Dexamethasone-pDMAEMA polymeric conjugates reduce inflammatory biomarkers in human intestinal epithelial monolayers

被引：37
作者：
Keely, Simon [1 ,2 ]
Ryan, Sinead M. [1 ,2 ]
Haddleton, David M. [3 ]
Limer, Adam [3 ]
Mantovani, Giuseppe [3 ]
Murphy, Evelyn P. [1 ,2 ]
Colgan, Sean P. [4 ]
Brayden, David J. [1 ,2 ]
机构：
[1] Univ Coll Dublin, Sch Agr Food Sci & Vet Med, Dublin 4, Ireland
[2] Univ Coll Dublin, UCD Conway Inst, Dublin 4, Ireland
[3] Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands, England
[4] Univ Colorado, Mucosal Inflammat Program, Denver, CO 80262 USA
来源：
JOURNAL OF CONTROLLED RELEASE | 2009年 / 135卷 / 01期
基金：
爱尔兰科学基金会;
关键词：
Polymeric conjugates; Mucus-covered epithelia; Inflammatory bowel disease; Dexamethasone; Prodrugs; LIVING RADICAL POLYMERIZATION; NUCLEAR RECEPTOR NURR1; PEPTIDE DRUG-DELIVERY; BOWEL-DISEASE; CACO-2; CELLS; MUCOADHESIVE PROPERTIES; CROHNS-DISEASE; ORAL DELIVERY; IN-VITRO; CHITOSAN;
D O I：
10.1016/j.jconrel.2008.12.001
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
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.
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页码：35 / 43
页数：9
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