Anti-VEGF PolysiRNA Polyplex for the Treatment of Choroidal Neovascularization

Choroidal neovascularization (CNV) is a major cause of severe vision loss in patients with age-related macular degeneration (AMD). Present ocular siRNA delivery technology is limited due to poor delivery through the retina to the choroid, where CNV originates. Our goal was to develop an optimized nanosized polyRNAi-based therapeutic delivery system to the subretinal space. We developed it by siRNA multimerization (polysiRNA) followed by coating with branched polyethylenimine and hyaluronic acid, and then evaluated its efficacy in vitro and in vivo. The polysiRNA polyplex showed a narrow size distribution (260.7 ± 43.27 nm) and negative charge (-4.98 ± 0.47 mV) owing to the hyaluronic acid outer layer. In vitro uptake of the polysiRNA polyplex by human ARPE cells was discovered, and the direct inhibition of VEGF mRNA translation was confirmed in B16F10 cells. The intravitreally administered polysiRNA polyplex overcame both the vitreous and retina barriers in vivo and reached the subretinal space efficiently. Intravitreal injection of the polysiRNA polyplex was not toxic to the retina in histopathology. Furthermore, intravitreal injections of the polysiRNA polyplex at both 1 and 7 days after laser photocoagulation inhibited laser-induced choroidal neovascularization, compared to that of the control (p < 0.05). These results suggest that anti-VEGF polysiRNA polyplexes show great potential in delivering multimeric RNAi-based therapeutics to treat retinal or choroidal disorders.