Angiogenesis inhibition and choroidal neovascularization suppression by sustained delivery of an integrin antagonist, EMD478761.

Abstract

PURPOSE:

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.

• Authors: Yingli Fu, M Lourdes Ponce, Michelle Thill, Peng Yuan, Nam Sun Wang, Karl G Csaky
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 48 Issue 11 Pg. 5184-90 (Nov 2007) ISSN: 0146-0404 [Print] United States
• PMID: 17962472 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Benzoxazines
• Drug Implants
• EMD478761
• Integrin alphaVbeta3
• Integrins
• Receptors, Vitronectin
• integrin alphaVbeta5
• Fibroblast Growth Factor 2

Topics

• Angiogenesis Inhibitors (administration & dosage)
• Animals
• Benzoxazines (administration & dosage)
• Chick Embryo
• Chorioallantoic Membrane (blood supply)
• Choroidal Neovascularization (pathology, prevention & control)
• Chromatography, High Pressure Liquid
• Disease Models, Animal
• Drug Delivery Systems
• Drug Implants
• Fibroblast Growth Factor 2 (toxicity)
• Injections
• Integrin alphaVbeta3 (antagonists & inhibitors)
• Integrins (antagonists & inhibitors)
• Laser Therapy
• Male
• Neovascularization, Pathologic (chemically induced, drug therapy)
• Rats
• Rats, Inbred BN
• Receptors, Vitronectin (antagonists & inhibitors)
• Vitreous Body (drug effects)