Abstract/Summary

Thiol functionalised organosilica nanoparticles were explored in this PhD project as a model carrier for targeted drug delivery to the hair follicles and the posterior segment of the eye. These two organs were chosen as they are equipped with multiple barriers which present a challenge for drug delivery and the development of a novel drug delivery system is required. Modification of these nanoparticles with polyethylene glycol (PEG) and fluorescent dye was feasible as they are readily functionalised. The first chapter provides an overview of thiol functionalised nanoparticles, their synthesis, and possible applications. In addition, the structure of the skin and the eye and barriers to drug delivery are discussed. Chapter two focuses on the synthesis of particles with predetermined size and was achieved after exploring different reaction parameters that govern the characteristics of the resulting nanoparticles using a pre-established modified Stöber protocol. The nanoparticles were characterised using several methods including dynamic light scattering, transmission electron microscopy and Ellman’s assay. Equations that can be used to design particles with the required size by changing the dielectric constant of the solvents used or varying the concentration of the catalyst NaOH when dimethylsulfoxide (DMSO) is used were established. The smallest nanoparticles (45 ± 3 nm) with high thiol content (249 ± 30 µmol/g) were produced when DMSO was used as the solvent and had a narrow polydispersity (0.181) and zeta potential of (-55 ± 7 mV); therefore, these particles were selected for subsequent studies. The mucoadhesive properties of these nanoparticles to several mucosal tissues including the eye, urinary bladder and the intestine were previously studied and modification with PEG was reported to improve the penetration and diffusion of the nanoparticles. Thus, in the third chapter, the nanoparticles were modified by PEGylation and fluorescently labelled and their penetration to the follicular appendages to overcome the barrier function of the stratum corneum was investigated using a tape stripping method and fluorescence microscopy. PEGylation was found to significantly improve the penetration of the nanoparticles with better penetration of particles functionalised with higher molecular weight PEG with penetration depth values of 1400 µm for PEGylated 5000 Da nanoparticles and 450 µm for PEGylated 750 Da nanoparticles. The fourth chapter investigates the diffusion of thiolated and PEGylated (750, 5000 and 10000 Da) nanoparticles in the vitreous humour (decanted into a cuvette) using a novel in vitro fluorescence-based method and measuring the distance travelled overtime. PEGylation enhanced the diffusion of the nanoparticles in the vitreous humour as they travelled around 20 µm compared to thiolated particles which did not diffuse. The final chapter discusses the general conclusions and possible future work. These nanoparticles were found to be a good model to explore surface modification of nanoparticles in drug delivery.