Topical Application of Hyaluronic Acid-RGD Peptide-Coated Gelatin/Epigallocatechin-3 Gallate (EGCG) Nanoparticles Inhibits Corneal Neovascularization Via Inhibition of VEGF Production. Miyagawa Takuya,Chen Zhi-Yu,Chang Che-Yi,Chen Ko-Hua,Wang Yang-Kao,Liu Guei-Sheung,Tseng Ching-Li Pharmaceutics 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. 10.3390/pharmaceutics12050404

Flt1 peptide-hyaluronate conjugate micelle-like nanoparticles encapsulating genistein for the treatment of ocular neovascularization. Kim Hyemin,Choi Jun-Sub,Kim Ki Su,Yang Jeong-A,Joo Choun-Ki,Hahn Sei Kwang Acta biomaterialia Flt1 peptide of GNQWFI is an antagonistic peptide for vascular endothelial growth factor receptor 1 (VEGFR1 or Flt1). In this work, Flt1 peptide-hyaluronate (HA) conjugates were successfully synthesized and the resulting micelle-like nanoparticles were exploited to encapsulate genistein, an inhibitor of tyrosine-specific protein kinases, for the treatment of ocular neovascularization. The mean diameter of genistein-loaded Flt1 peptide-HA conjugate micelles was measured to be 172.0±18.7 nm, with a drug-loading efficiency of 40-50%. In vitro release tests of genistein from the genistein-loaded Flt1 peptide-HA conjugate micelles exhibited the controlled release for longer than 24h. In vitro biological activity of genistein/Flt1 peptide-HA micelles was corroborated from the synergistic anti-proliferation of human umbilical vein endothelial cells (HUVECs). Furthermore, we could confirm the anti-angiogenic effect of genistein/Flt1 peptide-HA micelles from the statistically significant suppression of corneal neovascularization in silver nitrate cauterized corneas of SD rats. The retinal vascular hyperpermeability was also drastically reduced by the treatment in diabetic retinopathy model rats. 10.1016/j.actbio.2012.07.016

Micelle-solubilized axitinib for ocular administration in anti-neovascularization. Shi Shuai,Peng Fangli,Zheng Qianqian,Zeng Li,Chen Hao,Li Xingyi,Huang Jinhai International journal of pharmaceutics The development of new blood vessels is directly related to the occurrence of eye diseases. Anti-angiogenic drugs can theoretically be extended to the treatment of ophthalmic diseases. In this study, axitinib, a class of tyrosine kinase inhibitors, was loaded via the amphiphilic copolymer MPEG-PCL, improving its dispersibility in water. Axitinib-loaded micelles showed low toxicity in concentration gradient assays. Additionally, multiple doses by scratch assay confirmed that axitinib had no significant effect on normal cell migration, and biosafety test results showed good cell compatibility. After we established the corneal neovascularization model after an alkali burn in rats, the anti-angiogenic efficacy was tested, with dexamethasone as a positive control. The results showed that axitinib-loaded micelles had anti-angiogenic effects without obvious tissue toxicity. As a class of targeted tyrosine kinase inhibitors, axitinib can be used in the treatment of ocular neovascular diseases through nanocrystallization. 10.1016/j.ijpharm.2019.01.051

Development of mucoadhesive cationic polypeptide micelles for sustained cabozantinib release and inhibition of corneal neovascularization. Han Haijie,Yin Qichuan,Tang Xiajing,Yu Xiaoning,Gao Qiang,Tang Yelei,Grzybowski Andrzej,Yao Ke,Ji Jian,Shentu Xingchao Journal of materials chemistry. B Corneal neovascularization (CNV) is one of the leading risk factors for vision loss. Anti-angiogenic drugs can theoretically be extended to the treatment of CNV. However, the application of these drugs is often hindered by traditional administration methods, e.g., eye drops, which is ascribed to the unique structure of the cornea and tear film. In this study, cationic polypeptide nanoparticles with mucoadhesive ability that carry lipophilic cabozantinib (a tyrosine kinase inhibitor), called Cabo-NPs, were developed for sustained cabozantinib release and inhibition of CNV. The polypeptides were synthesized via N-carboxyanhydride ring-opening polymerization and could self-assemble into micelles with cabozantinib in aqueous solution. The Cabo-NPs possessed good biocompatibility both in corneal epithelial cells and mouse corneas. More importantly, in vitro angiogenesis assays demonstrated the strong inhibitory effect of Cabo-NPs on cell migration and tube formation. Furthermore, the Cabo-NPs exerted superior anti-angiogenic effects with remarkable reductions in the neovascular area, which were as effective as the clinical dexamethasone but without apparent side effects. The therapeutic mechanism of the Cabo-NPs is closely related to the significant decrease in proangiogenic and proinflammatory factors, suppressing neovascularization and inflammation. Overall, cationic Cabo-NPs offer a new prospect for safe and effective CNV treatment via enhancing the bioavailability of lipophilic cabozantinib. 10.1039/d0tb00874e