Key Laboratory of Vision Loss and Restoration, Ministry of Education, Department of Ophthalmology, Peking University People's Hospital, Xizhimen South Street 11, Xi Cheng District, 100044 Beijing, China.
J Pharmacol Exp Ther. 2012 Jul;342(1):131-9. doi: 10.1124/jpet.112.192575. Epub 2012 Apr 10.
Pathological retinal neovascularization and choroidal neovascularization are major causes of vision loss in a variety of clinical conditions, such as retinopathy of prematurity, age-related macular degeneration, and diabetic retinopathy. Pigment epithelial-derived factor (PEDF) has been found to be the most potent natural, endogenous inhibitor of neovascularization, but its application is restricted because of its instability and short half-life. Polyethylene glycol (PEG) has been used as a drug carrier to slow clearance rate for decades. The present study investigated PEGylated-PEDF for the first time and evaluated its long-term effects on preventing angiogenesis in vitro and in vivo. PEG showed lower cytotoxicity to human umbilical vein endothelial cells (HUVECs). In vitro, PEGylated-PEDF inhibited HUVEC proliferation, migration, tube formation, and vascular endothelium growth factor secretion and induced HUVEC apoptosis in a dose-dependent manner, and it showed a statistically significant difference compared with the PEDF treatment group. In vivo, PEGylated-PEDF had a long-lasting effect in both plasma and retinal concentrations. In an oxygen-induced retinopathy model, one intravitreous injection of PEGylated-PEDF after mouse pups were moved into room air resulted in a significant difference in the inhibition of retinal neovascularization, which decreased the nonperfusion area, compared with the PEDF-treated group. Our present study demonstrated for the first time the long-term inhibitory effects of PEGylated-PEDF on the prevention of neovascularization in vitro and in vivo. These data suggest that PEGylated-PEDF could offer an innovative therapeutic strategy for preventing retinal neovascularization.
病理性视网膜新生血管和脉络膜新生血管是多种临床情况下视力丧失的主要原因，如早产儿视网膜病变、年龄相关性黄斑变性和糖尿病性视网膜病变。现已发现色素上皮衍生因子（PEDF）是最强效的天然、内源性血管新生抑制剂，但由于其不稳定性和半衰期短，其应用受到限制。聚乙二醇（PEG）已被用作药物载体数十年来以减缓清除率。本研究首次研究了 PEG 化-PEDF，并评估了其在体外和体内预防血管生成的长期效果。PEG 对人脐静脉内皮细胞（HUVEC）的细胞毒性较低。在体外，PEG 化-PEDF 以剂量依赖性方式抑制 HUVEC 的增殖、迁移、管形成和血管内皮生长因子分泌，并诱导 HUVEC 凋亡，与 PEDF 治疗组相比，差异具有统计学意义。在体内，PEG 化-PEDF 在血浆和视网膜浓度中均具有持久作用。在氧诱导的视网膜病变模型中，在将小鼠幼仔移至空气后进行一次玻璃体内注射 PEG 化-PEDF，与 PEDF 治疗组相比，可显著抑制视网膜新生血管形成，减少无灌注区。本研究首次证明了 PEG 化-PEDF 对体外和体内血管生成预防的长期抑制作用。这些数据表明，PEG 化-PEDF 可为预防视网膜新生血管形成提供一种创新的治疗策略。
