Glaucoma is a leading cause of visual impairment and blindness in the world. Long-term maintenance of low intraocular pressure (IOP) levels is the only proven solution among glaucoma patients for preventing or reducing progressive vision loss. The objective of this project is to develop an advanced topical delivery system to increase the ocular bioavailability and to sustain therapeutic efficacy as a means of reducing patient noncompliance, the leading problem in glaucoma therapy. We have developed a novel hybrid dendrimer hydrogel nanoparticle platform (HDNP), which can be fabricated into an ophthalmic hydrogel formulation to deliver both hydrophilic and hydrophobic antiglaucoma drugs. One-time topical instillation brings about sustained IOP-lowering effect for 4 days. This hybrid platform has adaptable structure and properties, making possible fine-tuning of drug release kinetics and dose regimen for optimal and personalized treatment. The central hypothesis of this grant application is that a topically applied nanoparticle formulation capable of sustaining IOP reduction for one week after single dosing can be developed using copper-free click chemistry and our novel HDNP platform. To test this hypothesis, we propose the following three aims.
Aim 1 : To develop clickable dendrimer hydrogel and HDNP (cHDNP) with enhanced mucoadhesion, enhanced cell entry, and reduced cytotoxicity. We will develop a novel, highly efficient clickable dendrimer hydrogel by avoiding photoinitiator use and generation of harmful free radicals. We will structurally and compositionally optimize hybrid nanoparticles for enhanced mucoadhesion, enhanced cell entry, and reduced cytotoxicity.
Aim 2 : To determine whether cHDNP enhances and sustains drug exposure in eye tissues for one week after single topical administration. Timolol maleate, a widely used antiglaucoma drug, a potent noncardioselective ?-adrenoceptor blocking agent, will be used as a model drug. We will determine whether uptake and/or retention of the nanoparticles/drug is enhanced in eye tissues by cHDNP using a rabbit model. Furthermore, we will determine whether nanoparticle entry into the subconjunctival space contributes to sustained drug delivery.
Aim 3 : To determine whether cHDNP exerts sustained drug efficacy in vivo with once a week topical administration, without exerting any adverse effects on the eye. We will initially identify a cHDNP formulation capable of sustained, statistically significant reduction of IOP in a normotensive rabbit model and a chronic ocular hypertensive rat model following repeated administrations. Safety studies will also be conducted in rat and rabbit models. Developing long-acting antiglaucoma drug dosage formulations represents an unmet clinical need for improving long-term patient compliance. The proposed topical nanoparticle system has great promise in sustaining drug delivery and antiglaucoma effects longer than existing topical formulations. Such a system will profoundly improve patient compliance and adherence and reduce health care costs and societal burdens associated with glaucoma treatment.

Public Health Relevance

The objective of this project is to develop an advanced topical delivery system to increase the ocular bioavailability and to sustain therapeutic efficacy as a means of reducing patient noncompliance, the leading problem in glaucoma therapy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024072-03
Application #
9090184
Study Section
Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section (BNVT)
Program Officer
Liberman, Ellen S
Project Start
2014-09-30
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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