Miyagawa Takuya, Chen Zhi-Yu, Chang Che-Yi, Chen Ko-Hua, Wang Yang-Kao, Liu Guei-Sheung, Tseng Ching-Li
Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City 110, Taiwan.
B CUBE, Center for Molecular Bioengineering, Technische Universität Dresden, Tatzberg 41, 01307 Dresden, Germany.
Pharmaceutics. 2020 Apr 28;12(5):404. doi: 10.3390/pharmaceutics12050404.
Neovascularization (NV) of the cornea disrupts vision which leads to blindness. Investigation of antiangiogenic, slow-release and biocompatible approaches for treating corneal NV is of great importance. We designed an eye drop formulation containing gelatin/epigallocatechin-3-gallate (EGCG) nanoparticles (NPs) for targeted therapy in corneal NV. Gelatin-EGCG self-assembled NPs with hyaluronic acid (HA) coating on its surface (named GEH) and hyaluronic acid conjugated with arginine-glycine-aspartic acid (RGD) (GEH-RGD) were synthesized. Human umbilical vein endothelial cells (HUVECs) were used to evaluate the antiangiogenic effect of GEH-RGD NPs in vitro. Moreover, a mouse model of chemical corneal cauterization was employed to evaluate the antiangiogenic effects of GEH-RGD NPs in vivo. GEH-RGD NP treatment significantly reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro. Topical application of GEH-RGD NPs (once daily for a week) significantly attenuated the formation of pathological vessels in the mouse cornea after chemical cauterization. Reduction in both vascular endothelial growth factor (VEGF) and MMP-9 protein in the GEH-RGD NP-treated cauterized corneas was observed. These results confirm the molecular mechanism of the antiangiogenic effect of GEH-RGD NPs in suppressing pathological corneal NV.
角膜新生血管化（NV）会破坏视力并导致失明。研究用于治疗角膜NV的抗血管生成、缓释和生物相容性方法具有重要意义。我们设计了一种含有明胶/表没食子儿茶素-3-没食子酸酯（EGCG）纳米颗粒（NPs）的眼药水制剂，用于角膜NV的靶向治疗。合成了表面带有透明质酸（HA）涂层的明胶-EGCG自组装纳米颗粒（命名为GEH）以及与精氨酸-甘氨酸-天冬氨酸（RGD）偶联的透明质酸（GEH-RGD）。使用人脐静脉内皮细胞（HUVECs）在体外评估GEH-RGD纳米颗粒的抗血管生成作用。此外，采用化学性角膜烧灼小鼠模型在体内评估GEH-RGD纳米颗粒的抗血管生成作用。GEH-RGD纳米颗粒处理在体外显著减少了HUVECs中的内皮细胞管形成，并抑制了金属蛋白酶（MMP）-2和MMP-9的活性。局部应用GEH-RGD纳米颗粒（每天一次，持续一周）显著减轻了化学烧灼后小鼠角膜中病理性血管的形成。观察到GEH-RGD纳米颗粒处理的烧灼角膜中血管内皮生长因子（VEGF）和MMP-9蛋白均减少。这些结果证实了GEH-RGD纳米颗粒在抑制病理性角膜NV中的抗血管生成作用的分子机制。
