<p> Photoresponsive polymers can act as controllable drug delivery systems that may revolutionize ophthalmic drug delivery for disease treatment in the posterior segment of the eye. Localized, controlled drug delivery devices have significant therapeutic advantages for treating diseases of back of the eye by increasing patient compliance and maintaining therapeutic levels of drug in the tissue. Sustained-release delivery systems that respond to light/laser stimuli are under development to control the rate of delivery resulting in a tuneable treatment profile ideal for retinal diseases. The use of light as a crosslinking mechanism has the potential to create unique materials with controllable swelling, degradation and diffusion properties. </p> <p> This thesis investigates the synthesis and development of universal, graftable PEG-anthracene molecules and their applications in photosensitive alginate and hyaluronate (HA) "photogels". Anthracene undergoes reversible dimerization with wavelengths above 300 nm and de-dimerization/dissociation below 300 nm; due to its well-understood chemistry and symmetry, it was used as a starting point and proof-ofconcept for the synthesis of reversible dimerizing crosslinkers that may be generically grafted to different polymers to cause crosslinking/decrosslinking. After synthesis, watersoluble PEG-anthracene macromolecules were grafting via carbodiimide chemistry to the carboxyl groups along the polymer backbone of alginate and HA at various densities to create viscous liquids or gels with good handling properties. </p> <p> Light irradiation can be used to control the swelling and effective crosslinking density of the photogels which in tum can control drug delivery from photocrosslinked hydro gels as illustrated through the decrease or increase in the delivery of a variety of low molecular weight (<1000 Da) and high molecular weight (>10,000 Da) model drug compounds from both alginate and HA photogels with various light treatments. Novel loading mechanisms were developed through the loading of compounds into uncrosslinked gels followed by crosslinking 365 nm exposures to "lock" in the model drug compounds. Diffusion coefficients effectively compared the different systems showing increase exposures of 365 nm resulted in greater decrease in release of compounds demonstrating the ability to fine-tune release rates. Different formulations and control gels demonstrate a variety of different release profiles. The photogels were valuable long-term controlled release systems (>80 days) that also demonstrate high cytocompatibility when grown with ophthalmic cell lines. </p> <p> Novel photoresponsive biomaterials for smart delivery of therapeutics which use light-controlled crosslinking and decrosslinking mechanisms have been developed. The PEG-anthracene graftable photocrosslinkers show the ability to introduce photocontrolled crosslinking into hydrogel systems. While anthracene as the photodimerizer and alginate and HA as the bulk materials are used as a proof-of-concept in this work, this grafting system can be further manipulated to include new photosensitive dimerizers and other applicable polymers. The ability to use light stimuli to control release rates in a continual fashion, rather than having delivery that is strictly on or off, is a valuable finding that may lead to the development of drug delivery systems that can be catered towards individuals and the progression of their disease. </p> / Thesis / Doctor of Philosophy (PhD)

