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M.B. Grant, S. Caballero, R.N. Mames, G. Shapiro; Designer Drugs: Peptidomimetics of Somatostatin Specifically Target Ocular Neovascularization . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4171.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Therapy with somatostatin (SST) analogs such as octreotide can result in regression of neovascularization and improve visual acuity in patients with advanced diabetic retinopathy. Clinical results have been variable and have favored patients receiving high dosage regimens, suggesting that the peptide drugs currently in use may not be reaching target tissues because of inadequate penetration of the blood retinal barrier (BRB). We have developed peptidomimetic molecules that bind to selective SST receptors. These agents are non–peptide lipophilic imidazolin–2,4–dione derivatives that are specifically designed to effectively penetrate the BRB. Methods: We tested 12 SST peptidomimetics in vitro and in vivo. One compound, SCR–011, proved more effective and with fewer detrimental side effects in initial studies and was therefore examined extensively. We tested the effect of SCR–011 on human retinal endothelial cell (HREC) proliferation using BrdU incorporation, and migration using modified Boyden chambers. We evaluated the efficacy of SCR–011 in vivo using the neonatal mouse model of oxygen–induced retinopathy (OIR) as well as the adult model of Bruch’s membrane rupture by laser. For these studies, mice were given SCR–011 either intravitreally (weekly) or intraperitoneally (X2 daily). Results: Exposure of HREC to SCR–011 resulted in a dose–dependent inhibition of growth factor–induced proliferation and migration, comparable to octreotide. SCR–011 at a dose of 1 mg/kg/day resulted in a 45% reduction (p<0.01) and at 3 mg/kg/day resulted in a 73% reduction (p<0.05) in preretinal neovascularization in the OIR model. These results improved on those observed with octreotide. In the adult model of laser–induced CNV, intravitreal injection of SCR–011 resulted in a 56% reduction (p<0.01) in CNV lesion volume without toxicity to the retina, RPE or choroid. Systemic injection was slightly less effective, resulting in a 35% reduction (p<0.05) in CNV area. Conclusions: Non–peptide compounds that mimic the receptor–binding domain of somatostatin appear to be more efficacious against pathological ocular neovascularization than peptide analogs such as octreotide, especially when administered intravitreally. Compounds such as SCR–011 have an immediate potential for clinical therapeutic use against ocular neovascular diseases by being easier to synthesize and having greater BRB penetration than peptide analogs of somatostatin.
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