Abstract
Abstract: :
Purpose: To assess the efficacy of organic antagonists of integrins αvß3 and αvß5 in rabbit corneal or mouse retinal models of angiogenesis after intrascleral or intravitreal administration. Methods: Corneal angiogenesis was induced by implanting bFGF-containing Hydron pellets 2.0 mm from the limbus. Non-peptidic compound (EMD 220201) with nanomolar IC50 activity for αvß3 and αvß5 was solubilized at 2.0 mg/ml in PBS and administered as a single 100 µl intrascleral or intrastromal injection near the site of pellet implantation immediately after surgery. Seven days later the area of corneal neovascularization was quantified. Eight-day-old mice received intravitreal injection of 2.0 µl of PBS or organic antagonist in PBS. On post-natal day 12 retinas were collected, stained with collagen IV and the extent of secondary, deep vascular development was assessed by confocal microscopy. Results: Pellets containing bFGF were implanted in rabbit corneas in two experimental series; data from the combined experiments show 50.5% inhibition with antagonist compared to PBS at 7 days. In the first experiment the organic integrin antagonist administered as a single intrascleral injection repeatedly inhibited bFGF-induced angiogenesis at seven days (52.3% inhibition, p<.01) compared to eyes treated with PBS. In the second experiment, the organic integrin antagonist repeatedly inhibited bFGF-induced angiogenesis at seven days (48.3% inhibition, p<.003) compared to eyes treated with PBS. Multiple injections of the same compound also inhibited FGF-induced angiogenesis in this model. In one experiment, intrastromal injection of EMD220201 was found to inhibit bFGF-induced corneal angiogenesis at seven days (24.8%, p<.01). In the neonatal mouse retinal experiments 20 of 43 (46.5%) antagonist-treated eyes had complete inhibition of the outer, secondary vascular layer. All but 4 of the remaining 23 eyes showed varying degrees of inhibition. Three of 36 (8.3%) PBS-treated eyes showed complete inhibition of the outer layer. Conclusion: Corneal angiogenesis induced by bFGF can be reduced by 50.5% after intrascleral injection of organic antagonists of αvß3 and αvß5. A single intravitreal injection of the antagonist completely inhibits new vessel formation in over half of treated eyes in the mouse retinal model while less than 10% of control-treated eyes exhibit a comparable effect. These results suggest that locally administered integrin antagonists may be useful in the treatment of neovascular eye diseases.
Keywords: 483 neovascularization • 566 retinal neovascularization • 370 cornea: basic science