Paull, DJ; (2012) The biological effects of slow release implantable tablets for the delivery of anti-scarring agents following glaucoma filtration surgery. Doctoral thesis , UCL (University College London).

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Abstract

The scarring response that follows glaucoma filtration surgery (GFS), an incisional surgery aimed at reducing glaucoma-related pressure increases within the eye, often prevents a successful outcome leading to further disease progression. Whilst a number of drugs have been shown to regulate scarring, a number of side effects are also induced largely related to the delivery method. Following on from previous work initiated in the lab whereby drugs (including the cytotoxic drugs, 5-fluorouracil (5-FU) and mitomycin-C (MMC), the anti-vascular endothelial growth factor (VEGF) monoclonal antibody, bevacizumab, and the matrix metalloproteinase inhibitor, ilomastat) had been fabricated into solid, slow release, implantable tablets, a number of questions remained pertaining to their effectiveness within a biological context. Using 5-FU, it was shown that concentrations at which the drug is released from the tablet can inhibit fibroblast activity (such as proliferation) as effectively as when using conventional concentrations for up to a 30 day period. Furthermore, it has been shown, for the first time, how gene expression within healing tissue (in-vivo) is altered upon the application of 5-FU at currently used clinical concentrations. Results from this study indicated that genes involved in apoptosis such as TP53, RelA, Bax, MYC and TXN were downregulated indicative of a response by the cells to limit the effects of apoptosis on tissue exposed to 5-FU. Secondly this thesis focuses on angiogenesis where it was shown that solid-dosage bevacizumab tablets functioned as effectively as bevacizumab solution in-vitro, with excipients of this drug such as trehalose shown to have implications in modulating wound healing. Furthermore, VEGF was shown for the first time to be a positiveregulator of fibroblast activity, such as in its ability to promote matrix metalloproteinase (MMP) production, presenting mechanisms by which anti-VEGF drugs may function to inhibit the wound healing process. Finally this thesis focuses on the effects of exposing cells and tissue to ilomastat, whereby microarray screening was utilised to uncover novel changes in gene expression that both regulate the direct activity of ilomastat, as well as highlight secondary effects of the drug. For example, a dampening of the immune response (such as in the downregulation of IL-1a, IL-6, IL-8, Bip and XBP1) was observed following ilomastat injection. Importantly however, these experiments also highlighted a previously uncharacterised foreign body response that was observed upon implantation of the ilomastat tablet in-vivo, with the widespread upregulation of genes involved in this process observed including TNF, FN1, IL-1β and IL-6. As such, whilst these experiments exposed novel mechanisms through which these drugs function, care will be required in moving forward with the use of such agents and delivery methods to ensure thatmaximum biocompatibility is achieved.

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