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A physicochemical assessment of the thermal stability of dextrin–colistin conjugates
Attachment of polysaccharide carriers is increasingly being used to achieve precision delivery and improved effectiveness of protein and peptide drugs. Although it is clear that their clinical effectiveness relies on the purity and integrity of the conjugate in storage, as well as following administ...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134461/ https://www.ncbi.nlm.nih.gov/pubmed/34011987 http://dx.doi.org/10.1038/s41598-021-89946-2 |
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author | Chiron, Emilie Varache, Mathieu Stokniene, Joana Thomas, David W. Ferguson, Elaine L. |
author_facet | Chiron, Emilie Varache, Mathieu Stokniene, Joana Thomas, David W. Ferguson, Elaine L. |
author_sort | Chiron, Emilie |
collection | PubMed |
description | Attachment of polysaccharide carriers is increasingly being used to achieve precision delivery and improved effectiveness of protein and peptide drugs. Although it is clear that their clinical effectiveness relies on the purity and integrity of the conjugate in storage, as well as following administration, instability of polysaccharide-based conjugates can reduce the protective efficacy of the polymer, which may adversely affect the bioactive’s potency. As a model, these studies used dextrin–colistin conjugates, with varying degrees of polymer modification (1, 2.5 and 7.5 mol% succinoylation) to assess the effect of storage temperature (− 20, 4, 21 and 37 °C) and duration (up to 12 months) on saccharide and colistin release and antimicrobial activity. Estimation of the proportion of saccharide release (by comparison of area under the curve from size exclusion chromatograms) was more pronounced at higher temperatures (up to 3 and 35% at − 20 °C and 37 °C, respectively after 12 months), however, repeated freeze–thaw did not produce any measurable release of saccharides, while addition of amylase (20, 100, 500 IU/L) caused rapid release of saccharides (> 70% total within 24 h). At all temperatures, conjugates containing the lowest degree of succinoylation released the highest proportion of free colistin, which increased with storage temperature, however no trend in saccharide release was observed. Despite the clear physical effects of prolonged storage, antimicrobial activity of all samples was only altered after storage at 37 °C for 12 months (> threefold decreased activity). These results demonstrate significant release of saccharides from dextrin–colistin conjugates during prolonged storage in buffered solution, especially at elevated temperature, which, in most cases, did not affect antimicrobial activity. These findings provide vital information about the structure–activity relationship of dextrin–colistin conjugates, prior to full-scale commercial development, which can subsequently be applied to other polysaccharide-protein and -peptide conjugates. |
format | Online Article Text |
id | pubmed-8134461 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81344612021-05-25 A physicochemical assessment of the thermal stability of dextrin–colistin conjugates Chiron, Emilie Varache, Mathieu Stokniene, Joana Thomas, David W. Ferguson, Elaine L. Sci Rep Article Attachment of polysaccharide carriers is increasingly being used to achieve precision delivery and improved effectiveness of protein and peptide drugs. Although it is clear that their clinical effectiveness relies on the purity and integrity of the conjugate in storage, as well as following administration, instability of polysaccharide-based conjugates can reduce the protective efficacy of the polymer, which may adversely affect the bioactive’s potency. As a model, these studies used dextrin–colistin conjugates, with varying degrees of polymer modification (1, 2.5 and 7.5 mol% succinoylation) to assess the effect of storage temperature (− 20, 4, 21 and 37 °C) and duration (up to 12 months) on saccharide and colistin release and antimicrobial activity. Estimation of the proportion of saccharide release (by comparison of area under the curve from size exclusion chromatograms) was more pronounced at higher temperatures (up to 3 and 35% at − 20 °C and 37 °C, respectively after 12 months), however, repeated freeze–thaw did not produce any measurable release of saccharides, while addition of amylase (20, 100, 500 IU/L) caused rapid release of saccharides (> 70% total within 24 h). At all temperatures, conjugates containing the lowest degree of succinoylation released the highest proportion of free colistin, which increased with storage temperature, however no trend in saccharide release was observed. Despite the clear physical effects of prolonged storage, antimicrobial activity of all samples was only altered after storage at 37 °C for 12 months (> threefold decreased activity). These results demonstrate significant release of saccharides from dextrin–colistin conjugates during prolonged storage in buffered solution, especially at elevated temperature, which, in most cases, did not affect antimicrobial activity. These findings provide vital information about the structure–activity relationship of dextrin–colistin conjugates, prior to full-scale commercial development, which can subsequently be applied to other polysaccharide-protein and -peptide conjugates. Nature Publishing Group UK 2021-05-19 /pmc/articles/PMC8134461/ /pubmed/34011987 http://dx.doi.org/10.1038/s41598-021-89946-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Chiron, Emilie Varache, Mathieu Stokniene, Joana Thomas, David W. Ferguson, Elaine L. A physicochemical assessment of the thermal stability of dextrin–colistin conjugates |
title | A physicochemical assessment of the thermal stability of dextrin–colistin conjugates |
title_full | A physicochemical assessment of the thermal stability of dextrin–colistin conjugates |
title_fullStr | A physicochemical assessment of the thermal stability of dextrin–colistin conjugates |
title_full_unstemmed | A physicochemical assessment of the thermal stability of dextrin–colistin conjugates |
title_short | A physicochemical assessment of the thermal stability of dextrin–colistin conjugates |
title_sort | physicochemical assessment of the thermal stability of dextrin–colistin conjugates |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134461/ https://www.ncbi.nlm.nih.gov/pubmed/34011987 http://dx.doi.org/10.1038/s41598-021-89946-2 |
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