Martinho, N;
Silva, LC;
Florindo, HF;
Brocchini, S;
Zloh, M;
Barata, TS;
(2017)
Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties.
International Journal of Nanomedicine
, 12
pp. 7053-7073.
10.2147/IJN.S135475.
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Abstract
Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure–activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(L-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behavior. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD-PG-G4 can provide a suitable scaffold to be used for biophysical studies of surface-modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system.
| Type: | Article |
|---|---|
| Title: | Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.2147/IJN.S135475 |
| Publisher version: | https://doi.org/10.2147/IJN.S135475 |
| Language: | English |
| Additional information: | © 2017 Martinho et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php) |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Nanoscience & Nanotechnology, Pharmacology & Pharmacy, Science & Technology - Other Topics, Dendrimers, Peptide Dendrimers, Molecular Dynamics, Fluorescence, Charmm, Structure-Activity, Surface Properties, Molecular-Dynamics Simulations, Biomedical Applications, Pamam Dendrimers, Delivery, Field, Nanoparticles, Doxorubicin, Automation, Package, Binding |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10025105 |
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