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Originally published In Press as doi:10.1167/iovs.08-2289 on July 3, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:5094-5102.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-2289
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Nonpeptide Somatostatin Receptor Agonists Specifically Target Ocular Neovascularization via the Somatostatin Type 2 Receptor

Stela S. Palii,1 Aqeela Afzal,1 Lynn C. Shaw,1 Hao Pan,1 Sergio Caballero,1 Rehae C. Miller,2 Simona Jurczyk,3 Jean-Claude Reubi,4 Yufei Tan,5 Guenther Hochhaus,5 Henry Edelhauser,6 Dayle Geroski,6 Gideon Shapiro,3 and Maria B. Grant1

1From the Departments of Pharmacology and Therapeutics, 2Ophthalmology, and 5Pharmaceutics, University of Florida, Gainesville, Florida; 3RFE Pharma, Alachua, Florida; the 4Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Bern, Bern, Switzerland; and the 6Department of Ophthalmology, Emory University, Atlanta, Georgia.

PURPOSE. To define the molecular pharmacology underlying the antiangiogenic effects of nonpeptide imidazolidine-2,4-dione somatostatin receptor agonists (NISAs) and evaluate the efficacy of NISA in ocular versus systemic delivery routes in ocular disease models.

METHODS. Functional inhibitory effects of the NISAs and the somatostatin peptide analogue octreotide were evaluated in vitro by chemotaxis, proliferation, and tube-formation assays. The oxygen-induced retinopathy (OIR) model and the laser model of choroidal neovascularization (CNV) were used to test the in vivo efficacy of NISAs. Transscleral permeability of a candidate NISA was also measured.

RESULTS. NISAs inhibited growth factor–induced HREC proliferation, migration and tube formation with submicromolar potencies (IC50, 0.1–1.0 µM) comparable to octreotide. In the OIR model, systemic administration of the NISAs RFE-007 and RFE-011 inhibited retinal neovascularization in a dose-dependent manner, comparable to octreotide. In the CNV model, intravitreal RFE-011 resulted in a 56% reduction (P < 0.01) in CNV lesion area, whereas systemic administration resulted in a 35% reduction (P < 0.05) in lesion area. RFE-011 demonstrated transscleral penetration.

CONCLUSIONS. Micromolar concentrations of octreotide and NISAs are necessary for antiangiogenic effects, whereas nanomolar concentrations are effective for endocrine inhibition. This suggests that the antiangiogenic activity of NISAs and octreotide is mediated by an overall much less efficient downstream coupling mechanism than is growth hormone release. As a result, the intravitreal or transscleral route of administration should be seriously considered for future clinical studies of SSTR2 agonists used for treatment of ocular neovascularization to ensure efficacious concentrations in the target retinal and choroidal tissue.






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