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Degradable dendritic nanogels as carriers for antimicrobial peptides
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Farmaceutisk fysikalisk kemi)ORCID iD: 0000-0001-5626-3959
Kungliga Tekniska Högskolan.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Farmaceutisk fysikalisk kemi)
Kungliga Tekniska Högskolan.
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2019 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 554, p. 592-602Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 554, p. 592-602
Keywords [en]
Antimicrobial peptide, Degradable, Dendritic, Hyperbranched, drug delivery, Membrane, Nanogel
National Category
Pharmaceutical Sciences Physical Chemistry
Research subject
Pharmaceutical Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-389746DOI: 10.1016/j.jcis.2019.07.028ISI: 000487346200061PubMedID: 31330426OAI: oai:DiVA.org:uu-389746DiVA, id: diva2:1338595
Funder
Swedish Research Council, 2016-05157Swedish Research Council, 2017-02341EU, FP7, Seventh Framework Programme, 604182Available from: 2019-07-23 Created: 2019-07-23 Last updated: 2019-11-01Bibliographically approved
In thesis
1. Polymeric Nanoparticles as Carriers for Antimicrobial Peptides: Factors Affecting Peptide and Membrane Interactions
Open this publication in new window or tab >>Polymeric Nanoparticles as Carriers for Antimicrobial Peptides: Factors Affecting Peptide and Membrane Interactions
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

As resistance towards conventional antibiotics is becoming more pronounced, cationic antimicrobial peptides (AMPs) have received considerable attention as possible therapeutic alternatives. Thousands of potent AMPs occur in humans, animals, plants and fungi as a natural part of the immune system. However, there are several challenges with AMP therapeutics related to formulation and delivery. Examples include proteolytic sensitivity and serum protein binding, resulting in quick degradation, loss of activity and clearance. Therefore, it is important to find a suitable drug delivery system to meet these protection and delivery challenges. Micro-/nanogels are loosely crosslinked polymer colloids with high water content that can be made to trigger at a wide range of stimuli. They have shown promise as delivery systems for AMPs, as the aqueous environment they create allows the peptides to maintain their natural conformation, while their gel networks offer protection and triggered release. This thesis aims towards expanding the knowledge about degradable and non-degradable pH-responsive micro-/nanogels as carriers for AMPs.

The results in this thesis show that factors relating to the drug delivery system (degradability, charge and crosslinker density), the surrounding media (pH and ionic strength) and the peptide properties (length, charge, PEGylation) all affect the peptide loading to, protection, release from and effect of AMP-loaded gels. Studies of the interaction of AMP-loaded microgels with bacteria-modelling liposomes and lipid bilayers have verified peptide effect after gel incorporation, as further demonstrated by in vitro studies on several bacterial strains. Neutron reflectometry provided detailed mechanistic information on the interaction between AMP-loaded gels and bacteria-modelling lipid bilayers, showing that the antimicrobial unit is the released peptide. All gels showed low, promising hemolysis and some gels could offer protection against proteolytic degradation of AMPs.

In summary, non-degradable and degradable micro-/nanogels are versatile and interesting candidates as AMP carriers. Small changes in the gel composition or the AMP used can dramatically change the peptide loading, release and effect. It is therefore necessary to carefully consider and evaluate the optimal carrier for every AMP and the application at hand.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 74
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 280
Keywords
antimicrobial peptide, microgel, degradable, nanogel, drug delivery, PEGylation, secondary structure, model membrane, lipid bilayer, neutron reflectometry, ellipsometry
National Category
Pharmaceutical Sciences Physical Chemistry
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-383639 (URN)978-91-513-0778-7 (ISBN)
Public defence
2019-11-29, Room A1:107a, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-11-07 Created: 2019-10-12 Last updated: 2019-11-07

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Nordström, RandiSingh, ShaliniMalmsten, Martin

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