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|Title:||Self-assembled nanogels of hydrophobized methylcellulose|
|Abstract:||Topical administration is the most common method to deliver ocular therapeutics. However, the eye is highly resistant to foreign substances and its clearance mechanisms effectively remove drug, significantly limiting the efficiency of common topical formulations. In the search for improved ocular bioavailability, particle based delivery systems have arisen as a promising strategy to overcome these limitations while retaining the patient friendly aspects of topical formulations. Nanoparticles can be formed via the self-assembly of amphiphilic molecules into nano-sized aggregates consisting of hydrophilic networks crosslinked with hydrophobic domains and referred to as “nanogels”. The work presented in this thesis focuses on the design, synthesis and optimization of novel nanogels ultimately intended to improve the efficiency of the delivery of therapeutics to the eye. Methylcellulose, a hydrophilic, non-toxic and biodegradable natural biomaterial, has been extensively investigated for biomedical applications, including ocular applications, and was therefore the polymer of choice for the work. We first describe the synthesis of nanogels via self-assembly of methylcellulose (MC) hydrophobized with side chains of poly(N-tert-butylacrylamide) (MC-g-PNtBAm), and demonstrate that their properties can be tuned by adjusting the degree of hydrophobic grafting (Chapter 2). The results show the formation of stable monodispersed spherical particles of ~140 nm, presenting good cytocompatibility with human corneal epithelium cells. The impact of the methylcellulose molecular weight on the nanogel properties is investigated and the results demonstrate that the polysaccharide backbone length provides another lever to tailor the performances of the nano-aggregates as drug delivery systems (Chapter 3). These materials show the ability to encapsulate dexamethasone with an efficiency superior to 95% and release their payload for over 30 days. Phenylboronic acid (PBA) functionalization is introduced on the surface of the nanogels to improve their mucoadhesiveness and thereby prolong their residence time on the surface of the eye (Chapter 4). Dexamethasone release from the grafted particles is maintained over 12 days, with the results indicating that the additional PBA layer reduce the initial burst. In terms of mucoadhesion, zeta-potential measurements suggest interaction of some nanogel formulations with mucin. Finally, the surface of the nanogels is covered with chains of poly(ethylene glycol) (PEG) and the effect of PEGylation on the pharmacokinetics and mucoadhesive properties is studied (Chapter 5). PEG functionalization is found to significantly slow the release of dexamethasone phosphate from 1 day to over 8 days, and zeta-potential results also suggest coverage-dependant mucoadhesive properties. These materials show promise for the delivery of drugs to the anterior segment of the eye.|
|Appears in Collections:||Open Access Dissertations and Theses|
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