Anti-inflammatory and antiangiogenic effects of nanoparticle-mediated delivery of a natural angiogenic inhibitor.

PURPOSE The purpose of this study was to evaluate the inhibitory effects of the nanoparticle-mediated delivery of plasminogen kringle 5 (K5) on choroidal neovascularization (CNV) and retinal inflammation. METHODS CNV was induced by laser in adult rats. Nanoparticles with an expression plasmid of K5 (K5-NP) were injected into the vitreous. K5 expression was detected by immunohistochemistry. The CNV area was measured after fluorescein angiography. Retinal vascular permeability was quantified with Evans blue as a tracer. Expression of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and intercellular adhesion molecule (ICAM)-1 was measured by Western blot analysis or ELISA and real-time RT-PCR. RESULTS Intense K5 expression was detected in the retina 2 weeks after the injection of K5-NP. Areas of CNV were significantly decreased in the K5-NP treatment group compared with that in the control-NP group. The K5-NP injection also significantly reduced vascular permeability. The expression of VEGF was downregulated by K5-NP at both the protein and mRNA levels. Moreover, K5-NP also inhibited expression of TNF-α and ICAM-1. Similarly, K5-NP decreased retinal levels of total β-catenin. In cultured cells, K5-NP suppressed hypoxia-induced secretion of MCP-1 and TNF-α. CONCLUSIONS K5 has a novel anti-inflammatory activity. K5-NP mediates a sustained inhibitory effect on CNV and thus has therapeutic potential for age-related macular degeneration.