Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization

Jiang Hui Wang, Ching Li Tseng, Fan Li Lin, Jinying Chen, Erh Hsuan Hsieh, Suraj Lama, Yu Fan Chuang, Satheesh Kumar, Linxin Zhu, Myra B. McGuinness, Jessika Hernandez, Leilei Tu, Peng Yuan Wang, Guei Sheung Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Corneal neovascularization (CoNV) is a severe complication of various types of corneal diseases, that leads to permanent visual impairment. Current treatments for CoNV, such as steroids or anti-vascular endothelial growth factor (VEGF) agents, are argued over their therapeutic efficacy and adverse effects. Here, we demonstrate that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) plays an important role in the pathogenesis of CoNV. Methods: Angiogenic activities were assessed in ex vivo and in vitro models subjected to TAK1 inhibition by 5Z-7-oxozeaenol, a selective inhibitor of TAK1. RNA-Seq was used to examine pathways that could be potentially affected by TAK1 inhibition. A gelatin-nanoparticles (GNPs)-encapsulated 5Z-7-oxozeaenol was developed as the eyedrop to treat CoNV in a rodent model. Results: We showed that 5Z-7-oxozeaenol reduced angiogenic processes through impeding cell proliferation. Transcriptome analysis suggested 5Z-7-oxozeaenol principally suppresses cell cycle and DNA replication, thereby restraining cell proliferation. In addition, inhibition of TAK1 by 5Z-7-oxozeaenol blocked TNFα-mediated NFκB signalling, and its downstream genes related to angiogenesis and inflammation. 5Z-7-oxozeaenol also ameliorated pro-angiogenic activity, including endothelial migration and tube formation. Furthermore, topical administration of the gelatin nanoparticles (GNPs)-encapsulated 5Z-7-oxozeaenol led to significantly greater suppression of CoNV in a mouse model compared to the free form of 5Z-7-oxozeaenol, likely due to extended retention of 5Z-7-oxozeaenol in the cornea. Conclusion: Our study shows the potential of TAK1 as a therapeutic target for pathological angiogenesis, and the gelatin nanoparticle coupled with 5Z-7-oxozeaenol as a promising new eyedrop administration model in treatment of CoNV.

Original languageEnglish
Pages (from-to)657-674
Number of pages18
JournalTheranostics
Volume12
Issue number2
DOIs
Publication statusPublished - 2022

Keywords

  • 5Z-7-oxozeaenol
  • Anti-angiogenesis
  • Corneal neovascularization (CoNV)
  • Eye drops
  • Gelatin nanoparticles (GNPs)
  • Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1)

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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