Polymeric transfection agents for drug delivery to treat retinal damage and disease

Thareja, Abhinav ORCID: 0000-0003-1288-5566 (2025). Polymeric transfection agents for drug delivery to treat retinal damage and disease. University of Birmingham. Ph.D.

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Abstract

Diseases and damage in the posterior segment tissues of the eye mainly the retina-choroid and the optic nerve such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and traumatic optic neuropathy (TON) together constitute the biggest incidence of irreversible blindness globally due to their neurodegenerative nature. Current clinical management approaches of such diseases involve frequent intravitreal injections which besides being uncomfortable, can also cause serious complications, and thus lead to low compliance and a huge cost burden on health systems. The aim of this thesis was to overcome this challenge using non-invasive and minimally invasive prolonged acting sustained-release ocular drug delivery technologies based on biodegradable and biocompatible polymers to achieve a therapeutic bioavailability in the posterior segment and possibly deliver neuroprotective drugs. This aim was approached using two different platforms – a topical eye-drop formulation containing penetration enhancing agents (PEAs) to increase the permeability of an anti-inflammatory glucocorticoid dexamethasone sodium phosphate (DSP) across the defensive barriers of eye, and a sustained-release intravitreal depot-forming system using microspheres to deliver endogenous neuroprotective antioxidants. The PEAs included a novel polyacetylene (pAc) polymer synthesised in-house and we compared it with two previously described cell penetrating peptide (CPP) based PEAs, TAT and penetratin, with respect to increasing transcorneal permeability of dexamethasone in an ex-vivo model of porcine cornea, and also tested them for their toxicity both ex-vivo by immunofluorescent staining of tight junctions in corneal epithelium and in-vitro cytotoxicity in a cell line of human retinal epithelium. A significant increase of up to 5-7 times in the transcorneal permeability of DSP in formulation with PEAs was observed after 60 minutes. It was also established that the PEAs cause no damage to the barrier integrity of the defensive barrier ex-vivo and are also very well tolerated in-vitro in cell cultures. Second, the in-vivo efficacy of poly(lactic-co-glycolic acid) (PLGA) microspheres containing small-molecule endogenous antioxidants vitamin-E (VE) and melatonin (MEL), and dexamethasone (DEX) in different combinations, to provide neuroprotection and regeneration was tested in an optic nerve crush (ONC) model of degenerative TON in rats. Retinal ganglion cell (RGC) survival, and glial activation of astrocytes, Müller cells, and microglia in the retinas, and axonal regeneration in the optic nerves in immunostained tissue sections was measured 21 days post injury. It was observed that none of the formulations could provide neuroprotection to RGCs and instead exacerbated their degeneration and also increased the inflammatory response of the injury in the retina. However, VE containing formulations promoted axonal regeneration in the optic nerve, non-significantly, due to independent pathways involved in RGC survival and axonal regeneration. This was due to the inability of slow-release formulations to cope with the rapidly developing pathophysiology of the model characterised by exponential RGC loss very early in the injury. Overall, the topical drug delivery technology could potentially be used to achieve a significantly higher intraocular therapeutic bioavailability after topical eye drop administration, than currently afforded, whilst the intravitreal PLGA platform need to be tested as a pre-treatment in milder models of neurodegeneration for neuroprotective efficacy.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Ahmed, Zubair UNSPECIFIED orcid.org/0000-0001-6267-6442 Blanch, Richard UNSPECIFIED orcid.org/0000-0002-6142-3280 Fernandez-Trillo, Francisco UNSPECIFIED orcid.org/0000-0002-6680-5683 Alvarez-Lorenzo, Carmen UNSPECIFIED orcid.org/0000-0002-8546-7085 Hughes, Helen UNSPECIFIED orcid.org/0000-0002-5939-2323 Hakkarainen, Jenni UNSPECIFIED orcid.org/0000-0002-2528-7525 Herrero-Vanrell, Rocio UNSPECIFIED orcid.org/0000-0001-9764-7975
Licence:	All rights reserved
College/Faculty:	Colleges > College of Medicine and Health
School or Department:	Institute of Inflammation and Ageing
Funders:	European Commission
Subjects:	Q Science > Q Science (General) R Medicine > RE Ophthalmology R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica
URI:	http://etheses.bham.ac.uk/id/eprint/16261

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