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Peptide-Loaded Microgels as Antimicrobial and Anti-Inflammatory Surface Coatings
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.ORCID-id: 0000-0001-5236-9107
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.ORCID-id: 0000-0001-9070-6944
Lund University, Lund, Sweden; University of Copenhagen, Copenhagen, Denmark.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. University of Copenhagen, Copenhagen, Denmark.ORCID-id: 0000-0003-0046-5599
2018 (Engelska)Ingår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 19, nr 8, s. 3456-3466Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Here we report on covalently immobilized poly(ethyl acrylate- co-methacrylic acid) microgels loaded with the host defense peptide KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR), which is derived from human heparin cofactor II, as well as its poly(ethylene glycol)-conjugated (PEGylated) version, KYE28PEG. Peptide loading and release, as well as the consequences of these processes on the microgel and peptide properties, were studied by in situ ellipsometry, confocal microscopy, zeta potential measurements, and circular dichroism spectroscopy. The results show that the microgel-peptide interactions are electrostatically dominated, thus promoted at higher microgel charge density, while PEGylation suppresses peptide binding. PEGylation also enhances the α-helix induction observed for KYE28 upon microgel incorporation. Additionally, peptide release is facilitated at physiological salt concentration, particularly so for KYE28PEG, which illustrates the importance of electrostatic interactions. In vitro studies on Escherichia coli show that the microgel-modified surfaces display potent antifouling properties in both the absence and presence of the incorporated peptide. While contact killing dominates at low ionic strength for the peptide-loaded microgels, released peptides also provide antimicrobial activity in bulk at a high ionic strength. Additionally, KYE28- and KYE28PEG-loaded microgels display anti-inflammatory effects on human monocytes. Taken together, these results not only show that surface-bound microgels offer an interesting approach for local drug delivery of host defense peptides but also illustrate the need to achieve high surface loads of peptides for efficient biological effects.

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2018. Vol. 19, nr 8, s. 3456-3466
Nationell ämneskategori
Farmakologi och toxikologi Biomaterialvetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-358186DOI: 10.1021/acs.biomac.8b00776ISI: 000441852400029PubMedID: 29976055OAI: oai:DiVA.org:uu-358186DiVA, id: diva2:1241795
Forskningsfinansiär
Vetenskapsrådet, 2016-05157 2017-02341Tillgänglig från: 2018-08-24 Skapad: 2018-08-24 Senast uppdaterad: 2018-11-06Bibliografiskt granskad
Ingår i avhandling
1. Microgels as Carriers for Antimicrobial Peptides: Surface-bound microgels, and factors affecting peptide interactions
Öppna denna publikation i ny flik eller fönster >>Microgels as Carriers for Antimicrobial Peptides: Surface-bound microgels, and factors affecting peptide interactions
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

With a growing number of multi-resistant bacteria against conventional antibiotics, there is an urgent need to identify new antimicrobial therapeutics. One example that has gained considerable interest is antimicrobial peptides (AMPs). For AMPs to reach their full potential as therapeutics, as well as for other peptide and protein drugs, the right drug delivery system may overcome reported shortcomings, such as fast clearance in the bloodstream and proteolytic degradation. Microgels are weakly cross-linked polymer colloids, which can be made responsive to various stimuli. In the context of drug delivery, microgels are of particular interest as carriers for biomacromolecular drugs, such as peptides and proteins, as their water-rich environment offers both protection against enzymatic degradation and triggered release possibilities. Combining these, the aim of this thesis was to investigate electrostatically triggered surface-bound microgels as a delivery system for AMPs, as well as evaluate such systems as an antimicrobial and anti-inflammatory coating for biomaterials.

Results presented in this thesis demonstrate effects of microgel charge density, pH, and ionic strength on microgel volume transitions at solid interfaces, surface-induced microgel deformation and nanomechanical properties. In addition, effects of both microgel properties (charge density) and peptide properties (molecular weight, charge density, and posttranslational modifications) on peptide loading and release from surface-bound microgels were investigated. The presented thesis also reports in vitro studies of AMP-loaded microgels in dispersion and surface-bound, as either mono- or multilayers. Notably, the interplay between surface- and release-related effects for the antimicrobial properties of AMP-loaded microgels are investigated. In addition, anti-inflammatory properties of AMP-loaded microgels are also reported.

Taken together, microgels prove an interesting and versatile drug delivery system for AMPs. Results obtained in this thesis have demonstrated that several key factors need to be taken into consideration in the development of surface-bound microgels as a carrier for AMPs, and that small changes in microgel and peptide properties can alter peptide loading and release profiles.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 259
Nyckelord
Antimicrobial peptides, Biomaterial coating, Drug delivery, Host defence peptides, Microgels, pH-responsive, Surface-bound
Nationell ämneskategori
Farmaceutiska vetenskaper Biomaterialvetenskap Fysikalisk kemi
Forskningsämne
Farmaceutisk fysikalisk kemi
Identifikatorer
urn:nbn:se:uu:diva-360241 (URN)978-91-513-0473-1 (ISBN)
Disputation
2018-11-30, A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-11-09 Skapad: 2018-10-12 Senast uppdaterad: 2018-11-19

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