Currently there are no approved pharmacological approaches to prevent or delay diabetic retinopathy, a leading cause of blindness in the USA. Transscleral drug delivery is considered a new revolution in retinal drug delivery. While transscleral delivery has resulted in substantially greater retinal delivery compared to the systemic route, the extent of delivery is marginal. Further, the drug properties suitable for transscleral delivery and the barriers to transscleral delivery are not well understood. Thus, transscleral drug delivery is still in its infancy and it requires the development of better drugs with enhanced delivery for effective treatment of retinal complications of diabetes in humans. Our earlier studies indicated inefficient transscleral retinal delivery of a highly lipophilic drug, celecoxib, in pigmented animals compared to albino animals. This is due to non- productive binding of celecoxib in the pigmented choroid layer. These differences are further aggravated with sustained drug delivery, which is critical for treating diabetic retinopathy. Celecoxib has therapeutic potential in treating diabetic retinopathy. This project will test the hypothesis that transscleral retinal delivery and efficacy of highly lipophilic drugs can be enhanced by their polar prodrugs with reduced pigment binding. Since the use of a series of structurally related molecules allows us to more readily identify critical drug properties beneficial in delivery across barriers, this study will assess transscleral permeability for a series of prodrugs of celecoxib across various barriers including sclera-choroid-RPE. Further, using a series of celecoxib derivatives, another purpose of this study is to demonstrate that in vitro solute permeability across sclera-choroid-RPE correlates with in vivo drug delivery to the retina. Also, this study will identify a celecoxib prodrug with superior efficacy. Finally, the principles learned from celecoxib prodrugs will be extrapolated to three other model lipophilic drugs, budesonide, ruboxistaurin, and nimesulide. These drugs are of potential therapeutic value in treating diabetic retinopathy. This approach would allow us to validate the principles learned from a series of celecoxib prodrugs and to further translate and generalize the concepts. These hypotheses and related objectives will be assessed using the following four specific aims: 1) To determine the celecoxib chemical derivatives beneficial for enhancing transscleral drug transport. 2) To determine the usefulness of sclera-choroid-RPE permeability in predicting in vivo delivery of a series of chemically related celecoxib prodrugs. 3) To determine whether celecoxib derivatives with enhanced transscleral delivery exert greater efficacy. 4) To determine whether polar prodrugs enhance the delivery and efficacy of three other lipophilic drugs with potential application in the back of the eye. In addition to drug lipophilicity, this study will correlate other parameters including tissue and melanin pigment binding and prodrug bioconversion rates to transscleral drug delivery. This study will assess polymeric microparticulate systems encapsulating drug or permeable prodrugs of four drugs for their efficacy in diabetic rats. Besides developing transscleral drugs/prodrugs of therapeutic value in treating diabetic retinopathy, the significance of this study is that the drug properties identified for enhanced transscleral delivery can guide drug design for treating diabetic retinopathy as well as other retinal disorders.

Public Health Relevance

Currently there are no approved pharmacological approaches to prevent or delay diabetic retinopathy, a leading cause of blindness in the USA. Transscleral drug delivery is considered a new revolution in retinal drug delivery. While transscleral delivery has resulted in substantially greater retinal delivery compared to the systemic route, with some beneficial effects in diabetic retinas, the extent of delivery is still very low. The significance of this study is that the drug properties identified for enhanced transscleral delivery can guide drug design for treating diabetic retinopathy as well as other retinal disorders. Further, this project will identify new drugs for treating diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018940-03
Application #
8244512
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Shen, Grace L
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$396,348
Indirect Cost
$121,382
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Rajashekhar, Gangaraju; Shivanna, Mahesh; Kompella, Uday B et al. (2014) Role of MMP-9 in the breakdown of barrier integrity of the corneal endothelium in response to TNF-?. Exp Eye Res 122:77-85
Kim, Stephen J; Toma, Hassanain; Shah, Rohan et al. (2014) The safety, pharmacokinetics, and efficacy of intraocular celecoxib. Invest Ophthalmol Vis Sci 55:1409-18
Chowdhury, Sushovan; Guha, Rajdeep; Trivedi, Ruchit et al. (2013) Pirfenidone nanoparticles improve corneal wound healing and prevent scarring following alkali burn. PLoS One 8:e70528
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
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
Bargagna-Mohan, Paola; Deokule, Sunil P; Thompson, Kyle et al. (2013) Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis. PLoS One 8:e63881
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
Dhanda, Devender S; Tyagi, Puneet; Mirvish, Sidney S et al. (2013) Supercritical fluid technology based large porous celecoxib-PLGA microparticles do not induce pulmonary fibrosis and sustain drug delivery and efficacy for several weeks following a single dose. J Control Release 168:239-50
Baid, Rinku; Upadhyay, Arun K; Shinohara, Toshimichi et al. (2013) Biosynthesis, characterization, and efficacy in retinal degenerative diseases of lens epithelium-derived growth factor fragment (LEDGF1-326), a novel therapeutic protein. J Biol Chem 288:17372-83
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

Showing the most recent 10 out of 23 publications