Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor.
OBJECTIVE
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 (IC(50), 0.1-1.0 microM) 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.
Palii
Stela S
SS
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida 32610-0267, USA.
Afzal
Aqeela
A
Shaw
Lynn C
LC
Pan
Hao
H
Caballero
Sergio
S
Miller
Rehae C
RC
Jurczyk
Simona
S
Reubi
Jean-Claude
JC
Tan
Yufei
Y
Hochhaus
Guenther
G
Edelhauser
Henry
H
Geroski
Dayle
D
Shapiro
Gideon
G
Grant
Maria B
MB
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001345:Autoradiography; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D048289:Imidazolidines / Q000819:agonists*; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D015282:Octreotide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D009883:Ophthalmic Solutions; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D011817:Rabbits; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012590:Sclera; D016896:Treatment Outcome; D014822:Vitreous Body
D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D048289:Imidazolidines; D009883:Ophthalmic Solutions; D017481:Receptors, Somatostatin; C514490:imidazolidine-2,4-dione; D012313:RNA; C093733:somatostatin receptor 2; D015282:Octreotide