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- Title
Nanoparticle-Mediated Expression of an Angiogenic Inhibitor Ameliorates Ischemia-Induced Retinal Neovascularization and Diabetes-Induced Retinal Vascular Leakage.
- Authors
Park, Kyoungmin; Chen, Ying; Hu, Yang; Mayo, Aaron S.; Kompella, Uday B.; Longeras, Richard; Ma, Jian-xing
- Abstract
OBJECTIVE--The aim of the 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-coglycolide) to form K5 nanoparticles (K5-NP). Expression of K5 was determined by Western blot analysis and immunohistochemistry, and retinal vascular leakage was measured by permeability assay. Retinal neovascularization was evaluated using fluorescein-angiography and counting preretinal vascular cells in rats with oxygen-induced retinopathy. Effects of K5-NP on retinal inflammation were evaluated in streptozotocin-induced diabetic rats by leukostasis assay and Western blot analysis of intracellular adhesion molecule and vascular endothelial growth factor. Possible toxicities of K5-NP were evaluated using histology examination, retinal thickness measurement, and electroretinogram 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 during the 4 weeks they were analyzed. Injection of K5-NP significantly reduced retinal vascular leakage and attenuated retinal neovascularization, when compared with the contralateral eyes injected with Control-NP in oxygen-induced retinopathy rats. K5-NP attenuated vascular endothelial growth factor and intracellular adhesion molecule-1 overexpression and reduced leukostasis and vascular leakage for at least 4 weeks after a single injection in the retina of streptozotocin-induced diabetic rats. No toxicities of K5-NP were detected to retinal structure and function. CONCLUSIONS--K5-NP mediates efficient and sustained K5 expression in the retina and has therapeutic potential for diabetic retinopathy. Diabetes 58:1902-1913, 2009
- Subjects
NEOVASCULARIZATION inhibitors; DIABETIC retinopathy; NANOPARTICLES; DIABETES complications; VASCULAR endothelial growth factors; PLASMIDS; LABORATORY rats
- Publication
Diabetes, 2009, Vol 58, Issue 8, p1902
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db08-1327