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Effects of peptide cyclization on the interaction with oppositely charged microgels
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2011 (English)In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 391, no 1-3, 62-68 p.Article in journal (Refereed) Published
Abstract [en]

The effect of peptide cyclization on the interaction between antimicrobial peptides and oppositely charged poly(acrylic acid-co-acrylamide) microgels of various charge density was investigated for linear and cyclic variants of peptide oligomers (C(ARKKAAKA)nC) (n = 1, 1.5, 2, 3). Through this, peptide length could be varied without substantially affecting peptide charge density and mean hydrophobicity. Furthermore, the peptides were demonstrated to display random coil conformation both in aqueous solution and when bound to oppositely charged microgels, allowing effects of cyclization to be monitored without interference from conformational transitions. With increasing peptide length, both cyclic and linear peptide variants displayed increased binding affinity to oppositely charged microgels. For all peptide lengths, however, the difference between cyclic and linear peptide variants was marginal at most, hence cyclization had little or no influence in peptide incorporation to oppositely charged microgels. In parallel, microgel deswelling increased with peptide length for both linear and cyclic peptide variants, while linear and cyclic peptide variants of the same length displayed very similar peptide-induced deswelling. Also electrolyte-induced peptide desorption from the microgels was similar for linear and cyclic peptide variants. Taken together, these findings demonstrate that end-to-end cyclization does not markedly affect peptide incorporation into, and release from, oppositely charged microgels. This opens up opportunities for the use of microgels as carriers for peptides which have been cyclized in order to improve their proteolytic and chemical stability, or in order to achieve other therapeutic advantages compared to the corresponding linear peptide variant.

Place, publisher, year, edition, pages
2011. Vol. 391, no 1-3, 62-68 p.
Keyword [en]
Cyclization, Microgel, Peptide
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-168831DOI: 10.1016/j.colsurfa.2011.01.029ISI: 000299068100009OAI: oai:DiVA.org:uu-168831DiVA: diva2:503581
Note
18th International Symposium on Surfactants in Solution (SIS), Melbourne Australia, 14-19 November 2010Available from: 2012-02-16 Created: 2012-02-16 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Microgel Interactions with Peptides and Proteins: Consequence of Peptide and Microgel Properties
Open this publication in new window or tab >>Microgel Interactions with Peptides and Proteins: Consequence of Peptide and Microgel Properties
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Microgels are lightly cross-linked hydrogel particles in the sub-micrometer to micrometer size range with a capacity to drastically change their volume in response to changes in the external environment. Microgels have an ability to bind and store substances such as biomacromolecular drugs, notably proteins and peptides, and release them upon stimuli, making them potential candidates as drug delivery vehicles and functional biomaterials. This thesis aims at clarifying important factors affecting peptide-microgel interactions. These interactions were studied by micromanipulator-assisted light and fluorescence microscopy focusing on microgel deswelling in response to peptide binding, as well as re-swelling in response to peptide release or enzymatic degradation. To evaluate peptide uptake in microgels, solution depletion measurements were used whereas the peptide secondary structure was investigated by circular dichroism. In addition, the peptide and enzyme distribution within microgels was analyzed with confocal microscopy.

Results presented in this thesis demonstrate that peptide incorporation into microgels, as well as peptide-induced microgel deswelling, increases with peptide length and charge density. In addition, results demonstrate that the peptide charge (length) rather than peptide charge density determines microgels deswelling. End-to-end cyclization is shown to not noticeably influence peptide-microgel interactions, suggesting that peptide cyclization can be used in combination with oppositely charged microgel carriers to improve the proteolytic and chemical stability of the peptide compared to the corresponding linear variant. Peptide secondary structure is found to drastically affect peptide incorporation into, and release from, oppositely charged microgels. Furthermore, it is shown that microgel charge density, peptide molecular weight, and enzyme concentration all greatly influence microgel bound peptide degradation. Of importance for applications, protective effects of microgels against proteolytic peptide degradation are observed only at sufficiently high microgel charge densities. Enzyme-mediated microgel degradation is shown to increase with increasing enzyme concentration, while an increased peptide loading in microgels causes a concentration-dependent decrease in microgel degradation.

Taken together, results obtained in this work have provided some insight into factors of importance for rational use of microgels as delivery systems for protein or peptide drugs, but also in a host of other biomedical applications using weakly cross-linked polymer systems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 196
Keyword
Binding, Degradation, Enzyme, Gel, Hydrogel, Microgel, Peptide, Protein, Release
National Category
Pharmaceutical Sciences Physical Chemistry Materials Engineering
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-242893 (URN)978-91-554-9157-4 (ISBN)
Public defence
2015-03-20, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-02-24 Created: 2015-02-02 Last updated: 2015-03-11

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Publisher's full texthttp://www.sciencedirect.com/science/article/pii/S0927775711000550

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Månsson, RonjaMalmsten, Martin

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