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This work introduces novel approaches to enhance targeting of pharmacotherapies to cornea, ciliary body, choroid, and posterior segment of the eye using microneedles as a drug delivery platform. The first part of the work determines the ability to deliver protein therapeutics into the cornea using coated microneedles to suppress corneal neovascularization in a rabbit model. The data show that highly targeted delivery of the anti-vascular endothelial growth factor protein therapeutic gave a better biological response of suppressing neovascularization with 11,900 times less dosage compared to topical administration. The second part of the research aims to develop novel formulations to target ciliary body and choroid via suprachoroidal delivery. The results show that a strongly non-Newtonian fluid can be used to slow down the spreading of the particles at the injection site up to 2 months. The results also show that a high molecular weight formulation with weakly non-Newtonian fluid can be used to reach 100% coverage of the choroidal surface with a single injection. The third part of the research aims to determine the biological response of targeting anti-glaucoma therapeutics to the ciliary body in a rabbit model. The results show we can achieve 500- to 1000-fold dose sparing by targeted delivery via supraciliary delivery. The fourth and last part of the research aims to develop novel emulsion droplets to target different locations within the eye using a gravity-mediated delivery technique via suprachoroidal space injection. The results show that we can deliver up to 73% of injected polymeric particles posterior to the equator of the eye. Overall this work demonstrates that microneedles have the capability to deliver pharmacotherapies to cornea, ciliary body, choroid, and posterior of the eye in a highly targeted manner and provide significant dose sparing in the rabbit model.

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Lipid based non-viral delivery systems are potentially of great importance to the development of an effective and versatile therapeutic gene treatment. Many difficulties are faced in designing efficient lipid based gene delivery systems and addressing the problem of endosomal escape is one key area where efficiency could be greatly improved Molecules aimed at inducing aggregate disruption in response to changes in pH, or metal ion concentration, have been synthesised. Series of compounds were prepared based on cationic 5-alkyl-2-methylaminoalkyl pyridine amphiphiles and amphiphilic C(_8)-C(_16) EDTA dialkylamides. The critical aggregation concentration of each species was measured and a series of experiments undertaken, designed to assess the extent of pH, or metal ion concentration, induced aggregate disruption effects. The experiments were carried out by including the molecules to be examined as small mole percent co-aggregates in micellar and liposome model systems. Each group of compounds appears to exhibit disruption effects on the more strongly ordered bilayer membrane systems, with the EDTA based compounds displaying the most consistent pH dependent disruption. However, the more dynamic micellar aggregate models were less sensitive to disruption using the particular observation method employed.

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Thesis (DBA(DoctorateofBusinessAdministration))--University of South Australia, 2001.