Abstract

A rate limiting step in the development of therapeutic agents for treating diabetic retinopathy is retinal drug delivery. Although intravitreal injections allow significant drug delivery to the retina, repeated intravitreal injections can lead to endophthalmitis and retinal detachment. Therefore, alternative routes of administration are currently being investigated. Transscleral retinal drug delivery is one such approach. We hypothesized that the eye pigment reduces the extent of transscleral retinal drug delivery in vivo, with the reduction in delivery being greater for drugs with higher melanin binding. Further we hypothesized that diabetes increase transscleral drug delivery to the retina in vivo, due to leakier barriers. The above hypotheses will be assessed at a mechanistic level under two specific aims.
Aim 1 will investigate the mechanisms of drug interaction with melanin and determine influence of eye pigmentation on transscleral retinal drug delivery.
Aim 2 will correlate leakiness of blood-retinal barriers in diabetic animal models to transscleral retinal drug delivery. This study will investigate widely used model solutes with high and low melanin binding in conjunction with two antiinflammatory agents that are relevant for treating diabetic retinopathy. Both pigmented (Brown Norway) and non-pigmented (Sprague Dawley) rats with and without streptozotocin induced diabetes will be employed in this study. The findings of this study will be useful in developing drugs with enhanced transscleral delivery to the retina in order to treat diabetic retinopathy.

Public Health Relevance

Diabetic retinopathy, afflicting the retina of the eye, is a leading cause of vision loss. This study is advancing a drug administration approach that is safer than the intravitreal injections that are currently used for retinal drug delivery. Further, by investigating the influence of eye pigment as well as the state of diabetes on delivery of various drugs to the retina, this study will provide a new basis for drug selection in treating diabetic retinopathy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY017533-04A2
Application #
7388644
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Shen, Grace L
Project Start
2009-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$397,828
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Panda, Jiban J; Yandrapu, Sarath; Kadam, Rajendra S et al. (2013) Self-assembled phenylalanine-?,?-dehydrophenylalanine nanotubes for sustained intravitreal delivery of a multi-targeted tyrosine kinase inhibitor. J Control Release 172:1151-60
Yandrapu, Sarath; Kompella, Uday B (2013) Development of sustained-release microspheres for the delivery of SAR 1118, an LFA-1 antagonist intended for the treatment of vascular complications of the eye. J Ocul Pharmacol Ther 29:236-48
Kadam, Rajendra S; Williams, Jason; Tyagi, Puneet et al. (2013) Suprachoroidal delivery in a rabbit ex vivo eye model: influence of drug properties, regional differences in delivery, and comparison with intravitreal and intracameral routes. Mol Vis 19:1198-210
Tyagi, Puneet; Barros, Matthew; Stansbury, Jeffrey W et al. (2013) Light-activated, in situ forming gel for sustained suprachoroidal delivery of bevacizumab. Mol Pharm 10:2858-67
Kadam, Rajendra S; Ramamoorthy, Preveen; LaFlamme, Daniel J et al. (2013) Hypoxia alters ocular drug transporter expression and activity in rat and calf models: implications for drug delivery. Mol Pharm 10:2350-61
Kompella, Uday B; Amrite, Aniruddha C; Pacha Ravi, Rashmi et al. (2013) Nanomedicines for back of the eye drug delivery, gene delivery, and imaging. Prog Retin Eye Res 36:172-98
Scheinman, Robert (2013) NF-?B and Rheumatoid Arthritis: Will Understanding Genetic Risk Lead to a Therapeutic Reward? For Immunopathol Dis Therap 4:93-110
Kadam, Rajendra S; Vooturi, Sunil K; Kompella, Uday B (2013) Immunohistochemical and functional characterization of peptide, organic cation, neutral and basic amino acid, and monocarboxylate drug transporters in human ocular tissues. Drug Metab Dispos 41:466-74
Malik, Pradip; Kadam, Rajendra S; Cheruvu, Narayan P S et al. (2012) Hydrophilic prodrug approach for reduced pigment binding and enhanced transscleral retinal delivery of celecoxib. Mol Pharm 9:605-14
Vooturi, Sunil K; Kadam, Rajendra S; Kompella, Uday B (2012) Transporter targeted gatifloxacin prodrugs: synthesis, permeability, and topical ocular delivery. Mol Pharm 9:3136-46

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