TY - JOUR
T1 - Dexamethasone-pDMAEMA polymeric conjugates reduce inflammatory biomarkers in human intestinal epithelial monolayers
AU - Keely, Simon
AU - Ryan, Sinéad M.
AU - Haddleton, David M.
AU - Limer, Adam
AU - Mantovani, Giuseppe
AU - Murphy, Evelyn P.
AU - Colgan, Sean P.
AU - Brayden, David J.
PY - 2009/4/2
Y1 - 2009/4/2
N2 - 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 PGE2 and TNF-α, respectively. Conjugates also suppressed TNF-α 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.
AB - 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 PGE2 and TNF-α, respectively. Conjugates also suppressed TNF-α 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.
KW - Dexamethasone
KW - Inflammatory bowel disease
KW - Mucus-covered epithelia
KW - Polymeric conjugates
KW - Prodrugs
UR - https://www.scopus.com/pages/publications/61649101216
U2 - 10.1016/j.jconrel.2008.12.001
DO - 10.1016/j.jconrel.2008.12.001
M3 - Article
C2 - 19110018
AN - SCOPUS:61649101216
SN - 0168-3659
VL - 135
SP - 35
EP - 43
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 1
ER -