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Dexamethasone-pDMAEMA polymeric conjugates reduce inflammatory biomarkers in human intestinal epithelial monolayers
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Keely, Simon, Ryan, Sinead M., Haddleton, David M., Limer, Adam, Mantovani, Giuseppe, Murphy, Evelyn P., Colgan, Sean P. and Brayden, David J.. (2009) Dexamethasone-pDMAEMA polymeric conjugates reduce inflammatory biomarkers in human intestinal epithelial monolayers. Journal of Controlled Release, Vol.135 (No.1). pp. 35-43. ISSN 01683659
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Official URL: http://dx.doi.org/10.1016/j.jconrel.2008.12.001
Abstract
The mucoadhesive polymer, poly(dimethylamino)ethyl methacrylate, (pDMAEMA), was synthesised by living radical polymerisation and subsequently conjugated by quaternisation reaction to a functionalised anti-inflammatory corticosteroid dexamethasone, to separately yield two conjugates with either 9:1 or 18:1 molar ratios of dexamethasone: polymer respectively. The hypothesis was to test whether the active agent maintained in vitro bioactivity when exposed to the apical side of human intestinal epithelial monolayers, Caco-2 and mucos-covered HT29-MTX-E12 (E12). HPLC analysis indicated high conjugate purity. Similar to pDMAEMA, fluorescently-labelled dexamethasone-pDMAEMA conjugates were bioadhesive to Caco-2 and mucoadhesive to E12. Apical addition of conjugates suppressed mRNA expression of the inflammatory markers, NURR1 and ICAM-1 in E12 following stimulation by PGE(2) and TNF-alpha, respectively. Conjugates also suppressed TNF-alpha stimulated cytokine secretion to the basolateral side of Caco-2 monolayers. Measurement of dexamethasone permeability from conjugates across monolayers suggested that conjugation reduced permeability compared to free dexamethasone. LDH assay indicated that conjugates were not cytotoxic to monolayers. Anti-inflammatory agents can therefore be successfully conjugated to polymers and they retain adhesion and bioactivity and have potential to be formulated for topical administration. (C) 2008 Elsevier B.V. All rights reserved.
| Item Type: | Journal Article |
|---|---|
| Subjects: | Q Science > QD Chemistry R Medicine > RS Pharmacy and materia medica |
| Divisions: | Faculty of Science > Chemistry |
| Journal or Publication Title: | Journal of Controlled Release |
| Publisher: | Elsevier BV |
| ISSN: | 01683659 |
| Date: | 2 April 2009 |
| Volume: | Vol.135 |
| Number: | No.1 |
| Number of Pages: | 9 |
| Page Range: | pp. 35-43 |
| Identification Number: | 10.1016/j.jconrel.2008.12.001 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Restricted or Subscription Access |
| Funder: | Science Foundation Ireland Investigator grant |
| Grant number: | 04 IN3 B575 |
| URI: | http://wrap.warwick.ac.uk/id/eprint/28166 |
Data sourced from Thomson Reuters' Web of Knowledge
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