Angiogenesis inhibition and choroidal neovascularization suppression by sustained delivery of an integrin antagonist, EMD478761.
OBJECTIVE
To evaluate the angiogenic inhibitory effects of an alpha(v)beta(3)/alpha(v)beta(5) integrin antagonist, EMD478761, released from a polymeric implant in a chick chorioallantoic membrane (CAM) assay and laser-induced experimental choroidal neovascularization (CNV) in rats.


METHODS
Polyvinyl alcohol-based reservoir implants releasing EMD478761 were designed for placement onto a CAM or intravitreally in rats. In vitro release rates of the implants were measured using HPLC. Angiogenesis was induced on 10-day-old chick embryos by basic fibroblast growth factor (bFGF), and areas of neovascularization were measured. Experimental CNV was induced in the Brown-Norway rat with a diode laser. EMD478761 or sham microimplants were placed within the vitreous chamber of Brown-Norway rats. Two weeks later, areas of CNV were determined by FITC-dextran staining of choroidal flatmounts.


RESULTS
Sustained delivery of EMD478761 significantly inhibited bFGF-induced angiogenesis in CAM, as determined by a reduction in angiogenesis areas, without drug toxicity to the normal CAM vasculature. In an experimental rat model, intravitreal EMD478761 implants significantly suppressed laser-induced CNV compared with intravitreal sham implants, with the mean area reduced by 63% (P < 0.05).


CONCLUSIONS
Sustained delivery of EMD478761demonstrates potent antiangiogenic properties in vivo. These results suggest that an EMD478761 implant may be beneficial in the treatment of neovascular ocular diseases.
Fu
Yingli
Y
National Eye Institute, NIH, Bethesda, MD, USA.
Ponce
M Lourdes
ML
Thill
Michelle
M
Yuan
Peng
P
Wang
Nam Sun
NS
Csaky
Karl G
KG
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage*; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply*; D020256:Choroidal Neovascularization / Q000473:pathology / Q000517:prevention & control*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004343:Drug Implants; D016222:Fibroblast Growth Factor 2 / Q000633:toxicity; D007267:Injections; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D053685:Laser Therapy; D008297:Male; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D011914:Rats, Inbred BN; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D014822:Vitreous Body / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D048588:Benzoxazines; D004343:Drug Implants; C524580:EMD478761; D039302:Integrin alphaVbeta3; D016023:Integrins; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D016222:Fibroblast Growth Factor 2