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Degradable dendritic nanogels as carriers for antimicrobial peptides

Nordström, R.; Andrén, Oliver C.J.; Singh, Shalini; Malkoch, Michael; Davoudi, Mina LU ; Schmidtchen, A. LU and Malmsten, Martin LU (2019) In Journal of Colloid and Interface Science 554. p.592-602
Abstract

In the present study, we investigate degradable anionic dendritic nanogels (DNG) as carriers for antimicrobial peptides (AMPs). In such systems, the dendritic part contains carboxylic acid-based anionic binding sites for cationic AMPs, whereas linear poly(ethylene glycol) (PEG) chains form a shell for promotion of biological stealth. In order to clarify factors influencing membrane interactions of such systems, we here address effects of nanogel charge, cross-linking, and degradation on peptide loading/release, as well as consequences of these factors for lipid membrane interactions and antimicrobial effects. The DNGs were found to bind the AMPs LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) and DPK-060 (GKHKNKGKKNGKHNGWKWWW). For the... (More)

In the present study, we investigate degradable anionic dendritic nanogels (DNG) as carriers for antimicrobial peptides (AMPs). In such systems, the dendritic part contains carboxylic acid-based anionic binding sites for cationic AMPs, whereas linear poly(ethylene glycol) (PEG) chains form a shell for promotion of biological stealth. In order to clarify factors influencing membrane interactions of such systems, we here address effects of nanogel charge, cross-linking, and degradation on peptide loading/release, as well as consequences of these factors for lipid membrane interactions and antimicrobial effects. The DNGs were found to bind the AMPs LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) and DPK-060 (GKHKNKGKKNGKHNGWKWWW). For the smaller DPK-060 peptide, loading was found to increase with increasing nanogel charge density. For the larger LL-37, on the other hand, peptide loading was largely insensitive to nanogel charge density. In line with this, results on the secondary structure, as well as on the absence of stabilization from proteolytic degradation by the nanogels, show that the larger LL-37 is unable to enter into the interior of the nanogels. While 40–60% nanogel degradation occurred over 10 days, promoted at high ionic strength and lower cross-linking density/higher anionic charge content, peptide release at physiological ionic strength was substantially faster, and membrane destabilization not relying on nanogel degradation. Ellipsometry and liposome leakage experiments showed both free peptide and peptide/DNG complexes to cause membrane destabilization, indicated also by antimicrobial activities being comparable for nanogel-bound and free peptide. Finally, the DNGs were demonstrated to display low toxicity towards erythrocytes even at peptide concentrations of 100 µM.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antimicrobial peptide, Degradable, Dendritic, Hyperbranched drug delivery, Membrane, Nanogel
in
Journal of Colloid and Interface Science
volume
554
pages
11 pages
publisher
Elsevier
external identifiers
  • scopus:85069570924
ISSN
0021-9797
DOI
10.1016/j.jcis.2019.07.028
language
English
LU publication?
yes
id
1cb2be29-4518-4c93-938b-5a1afabfb206
date added to LUP
2019-08-02 12:46:43
date last changed
2019-08-28 04:57:35
@article{1cb2be29-4518-4c93-938b-5a1afabfb206,
  abstract     = {<p>In the present study, we investigate degradable anionic dendritic nanogels (DNG) as carriers for antimicrobial peptides (AMPs). In such systems, the dendritic part contains carboxylic acid-based anionic binding sites for cationic AMPs, whereas linear poly(ethylene glycol) (PEG) chains form a shell for promotion of biological stealth. In order to clarify factors influencing membrane interactions of such systems, we here address effects of nanogel charge, cross-linking, and degradation on peptide loading/release, as well as consequences of these factors for lipid membrane interactions and antimicrobial effects. The DNGs were found to bind the AMPs LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) and DPK-060 (GKHKNKGKKNGKHNGWKWWW). For the smaller DPK-060 peptide, loading was found to increase with increasing nanogel charge density. For the larger LL-37, on the other hand, peptide loading was largely insensitive to nanogel charge density. In line with this, results on the secondary structure, as well as on the absence of stabilization from proteolytic degradation by the nanogels, show that the larger LL-37 is unable to enter into the interior of the nanogels. While 40–60% nanogel degradation occurred over 10 days, promoted at high ionic strength and lower cross-linking density/higher anionic charge content, peptide release at physiological ionic strength was substantially faster, and membrane destabilization not relying on nanogel degradation. Ellipsometry and liposome leakage experiments showed both free peptide and peptide/DNG complexes to cause membrane destabilization, indicated also by antimicrobial activities being comparable for nanogel-bound and free peptide. Finally, the DNGs were demonstrated to display low toxicity towards erythrocytes even at peptide concentrations of 100 µM.</p>},
  author       = {Nordström, R. and Andrén, Oliver C.J. and Singh, Shalini and Malkoch, Michael and Davoudi, Mina and Schmidtchen, A. and Malmsten, Martin},
  issn         = {0021-9797},
  keyword      = {Antimicrobial peptide,Degradable,Dendritic,Hyperbranched drug delivery,Membrane,Nanogel},
  language     = {eng},
  month        = {10},
  pages        = {592--602},
  publisher    = {Elsevier},
  series       = {Journal of Colloid and Interface Science},
  title        = {Degradable dendritic nanogels as carriers for antimicrobial peptides},
  url          = {http://dx.doi.org/10.1016/j.jcis.2019.07.028},
  volume       = {554},
  year         = {2019},
}