Studies on Regulation of Retinal and Choroidal Neovascularization via Intravitreal Injection of Nanoparticles

Abstract

Introduction: Retinal and choroidal neovascularization is one of the pathognomonic features in various retinal diseases including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. Vascular endothelial growth factor is the main factor to drive retinal and choroidal neovascularization. As an effort to investigate potential therapeutic approaches to target pathological neovascularization in the retina, anti-angiogenic effects of nanoparticles were investigated as they were administered through intravitreal injection. Methods: With well-characterized gold, silica, and titanium dioxide nanoparticles, in vitro and in vivo experiments were performed including in vitro proliferation, migration, and tube formation assays using endothelial cells and in vivo models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. To demonstrate whether nanoparticles induced toxicity, cellular viability assays, histologic evaluation, Western blotting of caspase-3, terminal deoxynucleotidyl transferase dUTP nick end labeling, and gene expression microarray were performed. Nanoparticles were incubated in the vitreous ex vivo to mimic the local environment which they encountered when they were administered via intravitreal injection. Results: Inorganic nanoparticles including gold, silica, and titanium dioxide nanoparticles inhibited pathological angiogenesis in vitro and in vivo. It was remarkable that they demonstrated effective therapeutic effects without definite toxicity at the levels of gene expression, cellular viability, and histologic integrity when they were administered through intravitreal injection. In particular, size was the determining factor of anti-angiogenic effects of nanoparticles on retinal and choroidal neovascularization. Upon administration into the vitreous cavity, corona was formed around nanoparticles, which affected the biological action of nanoparticles. Conclusions: Taken together, intravitreally administered nanoparticles effectively suppressed pathological neovascularization in the retina. Mechanistic studies on these anti-angiogenic effects of nanoparticles might facilitate biomedical application of nanoparticle-based therapeutics against retinal and choroidal neovascularization.