Please use this identifier to cite or link to this item:
|Title:||Preactivated Thiomer Mucoadhesive Micelles for Anterior Ophthalmic Drug Delivery|
|Keywords:||Polymers, Biomaterials, Ocular, Drug Delivery, Mucoadhesion, Dry Eye Disease|
|Abstract:||Effective delivery of drugs to the anterior segment of the eye is notoriously inefficient due to the anatomical barriers in place. Topical administration is the most common method of drug delivery to the anterior segment. When applied to the ocular surface, topical solutions encounter barriers such as lacrimal drainage, rapid tear turnover, and reflex blinking which result in < 5% of instilled therapeutic reaching the intended tissue. One potential method to evade some of these anatomical barriers and improve the delivery of therapeutics is the use of mucoadhesive nanoparticles. These materials are designed to encapsulate a relevant ocular therapeutic and provide a means of maintaining the vehicle on the ocular surface by adhering to the mucin layer of the tear film. To this end, the work presented herein describes the design, characterization, and testing of a novel mucoadhesive polymeric nano-micelle ocular drug delivery system. The base polymer used was selected from a system that has been previously used in the Sheardown Lab. It was composed of poly(D,L-lactide)-block-poly(methacrylic acid-co-3-(acrylamido)phenylboronic acid) (PLA-b-P(MAA-co-3-AAPBA); LMP-20). The formulation was modified to replace the 3-AAPBA monomer, which contains phenyl boronic acid as the mucoadhesive component, with a preactivated thiol monomer (pyridyl disulfide ethyl methacrylate; PDSMA) to generate a novel polymer (LMS-20) to investigate the potential for drug incorporation and mucoadhesion. Modifications of the polymer were made with small thiol molecules cysteamine (Cys; LMC-20), glutathione (GSH; LMG-20), and N-acetyl cysteine (NAC; LMA-20) with a goal of reducing cytotoxicity associated with the 2-pyridinethione leaving group. Synthesis of the PDSMA monomer, LMS-20 and LMP-20 polymers, and modified polymers LMC-20, LMG-20, and LMA-20 were confirmed by 1H NMR. LMA-20 was chosen for further examination as it contained the most relevant thiol modification for ocular applications and was capable of nanoprecipitation to form aqueous micelles with previously developed methods. Micelles were formed from LMA-20 and LMP-20, with spherical morphology as confirmed by TEM. Effective diameters of 64 ± 5 nm and 72 ± 3 nm are reported for LMA-20 and LMP-20, respectively, as confirmed by DLS. Critical micelle concentration for LMA-20 of 217 mg/L was found via a pyrene fluorescence study, significantly lower than the concentration of intended application. LMA-20 and LMP-20 are predicted to be mucoadhesive based on results of zeta-potential studies. However, oscillatory rheology studies were inconclusive based on a negative rheological synergism. LMA-20 micelles loaded with 0.16% (w/w) Cyclosporine-A were able to provide sustained release of drug up to 3 days in vitro. These results suggest the possible future use of these preactivated thiomer-based materials for the delivery of therapeutics to the anterior segment.|
|Appears in Collections:||Open Access Dissertations and Theses|
Files in This Item:
|Goostrey_Taylor_C_202105_MASc.pdf||2.48 MB||Adobe PDF||View/Open|
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.