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PhD thesis_Madhuri Dandamudi.pdf

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Age-related Macular Degeneration (AMD) is a disease of the back of the eye and the most common cause of vision loss in elderly people. Existing therapies involve repeated intravitreal injections with poor patient compliance, which can be associated with serious side effects such as retinal detachment and haemorrhage. In light of the need for the development of a non-invasive treatment option for AMD, this study aims to develop a topically applied nanoparticulate system encapsulating a corticosteroid and a flavonoid for extended drug release. Triamcinolone acetonide (TA)-loaded chitosan-coated poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were fabricated using the thin-film hydration and oil-in-water emulsion techniques and characterized to assess their suitability. The particle size of uncoated and coated PLGA NPs fabricated using thin-film hydration ranged from 411 nm to 456 nm, with an encapsulation efficiency of 63%. The zeta potential of PLGA NPs was -4.10 mV increasing to +44.05 mV upon chitosan coating, indicating the formation of stable NPs with polydispersity indices ranging from 0.08 to 0.19. In-vitro TA release from the NPs was 28% in 32 hours, subsequently reaching a plateau, suggesting controlled release of the drug. An emulsion formulation technique was also used to optimize the chitosan-coated PLGA NPs encapsulating TA, using the Box-Behnken response surface statistical design. The optimized surface-modified NPs were stable with a particle size of 334 to 386 nm, PDI between 0.09 and 0.15 and zeta potential between +26 mV and +33 mV. These NPs encapsulated 55% – 57% of TA and displayed a controlled release of the drug that reached a plateau in 27 h. Different pathological conditions were simulated using ARPE-19 cells and exposed to various concentrations of TA and quercetin (QCN), in an attempt to investigate their potential for the treatment of AMD. The concentrations utilised were non-toxic on ARPE-19 cells and showed no signs of synergetic toxicity and changes in morphology of the cells (with cell viability >80%). The ARPE-19 cells treated with combination decreased the cytokines expression by 3.4, 5.2, 1.7, and 2.2 folds for IL-6, IL-8, MCP-1, and VEGF-C, respectively, indicating the anti-inflammatory and anti-VEGF effects. The combination drugs exhibited a synergetic antioxidant effect compared to the individual treatments (P <0.05). Investigated dual drugs were successfully encapsulated into the optimised NPs. Future work will focus on investigating the stability and transport of the dual drug-loaded NPs in in-vitro and ex-vivo conditions. The size of the NPs in conjunction with the biodegradable and biocompatible properties of the polymers suggest these particles might be promising for topical ocular drug delivery.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Ocular drug delivery
Departments or Groups: Pharmaceutical and Molecular Biotechnology Research Centre
Divisions: School of Science > Department of Chemical and Life Sciences
Depositing User: Derek Langford
Date Deposited: 09 Jun 2023 14:29
Last Modified: 09 Jun 2023 14:29

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