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Principal Investigator: NURAN ERCAL
Organization: MISSOURI UNIVERSITY OF SCIENCE & TECHNOLOGY
Fiscal Year: 2019
Award: $387,500
Funding agency: National Eye Institute
Project Summary/ Abstract
Surgery is the only effective treatment for cataract, the most common cause of blindness worldwide. Although
cataract surgery is routine and generally considered safe, it is costly and carries risks of serious complications
(e.g., capsular opacification or rupture). Thus, there is a high demand for an effective topical treatment that can
prevent this debilitating disease. Cataract is caused by the aggregation of lens proteins, which is associated with
accumulated oxidative damage that occurs throughout one’s lifetime. Glutathione (GSH), the most important
endogenous redox regulator, is highly concentrated in the lens and protects against oxidative damage. However,
levels of GSH in the lens decrease with age, leaving the lens vulnerable to oxidative damage. Antioxidants that
can penetrate ocular tissue have the potential to protect the lens proteins and to restore GSH. 2-
Mercaptopropionylglycine (MPG), also known as tiopronin, is a thiol antioxidant drug that appears to exhibit
anticataract activity. However, its ability to penetrate ocular tissues when administered in eye drop form is limited.
To overcome this problem, we will investigate a novel nanodiamond (ND) drug delivery vehicle for ocular
administration of MPG. The reasons for ND use are three-fold: (1) NDs can improve ocular uptake of topically
administered drugs by providing sustained release on the corneal surface, (2) NDs have been shown to enhance
antioxidant activity and suppress photodegradation of the adsorbed molecules, thereby protecting MPG from
premature oxidation and inactivation, and (3) NDs are excellent drug delivery platforms: they are non-toxic and
chemically stable, while also exhibiting large surface area-to-mass and highly tailorable surface chemistry for
optimization of interactions with drugs and tissues at their intended destination.
The project’s long-term goal is to develop a topically applied formulation that can halt or significantly delay
progression of cataracts. The Specific Aims of this proposed research are (1) to determine the optimal surface
chemistry of the novel nanodiamond (ND) drug delivery platform for enhancing corneal penetration of MPG, (2)
to determine whether NDs can preserve or promote the antioxidant efficacy of MPG, and (3) to investigate the
efficacy of NDs for promoting the anticataract effects of MPG in vivo. We will characterize NDs with various
surface chemistries and test their ability to deliver MPG using in vitro models of corneal and lens epithelium. We
will also investigate antioxidant properties and photostability of NDs alone and in complexes with MPG in both
in vitro models. To accomplish the third aim, we will use the Emory mouse, a model of age-related nuclear
cataracts, which will be treated with eye drops containing MPG adsorbed to NDs prior to cataract development.
We will evaluate the ability of ND-MPG eye drops to prevent cataracts by monitoring cataract formation via slit-
lamp microscopy during treatment. Levels of MPG and its metabolite 2-mercaptopropionic acid (MPA), will be
measured in tear fluid and ocular tissues to determine the extent of drug release and penetration. Various
markers of oxidative stress including GSH/GSSG ratio, antioxidant enzyme activities, and lipid peroxidation will
be measured in the ocular tissues to determine if ND improve antioxidant activity of MPG.
Terms: <Abscission><Acids><Address><Adsorption><Age><Americas><Animal Model><Animal Models and Related Studies><Animals><Antioxidants><Area><Blindness><Body Tissues><Cataract><Cataract Extraction><Chemicals><Chemistry><Complex><Cornea><Crystallins><Destinations><Development><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drugs><Ensure><Epithelial><Epithelium><Epithelium Part><Equilibrium><Eugenol><Excision><Exhibits><Extirpation><Eye><Eye Drops><Eyeball><Eyedrops><Formulation><Free Radical Scavenging><GSSG><Gel><Glutathione><Glutathione Disulfide><Goals><Human><In Vitro><Lens Opacities><Lipid Peroxidation><Liquid substance><Measures><Mechanics><Medication><Mercaptans><Mercapto Compounds><Mice><Mice Mammals><Microscopy><Modeling><Modern Man><Monitor><Murine><Mus><Nuclear><Operative Procedures><Operative Surgical Procedures><Oral><Oxidation-Reduction><Oxidative Stress><Oxidized Glutathione><Patients><Penetration><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Pharmacology><Poloxamers><Property><Public Health><Redox><Removal><Reporting><Research><Risk><Rodent><Rodentia><Rodents Mammals><Role><Route><Rupture><Site><Sulfhydryl Compounds><Surface><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Testing><Thiols><Time><Tissues><Topical Drug Administration><Topical application><Vascular blood supply><World Health Organization><age dependent><age related><ages><anterior chamber><anti-oxidant><anti-oxidant enzyme><antioxidant enzyme><balance><balance function><base><biocompatibility><biomaterial compatibility><blood supply><carboxylate><cataract surgery><cataractogenesis><cataractous lenses><common treatment><corneal><corneal epithelial><corneal epithelium><cost><design><designing><developmental><drug/agent><effective therapy><effective treatment><enzyme activity><experiment><experimental research><experimental study><eye chamber><eye preservation><fluid><functional group><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><improved><in vitro Model><in vivo><insight><lens><lens protein><lens transparency><lenses><liquid><mechanical><model of animal><model organism><nano particle><nano-sized particle><nanodiamond><nanoparticle><nanosized particle><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><oxidation><oxidation reduction reaction><oxidative damage><premature><prematurity><preservation><prevent><preventing><resection><residence><residential site><side effect><social role><sulfhydryl group><surgery><theranostics><topical administration><topical delivery><topical drug application><topical treatment><topically applied><uptake><vascular supply><vision loss><visual loss><zeta potential>