This study proposes subconjunctivally injectable biodegradable nano- and micro-particles to sustain the delivery of budesonide, a corticosteroid, to the posterior segment of the eye for a few months. The concept of continuous delivery of ultra-low amounts of budesonide to the posterior segment of the eye will significantly advance the therapy of disorders associated with difficult to reach tissues such as choroid, retina, and vitreous. Budesonide, a very potent corticosteroid with high local activity, low systemic activity, and vascular endothelial growth factor (VEGF)-inhibitory activity, is likely to find application in treating multiple inflammatory, proliferative, and neovascular disorders of the eye. The proposed study will enable the PI to begin establishing his research with this promising new therapeutic agent for ocular therapies. In this study, budesonide particles will be prepared using poly(lactic-co-glycolic acid) (PLGA), a biodegradable polymer that has been used in surgical sutures for over 30 years. The proposed research on subconjunctival budesonide-PLGA particles for prolonged budesonide delivery is likely to advance the delivery of other therapeutic agents targeted to the posterior segment. The objective of this study is to test the hypothesis that subconjunctival injection of budesonide-PLGA particles will sustain budesonide delivery to the posterior segment for up to 4 months.
The specific aims of this study are: (1) To prepare and characterize biodegradable particles capable of releasing budesonide for about four months. (2) To determine whether the tissue budesonide levels increase with increasing subconjunctival dose of budesonide-PLGA(poly(lactic-co-glycolic acid) particles, without inducing lens opacities or ocular hypertension. This study entails fabrication of budesonide-PLGA particles and in vivo drug delivery studies. The proposed budesonide-delivery system is likely to benefit several disorders of the eye including proliferative vitreoretinopathy, cystoid macular edema, macular degeneration, uveitis, sarcoidosis, and scleritis. Based on this study, the PI will submit an RO-l proposal to assess subconjunctival budesonide-PLGA particles for the therapy of posterior segment disorders associated with inflammation and/or VEGF elevation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Research Grants (R03)
Project #
5R03EY013842-02
Application #
6781740
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Dudley, Peter A
Project Start
2003-08-01
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$147,000
Indirect Cost
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Mayo, Aaron S; Ambati, Balamurali K; Kompella, Uday B (2010) Gene delivery nanoparticles fabricated by supercritical fluid extraction of emulsions. Int J Pharm 387:278-85
Sundaram, Sneha; Roy, Shyamal K; Kompella, Uday B (2009) Differential expression of LHRH-receptor in bovine nasal tissue and its role in deslorelin delivery. Peptides 30:351-8
Sundaram, Sneha; Roy, Shyamal K; Ambati, Balamurali K et al. (2009) Surface-functionalized nanoparticles for targeted gene delivery across nasal respiratory epithelium. FASEB J 23:3752-65
Cheruvu, Narayan P S; Amrite, Aniruddha C; Kompella, Uday B (2008) Effect of eye pigmentation on transscleral drug delivery. Invest Ophthalmol Vis Sci 49:333-41
Amrite, Aniruddha C; Edelhauser, Henry F; Kompella, Uday B (2008) Modeling of corneal and retinal pharmacokinetics after periocular drug administration. Invest Ophthalmol Vis Sci 49:320-32
Amrite, Aniruddha C; Kompella, Uday B (2008) Celecoxib inhibits proliferation of retinal pigment epithelial and choroid-retinal endothelial cells by a cyclooxygenase-2-independent mechanism. J Pharmacol Exp Ther 324:749-58
Raghava, Swita; Kompella, Uday B (2007) AQ4, an antitumor anthracenedione, inhibits endothelial cell proliferation and vascular endothelial growth factor secretion: implications for the therapy of ocular neovascular disorders. Eur J Pharmacol 568:68-74
Amrite, Aniruddha C; Ayalasomayajula, Surya P; Cheruvu, Narayan P S et al. (2006) Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage. Invest Ophthalmol Vis Sci 47:1149-60
Kompella, Uday B; Sundaram, Sneha; Raghava, Swita et al. (2006) Luteinizing hormone-releasing hormone agonist and transferrin functionalizations enhance nanoparticle delivery in a novel bovine ex vivo eye model. Mol Vis 12:1185-98
Cheruvu, Narayan P S; Kompella, Uday B (2006) Bovine and porcine transscleral solute transport: influence of lipophilicity and the Choroid-Bruch's layer. Invest Ophthalmol Vis Sci 47:4513-22

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