uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Factors Affecting Peptide Interactions with Surface-Bound Microgels
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0001-5236-9107
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0001-5626-3959
Manchester University.
Manchester University.
Show others and affiliations
2016 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 17, no 2, p. 669-678Article in journal (Refereed) Published
Abstract [en]

Effects of electrostatics and peptide size on peptide interactions with surface-bound microgels were investigated with ellipsometry, confocal microscopy, and atomic force microscopy (AFM). Results show that binding of cationic poly-l-lysine (pLys) to anionic, covalently immobilized, poly(ethyl acrylate-co-methacrylic acid) microgels increased with increasing peptide net charge and microgel charge density. Furthermore, peptide release was facilitated by decreasing either microgel or peptide charge density. Analogously, increasing ionic strength facilitated peptide release for short peptides. As a result of peptide binding, the surface-bound microgels displayed pronounced deswelling and increased mechanical rigidity, the latter quantified by quantitative nanomechanical mapping. While short pLys was found to penetrate the entire microgel network and to result in almost complete charge neutralization, larger peptides were partially excluded from the microgel network, forming an outer peptide layer on the microgels. As a result of this difference, microgel flattening was more influenced by the lower Mw peptide than the higher. Peptide-induced deswelling was found to be lower for higher Mw pLys, the latter effect not observed for the corresponding microgels in the dispersed state. While the effects of electrostatics on peptide loading and release were similar to those observed for dispersed microgels, there were thus considerable effects of the underlying surface on peptide-induced microgel deswelling, which need to be considered in the design of surface-bound microgels as carriers of peptide loads, for example, in drug delivery or in functionalized biomaterials.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016. Vol. 17, no 2, p. 669-678
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-278894DOI: 10.1021/acs.biomac.5b01616ISI: 000369875900029PubMedID: 26750986OAI: oai:DiVA.org:uu-278894DiVA, id: diva2:907151
Funder
Swedish Research CouncilAvailable from: 2016-02-26 Created: 2016-02-26 Last updated: 2019-10-12Bibliographically approved
In thesis
1. Microgels as Carriers for Antimicrobial Peptides: Surface-bound microgels, and factors affecting peptide interactions
Open this publication in new window or tab >>Microgels as Carriers for Antimicrobial Peptides: Surface-bound microgels, and factors affecting peptide interactions
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 66
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 259
Keywords
Antimicrobial peptides, Biomaterial coating, Drug delivery, Host defence peptides, Microgels, pH-responsive, Surface-bound
National Category
Pharmaceutical Sciences Biomaterials Science Physical Chemistry
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-360241 (URN)978-91-513-0473-1 (ISBN)
Public defence
2018-11-30, A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-11-09 Created: 2018-10-12 Last updated: 2018-11-19
2. 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: 2019-11-27

Open Access in DiVA

fulltext(1385 kB)155 downloads
File information
File name FULLTEXT01.pdfFile size 1385 kBChecksum SHA-512
c4307809ba046aff7a8da7de785812572f5768329be790be936e337a4a93ceb0bf48e9b570ddfa4fcc8576680a102ce404161cfd0e48c648c2e1ed25ecd920b4
Type fulltextMimetype application/pdf
Supporting information(613 kB)25 downloads
File information
File name ATTACHMENT01.pdfFile size 613 kBChecksum SHA-512
988dffe661b102fa766d3ece730a5f8ee7adb61534a554eb89ee0170b842e2091a68c97af8171d76682556cab575dda17be002a12a8c796554375872b0f6edcc
Type attachmentMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Nyström, LinaNordström, RandiMalmsten, Martin

Search in DiVA

By author/editor
Nyström, LinaNordström, RandiMalmsten, Martin
By organisation
Department of Pharmacy
In the same journal
Biomacromolecules
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 155 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 294 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf