Intravitreal Bevacizumab nanoparticles ameliorates retinal vasculopathy in an in vivo mouse model of retinopathy of prematurity

Background: Nanoparticles enable sustained drug release. Infants with retinopathy of prematurity (ROP) treated with Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, develop systemic toxicity due to repeat dosing from a short half-life. We optimized fabrication of Bevacizumab nanoparticles in a mouse oxygen-induced retinopathy (OIR) model.

Methods: Bevacizumab nanoparticle fabrication was optimized for polymer type and ratio, solvent, drug loading capacity (DL) %, and encapsulation efficiency (EE) %. Nanoparticles were characterized using Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), and Fourier-transform infrared spectroscopy (FTIR). C57BL6/J mice exposed to OIR received intravitreal Empty (n = 18), Bevacizumab-loaded nanoparticles (n = 18), or Free Bevacizumab (n = 12) at P13 to right eyes. Fluorescein Angiography (FA) was performed at P20. Retinal avascular area, arterial tortuosity, and vein width were quantified.

Results: SEM showed spherical nanospheres. TEM and FTIR confirmed drugs within nanospheres. DL and EE were optimized at 2.3% and 80%. There was sustained drug release of 80% at 72 h. FA showed increased retinal avascular area, reduced retinal artery tortuosity, and retinal vein width in Bevacizumab nanoparticle treated right eyes.

Conclusions: Intravitreal administration of Bevacizumab-loaded nanoparticles significantly improved retinal vasculopathy in mice with OIR, without repeat dosing. Further toxicity studies are needed before clinical translation.

Impact: Retinopathy of Prematurity is treated with anti-vascular endothelial growth factor drugs such as Bevacizumab. Anti-VEGF drugs result in systemic toxicity from repeat dosing due to their short half-life. We, for the first time, show the feasibility and optimization of nanoparticle formulation of bevacizumab in a mouse model of ROP. Intravitreal Bevacizumab nanoparticles may prevent systemic toxicity and improve outcomes in infants with ROP.