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Theranostics 2022; 12(2):657-674. doi:10.7150/thno.65098 This issue Cite

Research Paper

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

Jiang-Hui Wang^1*, Ching-Li Tseng^2*, Fan-Li Lin^3,4, Jinying Chen⁵, Erh-Hsuan Hsieh², Suraj Lama³, Yu-Fan Chuang^3,4, Satheesh Kumar³, Linxin Zhu³, Myra B. McGuinness^1,6, Jessika Hernandez³, Leilei Tu⁵, Peng-Yuan Wang⁴, Guei-Sheung Liu^1,2,3,7,8✉

1. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia.
2. Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.
3. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
4. Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
5. Department of Ophthalmology, the First Affiliated Hospital of Jinan University, Guangzhou, China.
6. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
7. Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, Australia.
8. Aier Eye Institute, Changsha, Hunan, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Dr Guei-Sheung Liu (E-mail: rickliu0817com). Menzies Institute for Medical Research, University of Tasmania. Address: 17 Liverpool Street, Hobart, TAS 7000, Australia. Tel: +61362264250.

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 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-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-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.

Keywords: anti-angiogenesis, corneal neovascularization (CoNV), transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1), 5Z-7-oxozeaenol, gelatin nanoparticles (GNPs), eye drops

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