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Title: Delivery of nanocarrier-loaded hydrophobic drugs via the airways
Author: Merchant, Zahra I.
ISNI:       0000 0004 7226 3651
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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BACKGROUND AND PURPOSE: Systemic delivery of hydrophobic therapeutics represents substantial formulation challenges impeding optimal benefits due to side effects and sub-therapeutic drug levels at the target site consequently leading to progression of multi-drug resistance. This thesis describes three distinct novel nanotechnology-based strategies with desirable aerosolization characteristics for delivery via the airways, aimed at enhancing the therapeutic efficacy of hydrophobic drugs for pulmonary and neurological disorders. METHODS: The first approach involved the development of dry powder microparticles for pulmonary delivery of antifungal amphotericin B nanocomplexes, prepared by co-grinding the drug with ascorbic acid. Nanocomplexes developed were characterized for molecular interactions by FT-IR, size, zeta potential, morphology, in vitro aerodynamic behavior and antifungal activity. The second strategy entailed design of liposomes co-encapsulating rifampicin and ibuprofen using Design of Experiment, targeted to the mannose and/or scavenger receptors on the alveolar macrophages where TB infection resides. Spray dried microparticles were characterized for in vitro aerodynamic behavior and macrophage uptake using the flow cytometer in RAW 264.7 cells. The third approach involved the development of Kolliphor® HS 15 micelles incorporating neuroprotective agents CNB001 or curcumin and Kolliphor® TPGS micelles encapsulating curcumin for the treatment of neurodegeneration and neuroblastoma respectively. Nasal delivery of these micellar systems was intended for brain targeting. Micelles were characterized for size, charge, aerosol droplet size distribution, drug release, morphology and in vitro cellular studies on SH-SY5Y cells. RESULTS: Successful development of nanocarrier-based systems with a high encapsulation efficiency greater than 80% for all the systems was achieved, with particle size desirable for the end-use. Spray dried microparticles of amphotericin B nanocomplexes with L-leucine showed a high fine particle fraction of around 58% signifying likely deposition in the peripheral airways, to the areas of fungal infection. There was no loss of antifungal activity against Candida spp on complexation of amphotericin B. Microparticles of liposomes encapsulating antitubercular drugs showed good aerosolization, and up to 65% fine particle fraction on addition of L-leucine could be achieved. An enhanced in vitro cellular uptake was evident for negative-charged liposomes targeted to the scavenger receptors and the mannosylated liposomes targeted to the mannose receptors on the macrophage cell line RAW 264.7. Finally, Kolliphor® micelles encapsulating CNB001 or curcumin showed desired aerosol droplet size for delivery to the posterior nasal olfactory epithelium with median size of 42.75-54.86 μm when aerosolized by the NasalTM Mucosal Atomization Device. The formulations intended for neuroprotection showed improved cellular viability, reduction in reactive oxygen species and nuclear morphology in the in vitro Parkinson’s model. CONCLUSION: The nanotechnology-based formulations combined with administration to or through the airways using commercially available delivery devices, represent a highly attractive formulation strategy for delivery of hydrophobic agents to the target site at a therapeutic level to combat issues of multi-drug resistance.
Supervisor: Taylor, K. M. G. ; Buckton, G. ; Satyanarayana, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available