Tat PTD-Endostatin-RGD: A novel protein with anti-angiogenesis effect in retina via eye drops.

Publisher: Elsevier Pub. Co Country of Publication: Netherlands NLM ID: 0217513 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0006-3002 (Print) Linking ISSN: 00063002 NLM ISO Abbreviation: Biochim Biophys Acta Subsets: MEDLINE

Original Publication: Amsterdam : Elsevier Pub. Co.

Diabetic Retinopathy/*drug therapy ; Endostatins/*administration & dosage ; Neovascularization, Pathologic/*drug therapy ; Oligopeptides/*administration & dosage ; Recombinant Fusion Proteins/*administration & dosage ; Retinal Neovascularization/*drug therapy; Animals ; Blood-Retinal Barrier/drug effects ; Chick Embryo ; Chorioallantoic Membrane/drug effects ; Diabetic Retinopathy/genetics ; Diabetic Retinopathy/pathology ; Endostatins/metabolism ; Humans ; Integrin alphaVbeta3/biosynthesis ; Integrin alphaVbeta3/genetics ; Mice ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/pathology ; Oligopeptides/metabolism ; Ophthalmic Solutions/administration & dosage ; Rats ; Recombinant Fusion Proteins/metabolism ; Retina/drug effects ; Retina/pathology ; Retinal Neovascularization/pathology ; Retinal Vessels/drug effects ; Retinal Vessels/pathology ; S-Nitroso-N-Acetylpenicillamine/metabolism

Background: Diabetic retinopathy is a leading cause of blindness. The objective was to design a novel fusion protein, Tat PTD-Endostatin-RGD, to treat retinal neovascularization via eye drops instead of traditional intravitreal injection trepapeutical methods.
Method: The anti-angiogenesis ability was evaluated in vitro by chick embryo chorioallantoic membrane assay, wound healing assay and tube formation assay. Corneal barrier and blood-retina barrier were constructed in vitro to investigate the penetration ability of Tat PTD-Endostatin-RGD. Western blot was used to detect the integrin αvβ3 expression level in rat retina microvascular endothelial cells which was stimulated by S-nitroso-N-acetylpenicillamine. The binding affinity of Tat PTD-Endostatin-RGD to integrin αvβ3 was investigated by evaluating the penetration ability on blood-retina barriers treated with S-nitroso-N-acetylpenicillamine. The pharmacodynamics and efficacy analysis were further carried out in the oxygen-induced retinopathy model in vivo. In addition, the pharmacokinetic profile via eye drops was studied on a C57BL/6 mice model.
Result: Tat PTD-Endostatin-RGD showed high anti-angiogenesis activity and high ability to penetrate these two barriers in vitro. The Western blot results indicated S-nitroso-N-acetylpenicillamine upregulated the expression level of integrin αvβ3 in a dose-dependent manner. Tat PTD-Endostatin-RGD showed a high affinity to rat retina microvascular endothelial cells treated with S-nitroso-N-acetylpenicillamine. The results showed that Tat PTD-Endostatin-RGD could inhibit abnormal angiogenesis in retina via eye drops.
Conclusion: Tat PTD-Endostatin-RGD showed high penetration ability through ocular barriers, bound specifically to integrin αvβ3 and effectively inhibited the abnormal angiogenesis.
General Significance: Tat PTD-Endostatin-RGD represents a potent novel drug applied via eye drops for fundus oculi neovascularization diseases.
(Copyright © 2016 Elsevier B.V. All rights reserved.)

Keywords: Blood-retina barrier; Corneal barriers; Neovascularization; Oxygen-induced retinopathy

0 (Endostatins)
0 (Integrin alphaVbeta3)
0 (Oligopeptides)
0 (Ophthalmic Solutions)
0 (Recombinant Fusion Proteins)
0 (Tat PTD-endostatin)
78VO7F77PN (arginyl-glycyl-aspartic acid)
79032-48-7 (S-Nitroso-N-Acetylpenicillamine)

Date Created: 20160529 Date Completed: 20171103 Latest Revision: 20171103

20240829

10.1016/j.bbagen.2016.05.031

27233450