Lee, KV; (2013) Optimisation and analysis of sustained release drug delivery systems to treat ocular disease. Doctoral thesis , UCL (University College London).

Abstract

Transscleral drug delivery has been a moreviable alternative drug delivery route to the posterior segment than other more invasive methods. The drug absorption involves passing through several layers of tissue, including the sclera and retinal pigment epithelium (RPE), to reach the retina. Posterior scleral thickness in both humans and normal C57BL/6 mice decreases with age. Lipofuscin density in albino mice’s eyes were two-fold higher than in pigmented mice and the drug-binding to these pigments could affect drug bioavailability. Drug molecular weight didn’t correlate with penetration efficiency. The understanding of these factors all contributes to optimising drug delivery. Encapsulating proteins into polylactide-co-glycolide acid (PLGA) microparticles can provide a prolonged, sustained release of an active protein drug. When the microparticles are administered, they could reach the retina and cause macrophage recruitment at low levels within 24 hours. When these microparticles encapsulated with anti-vascular endothelial growth factors were periocularly injected in a rat model of choroidal neovascularisation (CNV), they were able to reduce the size and suppress the growth of the CNV. After successful local delivery to alleviate the wet form of age-related macular degeneration (AMD), vitamin D3, which was cheaper, more easily available and could be self-administered, was used to reduce amyloid β (Aβ) and inflammation associated with dry AMD. Apart from vitamin D3 ’s well-known role in regulating plasma calcium levels, it also affects immune regulation and may protect against aging. Vitamin D3-treated mice showed a significant improvement in retinal function. Vitamin D3 also reduces inflammation in relation to macrophage morphology and numbers, complement C3, Aβ and tumour necrosis factor-α in the Bruch’s membrane and outer segments in the eye. Likewise, it clears Aβ and C3 systemically in the aorta. Vitamin D3 may have a range of therapeutic effects in its immune protective role, and its impact on inflammation may be significant for AMD.

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