Abstract
Nanoparticles are promising carriers for the purpose of controlled pulmonary drug delivery because they can reside in the airways and slowly release a drug into the lung tissue. However, development into the clinic of nanoparticle products for pulmonary delivery has been limited to date due to the lack of control over the drug release process from these small carriers. In this work the feasibility of generating an inhaled nanoparticle system that could be administered to the airways, penetrate the respiratory mucus and act as a reservoir from which drug release could be controlled was explored.Nanoparticle systems were fabricated using an emulsion phase inversion technique and a nanoprecipitation method to produce lipid nanoparticle (LNPs) and polymer nanoparticles (PVA NPs), respectively. The LNPs had a particle size of ca. 50 nm and the PVA NPs had a size of ca. 250 nm respectively. Rifampicin was loaded into nanoparticles and the release was controlled using 2 different permeabilisation strategies that were designed to encourage the drug liberation from the particles. Both permeabilisation strategies involved mixing a chemical agent with the nanoparticles to induce a carrier structural change to occur. Both LNP and PVA particles were shown to be capable of controlling the release of rifampicin using their permeabilisation agents. However, using a multidimensional diffusion model the LNPs were shown to penetrate through the mucus barrier more quickly with a rate of 30.08 ± 2.49 × 104 nm2/s, compared to the PVA NPs (1.64 ± 0.37× 104 nm2/s). Therefore, the LNPs were used in all the subsequent work. A novel spray drying technique was designed to fabricate microparticles to deliver the LNPs into the lung using a dry powder inhaler. The LNPs were loaded with drug and the agent that initiated the permeabilisation mechanism was incorporated into with the LNPs in micropartcles with a suitable size for airway deposition. The incorporation of LNPs with the permeabiliser into the microparticles did not diminish the ability of the LNPs to control drug release. The fate of labelled LNPs was tracked following their administration to respiratory epithelial Calu-3 cells and macrophage U937 cell lines. LNPs were found to persist at the cell surface over 8 h when delivered to a Calu-3 cell monolayer, with less than 10% of the applied particles being internalised into the cells. The permeabilisation process increased the particle uptake by both cell types which was thought to be a consequence of the particles distending upon exposure the permeabiliser. A co-culture model was developed containing the airway epithelial cells and macrophages. When the co-culture was exposed to the LNPs, the particles were found in both cell types, with a great proportion internalisated by macrophage cells.
The ability of the LNP to distend upon exposure to a chemical permeabiliser controlled release, penetrate mucus and gain preferential entry into macrophage cells in the lung suggested they could be an attractive means to deliver therapeutic agents such as rifampicin into the lung.
| Date of Award | 2016 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Stuart Jones (Supervisor) & Ben Forbes (Supervisor) |