期刊
BIOMATERIALS
卷 156, 期 -, 页码 107-120出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2017.11.037
关键词
siRNA; Polyethylenimine; Polymeric nanoparticle; Heparin; Glycosaminoglycan; Polynucleotide delivery; Molecular dynamics
资金
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN 04460, RGPIN 341907]
- NSERC Collaborative Research and Training Experience Program for Regenerative Medicine (NCPRM)
- Canadian Institutes of Health Research (CIHR) [MOP 74452]
- Alberta Innovates Technology Futures (AITF)
- Canada Foundation for Innovation (CFI)
Delivery of polynucleotide-based therapeutics into target cells involves interactions with glycoSaminoglycan chains that are located on cell membrane milieu. Mechanisms governing glycosaminoglycan-mediated changes in the nanoparticulate structures of polymer-polynucleotide complexes are unknown, and cannot be fully elucidated without atomistic level details of molecular interactions. We selected a representative nanoparticulate system consisting of a short interfering RNA (siRNA)-poly-ethylenimine complex, and performed all-atom molecular dynamics simulations with the prototypical glycosaminoglycan heparin. We monitored the binding between the complex constituents and the heparin, and identified key features contributing to the response of the siRNA nanoparticles to heparin. We observed three main metastable states that the siRNA nanoparticles might visit in the presence of heparin, which can be translated into different functional outcomes. By correlating our data with the widely different and seemingly contradictory roles previously assigned to glycosaminoglycans, this study provides unique insights into the discrepancies in the experimental literature concerning the role of glycosaminoglycans in the polymeric nanoparticle delivery. (C) 2017 Elsevier Ltd. All rights reserved.
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