The effect of pH on PAMAM dendrimer-siRNA complexation:endosomal considerations as determined by molecular dynamics simulation


Intracellular degradation of genes, most notably within the endo-lysosomal compartment is considered a significant barrier to (non-viral) gene delivery in vivo. Previous reports based on in vitro studies claim that carriers possessing a mixture of primary, secondary and tertiary amines are able to buffer the acidic environment within the endosome, allowing for timely release of their contents, leading to higher transfection rates. In this report, we adopt an atomistic molecular dynamics (MD) simulation approach, comparing the complexation of 21-bp siRNA with low-generation polyamidoamine (PAMAM) dendrimers (G0 and G1) at both neutral and acidic pHs, the latter of which mimics the degradative environment within maturing 'late-endosomes'. Our simulations reveal that the time taken for the dendrimer-gene complex (dendriplex) to reach equilibrium is appreciably longer at low pH and this is accompanied by more compact packaging of the dendriplex, as compared to simulations performed at neutral pH. We also note larger absolute values of calculated binding free energies of the dendriplex at low pH, indicating a higher dendrimer-nucleic acid affinity in comparison with neutral pH. These novel simulations provide a more detailed understanding of low molecular-weight polymer-siRNA behavior, mimicking the endosomal environment and provide input of direct relevance to the "proton sponge theory", thereby advancing the rational design of non-viral gene delivery systems.

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Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
Additional Information: NOTICE: this is the author’s version of a work that was accepted for publication in Biophysical chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Ouyang, D, Zhang, H, Parekh, HS & Smith, SC 2011, 'The effect of pH on PAMAM dendrimer-siRNA complexation: endosomal considerations as determined by molecular dynamics simulation', Biophysical chemistry, vol 158, no. 2-3 (2011) DOI
Uncontrolled Keywords: dendrimers,hydrogen-ion concentration,molecular dynamics simulations,polyamines,small interfering RNA,thermodynamics,Biochemistry,Biophysics,Organic Chemistry
Publication ISSN: 1873-4200
Last Modified: 28 Mar 2024 08:10
Date Deposited: 19 Aug 2019 08:54
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2011-10
Published Online Date: 2011-06-22
Authors: Ouyang, Defang
Zhang, Hong
Parekh, Harendra S.
Smith, Sean C.



Version: Accepted Version

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