Nanoparticle-mediated expression of an angiogenic inhibitor ameliorates ischemia-induced retinal neovascularization and diabetes-induced retinal vascular leakage.
Nanoparticle-mediated expression of an angiogenic inhibitor ameliorates ischemia-induced retinal neovascularization and diabetes-induced retinal vascular leakage.
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作者：
Park K;Chen Y;Hu Y;Mayo AS;Kompella UB;Longeras R;Ma JX
该研究的目的是评估纳米颗粒介导的血管生成抑制剂基因递送对糖尿病视网膜病变视网膜炎症、血管渗漏和新生血管形成的影响。将天然血管生成抑制剂纤溶酶原 kringle 5 (K5) 的表达质粒用聚丙交酯-乙交酯共聚物封装，形成 K5 纳米颗粒 (K5-NP)。通过蛋白质印迹分析和免疫组织化学测定K5的表达，并通过渗透性测定测量视网膜血管渗漏。使用荧光素血管造影和计数氧诱导性视网膜病变大鼠的视网膜前血管细胞来评估视网膜新生血管形成。通过白细胞抑制试验和细胞内粘附分子和血管内皮生长因子的蛋白质印迹分析评估K5-NP对链脲佐菌素诱导的糖尿病大鼠视网膜炎症的影响。通过组织学检查、视网膜厚度测量和视网膜电图记录来评估 K5-NP 可能的毒性。 K5-NP 介导 K5 的有效表达并特异性抑制内皮细胞的生长。在分析的 4 周内，玻璃体内注射 K5-NP 导致大鼠视网膜内层 K5 高水平表达。在氧诱导的视网膜病变大鼠中，与注射对照-NP的对侧眼相比，注射K5-NP显着减少了视网膜血管渗漏并减弱了视网膜新生血管形成。在链脲佐菌素诱导的糖尿病大鼠视网膜单次注射后，K5-NP 可以减弱血管内皮生长因子和细胞内粘附分子 1 的过度表达，并减少白细胞停滞和血管渗漏至少 4 周。未检测到 K5-NP 对视网膜结构和功能的毒性。 K5-NP 介导视网膜中有效且持续的 K5 表达，具有治疗糖尿病视网膜病变的潜力。
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. 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. 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. K5-NP mediates efficient and sustained K5 expression in the retina and has therapeutic potential for diabetic retinopathy.
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