Department of Ophthalmology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China.
Biomaterials. 2018 Sep;178:23-35. doi: 10.1016/j.biomaterials.2018.06.006. Epub 2018 Jun 7.
Pathological angiogenesis is driven by uncontrolled growth of endothelial cells (ECs), which could lead to retinopathy, tumor and rheumatoid arthritis, etc. ECs must experience multiple cell division process to grow, and cytokinesis is the final step. The present study shows that PEGylated GNRs (PEG-GNRs) specifically target ECs cytokinesis process which results in high ratio of binucleated cells, and these binucleated ECs lose the ability to proliferate. Further data show that PEG-GNRs do not induce toxicity in vitro and in vivo. PEG-GNRs could inhibit ECs proliferation, migration, tube formation and inhibit angiogenesis in ex vivo model. Oxygen induced retinopathy and tumor angiogenesis model further show that PEG-GNRs can inhibit angiogenesis in vivo. Gene expression profiles reveal that PEG-GNRs mainly affect ECs cell division process, and PEG-GNRs treated ECs are arrested in G2/M phase. The mechanism is that PEG-GNRs could disrupt TGFβ pathway, and subsequently suppress the assembly of actin filaments in contractile ring site. These findings indicate that PEG-GNR is a novel cytokinesis inhibitor which can be used to interfere with retinal angiogenesis and tumor.
病理性血管生成是由内皮细胞（ECs）的失控生长驱动的，这可能导致视网膜病变、肿瘤和类风湿关节炎等疾病。ECs 必须经历多次细胞分裂过程才能生长，而胞质分裂是最后一步。本研究表明，聚乙二醇化 GNRs（PEG-GNRs）特异性靶向 ECs 的胞质分裂过程，导致双核细胞比例高，这些双核 ECs 失去增殖能力。进一步的数据表明，PEG-GNRs 在体外和体内均不会引起毒性。PEG-GNRs 可以抑制 ECs 的增殖、迁移、管形成，并抑制体外模型中的血管生成。氧诱导的视网膜病变和肿瘤血管生成模型进一步表明，PEG-GNRs 可以抑制体内的血管生成。基因表达谱显示，PEG-GNRs 主要影响 ECs 的细胞分裂过程，并且经 PEG-GNRs 处理的 ECs 被阻滞在 G2/M 期。其机制是 PEG-GNRs 可以破坏 TGFβ 途径，从而抑制收缩环部位肌动蛋白丝的组装。这些发现表明，PEG-GNR 是一种新型的胞质分裂抑制剂，可用于干扰视网膜血管生成和肿瘤。
