PhD Studentship: IBBS funded.
Cystic fibrosis (CF) is a lethal hereditary disorder characterised by the unregulated production of viscoelastic mucus, which poses a barrier to the effective delivery of drugs to the CF lung. The barrier properties of CF sputum are thought to be due to the high DNA and actin content that together with mucins form a tangled network, held together by electrostatic charges, hydrogen bonds and van der Waals forces. CF sputum affects the deposition pattern of aerosols on the epithelial surface of the upper respiratory tract and thereby, preventing drug diffusion. To improve drug delivery in CF it is vital to reduce or remove this barrier. Recent studies have suggested that negatively charged species such as unfractionated heparin (UFH), a member of the glycosaminoglycan family, may possess mucoactive properties and shows promise as a potential therapy for treating patients with chronic obstructive pulmonary disease (COPD) and CF. This study investigates the potential mucoactive properties of UFH, and describes the development of dry powder inhaler (DPI) formulations of UFH that can be administered to CF patients to treat airway obstruction.
In this study, a novel barrier function assay was employed to investigate the diffusion of the corticosteroid dexamethasone through CF sputum and calf-thymus DNA. In addition, atomic force microscopy (AFM) and confocal laser scanning microscopy (CLSM) were used to investigate the ultrastructure of both whole CF sputum and calf-thymus DNA. The effect of charged oligosaccharides and glycosaminoglycans, as potential mucoactive agents, on the barrier and structural properties of CF sputum were also investigated. The feasibility of producing dry powders of UFH, which are suitable for inhalation from DPIs, using spray drying, was investigated. The effect of these powders on CF sputum rheology was also studied.
Studies investigating the barrier properties of CF sputum, showed that sputum significantly (p