Drug delivery strategies to overcome ocular hypertension

Glaucoma, a group of ocular diseases that cause optic nerve damage and vision loss, is the second leading cause of irreversible blindness worldwide. Current treatments, primarily eye drops, require frequent administration due to natural tear fluid turnover and blinking, which reduces patient compliance and can lead to complications, such as blurred vision and systemic toxicity. To address these limitations, this thesis explores two innovative drug delivery strategies using anti-glaucoma drug-rich nanoparticles, called colloidal drug aggregates (CDAs). The first strategy involves a periocular hydrogel-nanoparticle composite designed for sustained, local delivery to the eye. Timolol prodrugs, synthesized to self-assemble into CDAs, were developed to avoid the systemic spikes in drug concentration associated with conventional timolol eye drops. Of the synthesized prodrugs, timolol palmitate displayed the most promising in vitro release profile over 28 days and was therefore tested in subsequent in vivo experiments. When dispersed in an in situ gelling hyaluronan-oxime hydrogel and injected into the subconjunctival space of the rat eye, the timolol palmitate CDA-hydrogel composite maintained an intraocular pressure-lowering effect for up to 49 days—far longer than the 6 hours achieved with conventional timolol maleate. This approach also significantly reduced systemic exposure, thereby minimizing potential side effects. The second strategy utilizes a co-delivery system of ionizable drug nanoparticles (IDNPs) that encapsulate both an ionizable colloid-forming small-molecule drug and an siRNA therapeutic, thereby simultaneously targeting multiple pathways implicated in glaucoma. Similar to conventional lipid nanoparticles, netarsudil was co-formulated with an siRNA to form IDNPs. By testing a series of formulations, the 45:5 molar ratio of netarsudil to SM-102, a highly potent ionizable lipid, was chosen to encapsulate an siRNA therapeutic based on its balance of drug loading efficiency and lipid excipient usage. Netarsudil/SM-102 nanoparticles showed dose-dependent uptake driven by apolipoprotein E adsorption and maintained the biological activity of netarsudil in vitro. The therapeutic potential of these IDNPs was tested in a fibrotic model with human trabecular meshwork cells, where they effectively reduced connective tissue growth factor expression—a marker of fibrosis. These strategies provide enhanced drug delivery through prolonged release or co-delivery, offering promising alternatives for the management of chronic ocular hypertension.

Department dc:contributor.department

Chemical Engineering Applied Chemistry

Year dc:date.issued

2025

Author dc:creator

• Dang, Mickael

Advisor dc:contributor.advisor

• Shoichet, Molly S

• Colloidal Drug Aggregates
• Drug Delivery
• Glaucoma
• Hydrogel
• Intraocular Pressure
• Long-Acting

Handle dc:identifier.uri

https://hdl.handle.net/1807/152279

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/152279