The Development of Nanoparticle Formulations for NAD+ Delivery Towards the Prevention of Age-Related Ocular Diseases

Casey-Power, Saoirse (2024) The Development of Nanoparticle Formulations for NAD+ Delivery Towards the Prevention of Age-Related Ocular Diseases. Doctoral thesis, SETU Waterford.

Text Final Completed PhD Thesis - Saoirse Casey-Power (30 May 2024).pdf Download (62MB)

Abstract

The decline in intracellular nicotinamide adenine dinucleotide (NAD+) is a critical risk factor for numerous neurodegenerative ocular diseases such as age-related macular degeneration, glaucoma, diabetic retinopathy, and dry eye. Such loss results in mitochondrial dysfunction, irreversible cellular damage and increased visual impairment. Ocular diseases are typically treated at the mid to late stages of their pathogeneses, which typically coincides with the development of debilitating visual conditions. As the eye itself contains numerous static and dynamic anatomical barriers, the efficacy of conventional ocular drug delivery systems (ODDs), such as eye drops and ointments, is limited by low therapeutic bioavailability at the target site, primarily attributed to poor ocular retention and intraocular clearance mechanisms. Such treatments are often administered frequently, presenting further challenges such as poor patient compliance and sporadic dosing, which can result in increased delocalised therapeutic absorption. Treatment options such as intravitreal injections offer enhanced bioavailability at the intraocular target site. However, continuous subjection to invasive surgical procedures poses the risk of adverse complications, such as vitritis, increased intraocular pressure, and retinal haemorrhaging . This research aims to develop and characterise a non-invasive nanomaterial formulation composed of polyelectrolyte biomaterials for the intraocular delivery of NAD+, as a means of upregulating cellular longevity and minimising deleterious ageing effects on ocular health. NAD+-associated hyaluronic acid (HA) and poly(L-lysine) (PLL) polyelectrolyte complexes (PECs), and chitosan and NAD+ complexes (CH-NAD+) were formulated via polyelectrolyte complexation/ ionotropic gelation in aqueous medium. The biopolymers were chosen based on their inherent biocompatibility, tunable charge densities, mucoadhesive capabilities and biodegradation profiles. Critical evaluations of the physicochemical attributes of the formulations for suitability for ocular application were conducted, with formulations exhibiting optimal sizes, surface charges, and NAD+ association efficiencies (AE) being selected for further in vitro release and stability studies. Under microfluidic conditions, NAD+ is released in a sustained manner from the respective formulations over 24 hours, thus indicating their suitability as a depot for NAD+ ocular delivery on a once or twice-daily basis. Assessment of their physiochemical behaviour in solutions mimicking that of the ocular environment in vivo highlighted the susceptibility of the formulations to changes in environmental stimuli, confirming that the final form of the nanomaterials would be a governing factor of long-term formulation stability.In vitro and ex vivo safety and efficacy assessments using porcine ocular tissues and immortalised human corneal epithelial cells confirmed that the association of NAD+, particularly to the PECs, resulted in formulations with high cytocompatibility that could attenuate oxidative stress-mediated damage upon successful internalisation into the intracellular environment over 24 hours. The screening of poly (lactic-co-glycolic acid (PLGA) and lipid-based nanoformulations, initially investigated as depots for the more targeted delivery of NAD+ to the posterior segment, highlighted the suitability of NAD+-laden liposomes for the intended application, primarily based on their physiochemical attributes. However, due to the high degree of variability observed in the in vitro release profile of this formulation under microfluidic conditions, this formulation will be subject to further investigations to improve the lipid later stability and NAD+ retention during release. Ultimately, this research project details, for the first time, the development of an NAD+-laden nanoformulation for supplementary treatment of the ocular surface. Outcomes from this research provide justification to conduct future work on extensive in vitro efficacy trials to assess the ability of the formulations to prevent mitochondrial damage and promote cellular respiration, with more emphasis being placed on the pharmacokinetic and cellular internalisation mechanisms.

Item Type:	Thesis (Doctoral)
Uncontrolled Keywords:	Nanoparticle Formulations, Age-Related Ocular Diseases
Departments or Groups:	Pharmaceutical and Molecular Biotechnology Research Centre
Divisions:	School of Science > Department of Chemical and Life Sciences
Depositing User:	Derek Langford
Date Deposited:	25 Jul 2024 13:55
Last Modified:	25 Jul 2024 13:55
URI:	https://repository.wit.ie/id/eprint/7820

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