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Y. Hu, K. Park, Y. Chen, A. S. Mayo, U. B. Kompella, R. Longeras, J.-X. Ma; Long-Term Therapeutic Effects of a Nanoparticle-Mediated Angiogenic Inhibitor on Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2412.
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© ARVO (1962-2015); The Authors (2016-present)
Abnormal retinal vascular leakage is one of the major pathological changes in diabetic retinopathy (DR). Our previous studies have shown that plasminogen kringle 5 (K5), a natural angiogenic inhibitor, effectively reduced retinal vascular leakage in DR animal models. However, the effect of K5 was transient after a single intravitreal injection. The purpose of this study is to develop a sustained delivery system and explore therapeutic potential of nanoparticle-mediated delivery of K5.
An expression plasmid of K5 was encapsulated with poly lactide-co-glycolide to form K5 nanoparticles (K5-NP). Adult Brown Norway rats were given a single intraperitoneal injection of streptozotocin (STZ) to induce diabetes. Expression and secretion of K5 were determined by Western blot analysis and immunohistochemistry. Vascular permeability was quantified by measuring leakage of FITC-albumin or Evans blue dye-albumin complex from the blood vessels into the retina. Possible toxicities were evaluated using histology examination and electroretinogram (ERG) recording.
An intravitreal injection of K5-NP resulted in high-level expression of K5 in the inner retina of rats, and the expression lasted for the entire 4 weeks analyzed. Significant reductions of retinal vascular leakage was observed 4 weeks after a single intravitreal injection of K5-NP, when compared to control group injected with Control nanoparticles in STZ-induced diabetic rats. Moreover, K5-NP attenuated retinal inflammation in STZ rats. K5-NP injection did not lead to any detectable toxicities to retinal structure and function.
K5-NP mediates efficient and sustained K5 expression in the retina and has therapeutic potential in diabetic macular edema.
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