Ocular Wnt/β-Catenin Pathway Inhibitor XAV939-Loaded Liposomes for Treating Alkali-Burned Corneal Wound and Neovascularization.

Yueyang Zhong,Xiaobo Zhang,Jiaming Wang,Kai Wang,Haijie Han,Yin Zhang,Qichuan Yin,Su Li,Ke Yao

doi:10.3389/fbioe.2021.753879

Abstract

Corneal wound involves a series of complex and coordinated physiological processes, leading to persistent epithelial defects and opacification. An obstacle in the treatment of ocular diseases is poor drug delivery and maintenance. In this study, we constructed a Wnt/β-catenin pathway inhibitor, XAV939-loaded liposome (XAV939 NPs), and revealed its anti-inflammatory and antiangiogenic effects. The XAV939 NPs possessed excellent biocompatibility in corneal epithelial cells and mouse corneas. In vitro corneal wound healing assays demonstrated their antiangiogenic effect, and LPS-induced expressions of pro-inflammatory genes of IL-1β, IL-6, and IL-17α were significantly suppressed by XAV939 NPs. In addition, the XAV939 NPs significantly ameliorated alkali-burned corneas with slight corneal opacity, reduced neovascularization, and faster recovery, which were attributed to the decreased gene expressions of angiogenic and inflammatory cytokines. The findings supported the potential of XAV939 NPs in ameliorating corneal wound and suppressing neovascularization, providing evidence for their clinical application in ocular vascular diseases.

Highlights

As one of the most vulnerable parts of the eye that is exposed to the external environment, the cornea is consistently susceptible to potential infectious and traumatic damages (Mobaraki et al, 2019; Chen F. et al, 2020; Han et al, 2020a)
The cryo-EM images show that XAV939 NPs are spherical and well-dispersed round-shaped vesicles and are predominantly unilamellar (Figure 1), similar to the previously reported liposomes (Cong et al, 2021)
To assess the cytotoxicity of XAV939 NPs, Human corneal epithelial cells (HCEs) cells incubated with different concentrations of XAV939 NPs were evaluated by the cell counting kit-8 (CCK-8) assay and Calcein-AM/PI assay

Summary

Introduction

As one of the most vulnerable parts of the eye that is exposed to the external environment, the cornea is consistently susceptible to potential infectious and traumatic damages (Mobaraki et al, 2019; Chen F. et al, 2020; Han et al, 2020a). Previous studies have illustrated the effectiveness of inhibiting inflammatory responses and blocking angiogenic signaling pathways in accelerating corneal wound healing, providing potential therapeutic options that target multiple processes in treating corneal wounds (Ellenberg et al, 2010; Chandler et al, 2019; Yang J. et al, 2020, Yang et al, 2020 S.; Rebibo et al, 2021). Various inhibitors along the Wnt signaling pathway have been identified to regulate abnormal gene activation, among which XAV939, a small molecule that stabilizes Axin and stimulates β-catenin degradation, exhibits therapeutic promise in treating Wnt pathway–dependent diseases (Huang et al, 2009). Further studies have identified the anti-inflammatory and antitumor activities of XAV939, yet its potential in treating ocular vascular diseases has not been reported (Li et al, 2018; Almasoud et al, 2020; Zhang et al, 2020)

Methods

Results

Conclusion