Novel Auto-regenerative Antioxidant Significantly Attenuates Pathologic Choroidal Neovascularization in Wet AMD Model

Abstract

Purpose : Owing to the auto-regenerative antioxidant properties, Cerium oxide nanoparticles (CeNPs) have been widely explored in the treatment of oxidative-related disorders (e.g., age-related macular degeneration - AMD). The most important challenges in studies of CeNP lies in its water solubility and stability. An optimal antioxidant formulation yet remains to be established. There is a growing evidence that pathological reactive oxygen species (ROS) play a pivotal role in both non-neovascular (“dry”) and neovascular (“wet”) forms of AMD. Wet AMD is highly regulated by ROS induced vascular endothelial growth factor (VEGF, a principal pro-angiogenic factor) expressions, and traditionally characterized by the invasion and leakage of new blood vessels, which are originated from the pre-existing choriocapillaris and navigate towards the neuronal retina that finally progress to severe vision loss.

Methods : To this end, we tested our hypothesis that newly developed biocompatible chitosan derivative coated water soluble, stable, and robust auto-regenerative CeO2NPs would suppress cumulative oxidative stress by for targeting and scavenging ROS. In this report, we have comprehensively characterized the novel CeO2NPs, evaluated their anti-oxidant, anti-angiogenic activity and safety using in vitro cell cultures of APRE-19 and HUVECs and in vivo laser induced choroidal neovascularization (CNV) mice models, a classical model for wet AMD. Antioxidant activity of CeO2NPs was also characterized by spin-trapping electron paramagnetic resonance (EPR).

Results : We report that novel CeO2NPs formulation significantly inhibited endothelial cell migration, tubular formation, vasopermeability, and VEGF expression. Surprisingly, we found that intravitreal injection of a single dose of CeO2NPs significantly inhibited the expression of VEGF, 4-hydroxy-2-nonenal (4-HNE, a most toxic lipid peroxidation protein product), and C-X-C chemokine receptor type 4 (CXCR4) expressions in a murine model of CNV.

Conclusions : Altogether, these results suggest that administration of the novel CeO2NPs can function as a promising exogenous antioxidant for the suppression of oxidative damage and inflammation, and thereby preventing CNV in a murine model of wet AMD, which explores significant implication of this alternative therapeutic strategy to deal with oxidative stress induced pathogenesis, such as AMD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.