Eye disorders are on the rise as a result of an ageing population, an increasing obesity problem and a growth in the number of diabetic patients. Conventional ophthalmic formulations do not maintain therapeutic drug concentration in the target tissues for a long duration due to the physiological and anatomical eye barriers. Novel delivery systems such as nanoparticles have been explored to enhance the delivery of therapeutic agents to the eye. These delivery systems have in general been assessed using in-vivo animal models, despite ethical concerns for animal wellbeing. The aims of this thesis were to synthesise and characterise four amphiphilic polymers, subsequently prepare and characterise four nano sized polymeric self-assemblies loaded with triamcinolone acetonide (TA), develop an in-vitro porcine eye model and to evaluate the permeation of nano sized self-assemblies using the developed model. Four comb-shaped amphiphilic polymers (Pa5, Pa5-MPEG, Ch5 and Da10) were synthesised with a high yield (>81%) and good reproducibility. These polymers formed spontaneous positive self-assemblies in aqueous media (114-314 nm). The mean hydrodynamic diameters of the positive spontaneous self-assemblies entrapping TA were in the range of 200–334 nm loading high concentrations (455-1263 μg mL-1) of TA, much greater than the TA inherent aqueous solubility or concentrations achieved using conventional solubilisers. A porcine in-vitro eye model was developed to assess drug permeation through anterior and posterior ocular tissues. The model was partially validated using tritiated water and a series of hydrophilic markers with increasing molecular weights. The integrity of porcine ocular tissue was checked by monitoring the permeation of tritiated water to ensure the membrane intactness. Tritiated water permeation at 15 min was exploited as a potential method to normalise drug flux, as tritiated water percentage permeation at 15 min had an inverse relationship with tissue thickness (R2 = 0.66), to reduce the inherent variability between tissue samples thus increasing the accuracy of the in-vitro eye model. Four markers (fluorescein sodium salt, 4, 10 and 20 kDa FITC-dextran) were used for the purpose of investigating the effect of increasing molecular weight on ocular tissue permeability. The permeability of the markers displayed an inverse relationship and abrupt decline with Mw in terms of the permeability through scleral and corneal tissues of human and porcine and the molecular weight of the markers. The developed porcine in-vitro eye model showed good correlation with the human in-vitro model providing strong evidence it can be used to screen potential formulations before testing in-vivo. The TA loaded self-assemblies and a few chemical enhancers (glutamic acid, tween 80, chitosan, Pa5 and elevate temperature (45 °C)), selected to assist drug delivery via two routes (paracellular and transcellular), were tested using the developed in-vitro eye model. The results showed there was no marker permeation enhancement effect in porcine and human ocular tissues using chemical enhancers. In summary, a porcine in-vitro eye model was developed to assess hydrophobic and hydrophilic penetrant permeation across anterior and posterior ocular tissues. The porcine in-vitro eye model showed good correlation with the human in-vitro model providing strong evidence that the porcine in-vitro eye model can be used to screen potential formulations before testing in-vivo using the porcine model which ultimately might correlate well with the in-vivo human responses. Although TA self-assemblies did not significantly increase drug flux through human or porcine scleral tissues, it might be of interest for ophthalmic topically administered formulations due to their positive charge and small nano size.

Microemulsions have gained interest from the pharmaceutical industry due to their ability to co-solubilize hydrophilic and lipophilic drugs, and to provide enhanced drug penetration. In this work, thermosensitive gelatin- and poloxamer 407-stabilized microemulsion-based gels (MBGs) were formulated using alcohol-free, low toxicity and low viscosity lecithin-based linker microemulsions. The addition of gelatin to water-rich bicontinuous microemulsions induced the formation of clear viscoelastic gels containing an oil-rich microemulsion as the gelatin seemed to dehydrate the original microemulsion. The addition of poloxamer 407 to water-continuous microemulsions produced MBGs with different gelation temperatures. High concentrations of lipophilic components in the microemulsion, particularly the oil, reduced sol-gel transition temperature, while hydrophilic components increased sol-gel transition temperature. Gelatin and poloxamer MBGs provided desirable viscoelastic properties for ophthalmic and transdermal applications with minimal impact on the transport properties of the original microemulsions.

Microemulsions have gained interest from the pharmaceutical industry due to their ability to co-solubilize hydrophilic and lipophilic drugs, and to provide enhanced drug penetration. In this work, thermosensitive gelatin- and poloxamer 407-stabilized microemulsion-based gels (MBGs) were formulated using alcohol-free, low toxicity and low viscosity lecithin-based linker microemulsions. The addition of gelatin to water-rich bicontinuous microemulsions induced the formation of clear viscoelastic gels containing an oil-rich microemulsion as the gelatin seemed to dehydrate the original microemulsion. The addition of poloxamer 407 to water-continuous microemulsions produced MBGs with different gelation temperatures. High concentrations of lipophilic components in the microemulsion, particularly the oil, reduced sol-gel transition temperature, while hydrophilic components increased sol-gel transition temperature. Gelatin and poloxamer MBGs provided desirable viscoelastic properties for ophthalmic and transdermal applications with minimal impact on the transport properties of the original microemulsions.