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Title: Studies on the interaction between inhaled drug molecules and mucin
Author: Giorgetti, Melania
ISNI:       0000 0004 6350 9939
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2016
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Mucus is a dynamic gel network primarily composed of water. The principal “non-water” component of mucus is mucin, a macromolecular glycoprotein largely responsible for the viscoelastic gel nature of mucus. Recent evidence indicates that some inhaled antibiotics are bound by mucus components and their biological activity reduced. This thesis focussed upon the mucin binding of a panel of epithelial sodium channel (ENaC) blockers that have been studied as experimental therapeutic agents for cystic fibrosis (CF). Using porcine gastric mucin (PGM) as a model system the directional transport of FL-Na, FITC dextran probes (4-70 kDa) and two ENaC blockers was determined using Franz diffusion cells. Size-dependent restriction of dextran transport was accompanied by a large disparity in the passage of two structurally similar ENaC blockers with differing lipophilic character. A 96-well ultrafiltration assay was developed to study mucin-binding of 12 related ENaC blockers of two main structural groups: quaternary amine compounds (QQA) and non-quaternary amine (NQQA) analogues. The extent of binding was variable within sub-groups and correlated well with Log P o/w. Other physical parameters (e.g. rotatable bond number, PSA) served as good correlates only for QQA structures. In contrast, the apical-basolateral transport of ENaC blockers across restrictive Calu-3 monolayers was not clearly predicated by solute hydrophobicity. Saturation Transfer Difference (STD)-NMR spectroscopy was used to gather structural details of mucin-drug interactions. These studies provide the first evidence that STD-NMR can be used to identify discrete molecular regions that participate in interactions with mucin. In conclusion, these data indicate that some inhaled drugs undergo reversible interactions with mucus. This finding could have wide implications for the design of new inhaled therapies for lung diseases where binding to supraphysiological amounts of airway mucus may modulate drug disposition and clinical response.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available