School of Therapeutic Sciences (ETDs)
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Item A thermo-responsive scleral device for the management of ocular tumours(University of the Witwatersrand, Johannesburg, 2024) Abdalla, Yosra Mahjoub AhmedSeveral ocular diseases that lead to blindness could benefit from effective treatment delivery to the site of action. Efficacy, however, remains restricted due to the multiple static and dynamic barriers present in the eye, despite substantial study into administration procedures and delivery vehicle. Ocular tumours are a broad group of diseases that range from benign to malignant and that occur in different anatomical regions within the eye. Ocular surface tumours are tumours of the conjunctiva of the eye and are therefore readily accessible for drug delivery. The management of ocular tumours is faced with the challenge of developing a suitable treatment strategy that meets individual patient needs, considering their anatomical location. Foremost is the need to develop strategies with high benefit to risk ratios. This is closely followed by the need to develop therapies that improve patient compliance while limiting the need for frequent hospital visits. Thirdly, the high cost of immune-therapeutic agents currently used for the management such as interferon demands sustained release strategies that deliver the same efficacy from much lower doses. Interferon alpha has been used to treat patients with ocular tumours for decades; however, its short half-life and poor tolerability necessitate frequent administration. This novel study employed a pH responsive/protective nanoparticle embedded into a thermo-responsive hydrogel for site-specific IFN-α2b delivery in the treatment of ocular tumours. Loading the IFN-α2b in a hydrogel isolates the drug from the releasing medium; the inclusion of core-shell nanoparticles increases the loading capacity of the drug and provided pH-responsiveness to the acidic tumour microenvironment, protecting the entrapped drug. As a result, the concentration gradient is reduced and the release pathway extended, furthermore, shielding the IFN-α2b against rapid clearance, and degradation at lower pH of the tumour microenvironment. Nano-embedded thermo-responsive hydrogel were prepared and their physiochemical properties, thermo-responsive behaviour, pH-responsiveness, in vitro and in vivo release and toxicity were evaluated. Fourier transform infrared (FTIR), 1H–nuclear magnetic resonance (1H-NMR), and X-ray powder diffraction (XRPD) analysis confirmed the synthesis of the copolymer. The rheological analysis revealed a sol-gel transition temperature in the range of 26-45°C which was concentration–dependent. A concentration of 20% w/v was selected based on suitability for in vivo application. The surface morphology of the hydrogel was evaluated using scanning electron microscopy (SEM) and porositometric analyser, the SEM images revealed the presence of a mesh-like structure on the surface of the hydrogel. The presence of the pores was further confirm by porositometric analysis. The presence of pores is critical for the diffusion of liquid within the hydrogel, which allows the NP to diffuse out of the hydrogel and release the loaded drug. The formed nanoparticles had particle sizes ranging from 137.1 to 230.6 nm (PDI 0.27–0.137) and zeta potentials ranging from -23.9 to -3.36 mV, demonstrating a pH-responsive controlled release in an acidic medium simulating the tumour environment, with an entrapment efficiency of 89%. The in vitro release studies demonstrated a two-phase release pattern of IFN-α2b and stability of the released IFN-α2b from IFN-α2b nano-embedded PECE hydrogel (IFNPH) for the duration of the study; thus, the IFNPH exhibits pH-protective and temperature-responsive properties. In vitro biocompatibility findings on the human retinal pigment epithelial cell line highlighted that the IFNPH is safe within the tested range of 5000 to 0.625 μg/mL and does not pose any adverse cytotoxic effects. The in vivo studies were performed by administering a single subconjunctival injection of the IFNPH to New Zealand albino rabbits. The pharmacokinetic data revealed that the Cmax of 129.7 pg/mL was reached after 24 hrs (Tmax) in the vitreous humour. The IFNPH delivered biological active IFN-α2b in a sustained manner, compared to eye drops and subconjunctival injection of IFN-α2b solution, thus limiting dosing frequency and enhancing patient compliance. This investigation highlights that the IFNPH is a potential suitable candidate for ocular delivery of IFN-α2b