Degree

Doctor of Philosophy (PhD)

Department

Biological and Agricultural Engineering

Document Type

Dissertation

Abstract

Advantages of polymeric nanoparticles as ocular drug delivery systems include controlled release, enhanced drug stability and bioavailability, and specific tissue targeting. Nanoparticle properties such as hydrophobicity, size, and charge, mucoadhesion, as well as administration route and suspension media affect their ability to overcome ocular barriers and distribute in the eye, and must be carefully designed for specific target tissues and ocular diseases. A review was conducted to serve as a guide to optimizing polymeric nanoparticle delivery systems for ocular drug delivery by discussing the effects of nanoparticle composition and administration method on their ocular penetration, distribution, elimination, toxicity, and efficacy, with potential impact on clinical applications.

Spatiotemporal distribution of polymeric nanoparticles in the eye as well as the physical stability of the nanoparticles in an ophthalmic formulation and thermal stability of the entrapped drug are critical regarding applicability of polymeric nanoparticles for drug delivery in the eye. To investigate these characteristics, Cy5-labeled, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (z-potential: -14.1±1.5 mV, size: 241.7±0.6 nm) and lutein-loaded PLGA nanoparticles (z-potential: -6.7±0.3 mV, size: 210.6±3.3 nm) were synthesized, and their stability and biodistribution were assessed. Lutein-loaded nanoparticles were stable at 4°C without significant changes in size and morphology, without significant lutein degradation, and 26% was released after 5 weeks in suspension. In contrast, lutein-loaded nanoparticles stored at 25°C and 37°C experienced significant changes in size, likely due to aggregation and surfactant dissociation; these nanoparticles showed signs of bulk degradation based on TEM, and had significant lutein degradation and over 40% release after 5 weeks. Lutein loaded in nanoparticles was more resistant to photodegradation compared to a free lutein solution when exposed to UV for 6 h, degrading 5 times slower than free lutein. To test the performance of nanoparticle therapeutics in vivo, Cy5-labled nanoparticles were applied topically to the eyes of rats and incubated for 15 min, 30 min, or 60 min in vivo. Exterior eye tissues including the cornea, episcleral tissue, and sclera showed the highest fluorescence intensity in animals that received fluorescent nanoparticles, while the choroid was the only inner eye tissue that was significantly higher in a treatment group compared to the control group. Additionally, decreases of fluorescence in all exterior eye tissues and the choroid between 30 min and 1 h indicated rapid elimination of nanoparticles from the eye.

Antioxidant therapies are of interest in the prevention and management of senile cataracts, however the delivery of antioxidants to the lens is complicated by anatomical barriers and lack of direct blood supply. Polymeric nanoparticles are a potential solution, as they can potentially penetrate the eye and carry otherwise unstable antioxidants such as lutein to targets within the eye. In this study, we investigated the ability of topically administered, lutein-loaded nanoparticles for attenuating the development of selenite-induced cataracts in rats. To enhance the corneal retention time and reduce elimination by lacrimal fluids, nanoparticles were embedded in a thermosensitive hydrogel which solidifies upon contact with the cornea. Among several nanoparticle formulations tested, animals treated with lutein-loaded PLGA nanoparticles at a lutein concentration of 1,278 µg/mL showed the greatest decrease in selenite-induced cataract severity compared other treatment groups and untreated animals. Future tests are warranted in larger animal models to support the hypothesis that topical application of lutein-loaded polymeric nanoparticles is an effective cataract prevention therapy.

Committee Chair

Sabliov, Cristina

DOI

10.31390/gradschool_dissertations.5329

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