Development of in situ depot forming photocrosslinked implants for sustained protein delivery to the posterior segment of the eye

Abstract

Due to the special anatomical structure of the eye, delivering therapeutic agents to the posterior segment represents a formidable challenge. Intravitreal injection currently stands as the main approach for drug delivery to the posterior segment of the eye. However, frequent injections may cause side effects, including endophthalmitis, haemorrhage, and retinal detachment. Age-related macular degeneration (AMD) and diabetic retinopathy (DR) stand as two of the most visually threatening diseases, commonly managed through intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents. Ocular implants, as one of ocular drug delivery system, has the capacity for sustained posterior segment drug delivery, thereby reducing dosing frequency. Nonetheless, due to pre-formed and non-biodegradable nature, surgical intervention becomes necessary for implantation and subsequent removal.

This study primarily developed solvent-induced in situ-forming depot photocrosslinkable implants (ISFPcls) for sustained release of ovalbumin (OVA) as a model protein to the posterior segment of the eye for a minimum duration of 12 months. The ISPFcls system was based on hydrophobic polymer poly (lactic-co-glycolic acid) (PLGA) and hydrophilic polymer poly (ethylene glycol) diacrylate (PEGDA) with OVA serving as the model protein for the anti-VEGF drug ranibizumab. The photoinitiators Irgacure® 2959 and 819 were employed for crosslinking. ISFPcls, formed due to solvent-induced phase inversion and subsequent photocrosslinking, at 365 nm UV, results in a depot formation which controls therapeutics release over several months. The ISFPcls gel composed of PLGA, PEGDA, OVA, and Irgacure® demonstrated good injectability via a 27-gauge needle and could be formed as an implant in an aqueous environment. The ISFPcls exhibited tailored/ desired properties based on photocrosslinking time and the type of Irgacure® used.

Furthermore, in vitro release studies indicated controllable and sustained release exceeding 12 months, with release rates and burst release being modifiable by varying photocrosslinking time and Irgacure® type. The biodegradability of ISFPcls occurred through hydrolysis, demonstrating biocompatibility with retinal pigment epithelial cells, as assessed. The hen's egg-chorioallantois membrane test (HET-CAM test) results suggested the absence of irritation in both ISFPcls and its released products. Ultimately, filtration was applied to achieve sterile production of the ISFPcls gels. ISFPcls holds significant promise for protein delivery to the posterior segment, particularly for the treatment of visually threatening diseases such as AMD and DR.

Thesis is embargoed until 31 July 2029.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Thakur Raghu Raj Singh (Supervisor), Lalitkumar Vora (Supervisor) & Dimitrios Lamprou (Supervisor)