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Y. Fu, M.R. Robinson, L. Ponce, P. Yuan, M. Wiesner, H.M. Bender, N.S. Wang, K.G. Csaky; Inhibition of Angiogenesis by an Integrin Antagonist in Chicken Choroiallantoic Membrane Assay From a Sustained–Release Implant . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3950.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Angiogenesis, an important component of diabetic retinopathy and age–related macular degeneration, has been previously shown to be partially regulated by integrins. Therefore, selective integrin antagonists may lead to a novel integrin–based therapeutic development for the treatment of ocular neovascularization. However, traditional drug delivery methods frequently require repeated drug application. In this study, we investigated the anti–angiogenic effect of an integrin antagonist in a modified chicken choroiallantonic membrane assay (CAM) using a sustained–release implant. Methods:A polyvinyl alcohol (PVA)–based reservoir type implant releasing a small molecular weight integrin antagonist (EMD 478761) (Merck KGaA, Darmstadt, Germany) was constructed. In vitro release rates were calculated by assaying drug concentrations over time using an HPLC quantification method. An in vivo modified chick CAM assay was employed with circular coverslips, coated with basic fibroblast growth factor (bFGF), induced angiogenesis in 10–day old embryos. The implant was placed in a pre–cut circular hole centrally in the coverslip to locally deliver the drug. CAM images were taken over time. Results:In vitro release rates showed that the implant delivered an initial burst over the first two days, followed by zero–order steady–state release kinetics over a 16–day period. In untreated bFGF–CAMs, 83% (24/29) had positive neovascular responses. Similarly, 90% (9/10) bFGF–CAMs exposed to sham (no drug) implants also developed neovascularization. However, no neovascularization (0/14) was observed under in bFGF–CAMs when exposed to EMD478761–implants. In addition, there were no signs of local drug toxicity and no effect on the normal CAM vasculature. Conclusions: The small molecular weight integrin antagonist demonstrated potent inhibition of angiogenesis using a sustained implant delivery device in the CAM assay. The results suggests that this integrin antagonist, delivered by a sustained–release implant, may be effective in treating eye diseases associated with neovascularization.
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