short double-stranded RNAs, which are known as short interfering RNA (siRNA), can be used to specifically down-regulate the expression of the targeted gene in a process known as RNA interference (RNAi). However, the success of gene silencing applications based on the use of synthetic siRNA critically depends on efficient intracellular delivery. Polycationic branched macromolecules such as poly(amidoamine) (PAMAM) dendrimers show a strong binding affinity for RNA molecules and, hence, can provide an effective, reproducible, and relatively nontoxic method for transferring siRNAs into animal cells. Notwithstanding these perspectives, relatively few attempts have been made so far along these lines to study in detail the molecular mechanisms underlying the complexation process between PAMAMs and siRNAs. In this work we combine molecular simulation and experimental approaches to study the molecular requirements of the interaction of RNA-based therapeutics and PAMAM dendrimers of different generations. The dendrimers and their siRNA complexes were structurally characterized, and the free energy of binding between each dendrimer and a model siRNA was quantified by using the well-known MM/PBSA approach. DOSY NMR experiments confirmed the structural in silico prediction and yielded further information on both the complex structure and stoichiometry at low N/P ratio values. siRNA/PAMAM complex formation was monitored at different N/P ratios using gel retardation assays, and a simple model was proposed, which related the amount of siRNA complexed to the entropy variation upon complex formation obtained from the computer simulations.
| Item Type: | Scientific journal article, Newspaper article or Magazine article |
|---|---|
| Subjects: | Physical sciences > Physics > Computational physics |
| Depositing User: | Andrea Danani |
| Date Deposited: | 03 Mar 2015 08:57 |
| Last Modified: | 08 Jul 2016 08:46 |
| URI: | http://repository.supsi.ch/id/eprint/6207 |
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