Abstract

Objective: The objective of the present study is to evaluate the effect of nanoparticle-mediated gene delivery of angiogenic inhibitors on retinal inflammation, vascular leakage and neovascularization in diabetic retinopathy.

Research design and methods: An expression plasmid of plasminogen kringle 5 (K5), a natural angiogenic inhibitor, was encapsulated with poly lactide-co-glycolide to form K5 nanoparticles (K5-NP). Expression of K5 was determined by Western blot analysis and immunohistochemistry. Retinal vascular leakage was measured by permeability assay. Retinal neovascularization was evaluated using fluorescein-angiography and counting pre-retinal vascular cells in rats with oxygen-induced retinopathy (OIR). Effects of K5-NP on retinal inflammation were evaluated in streptozotocin (STZ)-induced diabetic rats by leukostasis assay and Western blot analysis of ICAM and VEGF. Possible toxicities of K5-NP were evaluated using histology examination, retinal thickness measurement, and electroretinogram (ERG) recording.

Results: K5-NP mediated efficient expression of K5 and specifically inhibited growth of endothelial cells. An intravitreal injection of K5-NP resulted in high-level expression of K5 in the inner retina of rats for the entire 4 weeks analyzed. Injection of K5-NP significantly reduced retinal vascular leakage and attenuated retinal neovascularization, when compared to the contralateral eyes injected with Control-NP in OIR rats. K5-NP attenuated VEGF and ICAM-1 over-expression, reduced leukostasis and vascular leakage for at least 4 weeks after a single injection in the retina of STZ-induced diabetic rats. No toxicities of K5-NP were detected to retinal structure and function.

Conclusion: K5-NP mediates efficient and sustained K5 expression in the retina and has therapeutic potential for diabetic retinopathy.