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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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Related in: MedlinePlus

Effect of K5-NP on preretinal neovascularization in OIR rats. K5-NP was injected intravitreally into the right eyes and control-NP into the left eyes of six OIR rats at P12. The eyes were fixed, sectioned, and stained with hematoxylin and eosin at P18. A and B: Representative sections from the eyes injected with control-NP (A) and from that with K5-NP (B) injection. Scale bar: 40 μm. C: Preretinal vascular cells were counted in eight noncontinuous sections per eye and averaged as described in research design and methods. The average numbers of preretinal vascular cells (mean ± SD, n = 6) were compared with the eyes injected with K5-NP and those with Control-NP using paired Student's t test. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 6: Effect of K5-NP on preretinal neovascularization in OIR rats. K5-NP was injected intravitreally into the right eyes and control-NP into the left eyes of six OIR rats at P12. The eyes were fixed, sectioned, and stained with hematoxylin and eosin at P18. A and B: Representative sections from the eyes injected with control-NP (A) and from that with K5-NP (B) injection. Scale bar: 40 μm. C: Preretinal vascular cells were counted in eight noncontinuous sections per eye and averaged as described in research design and methods. The average numbers of preretinal vascular cells (mean ± SD, n = 6) were compared with the eyes injected with K5-NP and those with Control-NP using paired Student's t test. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: The effect of K5-NP on preretinal neovascularization was also quantified by counting vascular cells growing into the vitreous space (preretinal vascular cells) on eight noncontinuous cross-sections from each eye following an established method (27). The result showed that the eyes injected with K5-NP have significantly fewer preretinal neovascular cells, compared with the contralateral eyes injected with Control-NP (Fig. 6).


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 preretinal neovascularization in OIR rats. K5-NP was injected intravitreally into the right eyes and control-NP into the left eyes of six OIR rats at P12. The eyes were fixed, sectioned, and stained with hematoxylin and eosin at P18. A and B: Representative sections from the eyes injected with control-NP (A) and from that with K5-NP (B) injection. Scale bar: 40 μm. C: Preretinal vascular cells were counted in eight noncontinuous sections per eye and averaged as described in research design and methods. The average numbers of preretinal vascular cells (mean ± SD, n = 6) were compared with the eyes injected with K5-NP and those with Control-NP using paired Student's t test. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 6: Effect of K5-NP on preretinal neovascularization in OIR rats. K5-NP was injected intravitreally into the right eyes and control-NP into the left eyes of six OIR rats at P12. The eyes were fixed, sectioned, and stained with hematoxylin and eosin at P18. A and B: Representative sections from the eyes injected with control-NP (A) and from that with K5-NP (B) injection. Scale bar: 40 μm. C: Preretinal vascular cells were counted in eight noncontinuous sections per eye and averaged as described in research design and methods. The average numbers of preretinal vascular cells (mean ± SD, n = 6) were compared with the eyes injected with K5-NP and those with Control-NP using paired Student's t test. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: The effect of K5-NP on preretinal neovascularization was also quantified by counting vascular cells growing into the vitreous space (preretinal vascular cells) on eight noncontinuous cross-sections from each eye following an established method (27). The result showed that the eyes injected with K5-NP have significantly fewer preretinal neovascular cells, compared with the contralateral eyes injected with Control-NP (Fig. 6).

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