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Nanoparticle-mediated expression of an angiogenic inhibitor ameliorates ischemia-induced retinal neovascularization and diabetes-induced retinal vascular leakage.

Park K, Chen Y, Hu Y, Mayo AS, Kompella UB, Longeras R, Ma JX - Diabetes (2009)

Bottom Line: 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.No toxicities of K5-NP were detected to retinal structure and function.K5-NP mediates efficient and sustained K5 expression in the retina and has therapeutic potential for diabetic retinopathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

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.

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Effect of K5-NP on retinal vascular leakage in OIR rats. OIR rats received an intravitreal injection of 2.2 μg (A) or 8.8 μg (B) of K5-NP into the right eyes and the same dose of control-NP into the left eyes at P12. Retinal vascular permeability was measured using the Evans blue-albumin leakage method at P16. The vascular leakage was normalized by total protein concentrations in the retina, averaged within the group (mean ± SD, n = 7) and compared with contralateral eyes using paired Student's t test. The eyes injected with 8.8 μg of K5-NP showed a significantly lower retinal vascular permeability compared with the contralateral eye (P = 0.011) (B).
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Figure 4: Effect of K5-NP on retinal vascular leakage in OIR rats. OIR rats received an intravitreal injection of 2.2 μg (A) or 8.8 μg (B) of K5-NP into the right eyes and the same dose of control-NP into the left eyes at P12. Retinal vascular permeability was measured using the Evans blue-albumin leakage method at P16. The vascular leakage was normalized by total protein concentrations in the retina, averaged within the group (mean ± SD, n = 7) and compared with contralateral eyes using paired Student's t test. The eyes injected with 8.8 μg of K5-NP showed a significantly lower retinal vascular permeability compared with the contralateral eye (P = 0.011) (B).

Mentions: To evaluate the effect of K5-NP on retinal vascular leakage, K5-NP was injected intravitreally into the right eye (2.2 or 8.8 μg/eye) at age P12 and the same amount of Control-NP into the contralateral eyes. Retinal vascular leakage was measured at P16 using the Evans blue-albumin leakage method and compared with the contralateral eyes. The results showed that the eyes injected with 8.8 μg of K5-NP had significantly lower vascular permeability than that in the contralateral retinas injected with Control-NP (P = 0.011, n = 7; Fig. 4B). The injection of 2.2 μg of K5-NP did not result in a statistically significant decrease of vascular leakage (P = 0.0531, n = 7; Fig. 4A).


Nanoparticle-mediated expression of an angiogenic inhibitor ameliorates ischemia-induced retinal neovascularization and diabetes-induced retinal vascular leakage.

Park K, Chen Y, Hu Y, Mayo AS, Kompella UB, Longeras R, Ma JX - Diabetes (2009)

Effect of K5-NP on retinal vascular leakage in OIR rats. OIR rats received an intravitreal injection of 2.2 μg (A) or 8.8 μg (B) of K5-NP into the right eyes and the same dose of control-NP into the left eyes at P12. Retinal vascular permeability was measured using the Evans blue-albumin leakage method at P16. The vascular leakage was normalized by total protein concentrations in the retina, averaged within the group (mean ± SD, n = 7) and compared with contralateral eyes using paired Student's t test. The eyes injected with 8.8 μg of K5-NP showed a significantly lower retinal vascular permeability compared with the contralateral eye (P = 0.011) (B).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2712783&req=5

Figure 4: Effect of K5-NP on retinal vascular leakage in OIR rats. OIR rats received an intravitreal injection of 2.2 μg (A) or 8.8 μg (B) of K5-NP into the right eyes and the same dose of control-NP into the left eyes at P12. Retinal vascular permeability was measured using the Evans blue-albumin leakage method at P16. The vascular leakage was normalized by total protein concentrations in the retina, averaged within the group (mean ± SD, n = 7) and compared with contralateral eyes using paired Student's t test. The eyes injected with 8.8 μg of K5-NP showed a significantly lower retinal vascular permeability compared with the contralateral eye (P = 0.011) (B).
Mentions: To evaluate the effect of K5-NP on retinal vascular leakage, K5-NP was injected intravitreally into the right eye (2.2 or 8.8 μg/eye) at age P12 and the same amount of Control-NP into the contralateral eyes. Retinal vascular leakage was measured at P16 using the Evans blue-albumin leakage method and compared with the contralateral eyes. The results showed that the eyes injected with 8.8 μg of K5-NP had significantly lower vascular permeability than that in the contralateral retinas injected with Control-NP (P = 0.011, n = 7; Fig. 4B). The injection of 2.2 μg of K5-NP did not result in a statistically significant decrease of vascular leakage (P = 0.0531, n = 7; Fig. 4A).

Bottom Line: 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.No toxicities of K5-NP were detected to retinal structure and function.K5-NP mediates efficient and sustained K5 expression in the retina and has therapeutic potential for diabetic retinopathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

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.

Show MeSH
Related in: MedlinePlus