Li Qingqing, Yang Xianwei, Zhang Peipei, Mo Fei, Si Peiru, Kang Ximeng, Wang Menghan, Zhang Jiye
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, P. R. China.
Biomater Sci. 2021 Apr 7;9(7):2571-2583. doi: 10.1039/d0bm01599g. Epub 2021 Feb 16.
Corneal neovascularization (CNV) is one of the most important causes of visual impairment worldwide. Dasatinib, a poorly water-soluble tyrosine kinase inhibitor with dual Src family kinase and platelet derived growth factor receptor inhibiting capability, has great potential in the treatment of CNV. In this study, dasatinib was successfully encapsulated into a nanostructured lipid carrier (Dasa-NLC) and the size was approximately 78 nm with a small polydispersity index. The NLC increased the solubility of dasatinib by more than 1220 times, sustained the drug release, reduced the ocular toxicity and facilitated its penetration into the cornea. Dasa-NLC significantly inhibited the proliferation, migration and tube formation of HUVEC cells, the three most important angiogenesis-related cellular changes of the CNV. Next, the in vivo anti-CNV effect of Dasa-NLC was evaluated using an alkaline burned mice CNV model, in which the development of the CNV and pathological changes of the cornea were significantly inhibited. The immunohistochemistry analysis indicated that Dasa-NLC could inhibit both the expression and activation of Src family kinase, a key component in the angiogenesis cascade. Therefore, Dasa-NLC showed considerable promise in the treatment of CNV.
角膜新生血管化（CNV）是全球范围内视力损害的最重要原因之一。达沙替尼是一种水溶性较差的酪氨酸激酶抑制剂，具有双重抑制Src家族激酶和血小板衍生生长因子受体的能力，在治疗CNV方面具有巨大潜力。在本研究中，达沙替尼成功被包封于纳米结构脂质载体（Dasa-NLC）中，其粒径约为78 nm，多分散指数较小。该纳米结构脂质载体使达沙替尼的溶解度提高了1220倍以上，实现了药物的缓释，降低了眼毒性，并促进其渗透进入角膜。Dasa-NLC显著抑制了人脐静脉内皮细胞（HUVEC）的增殖、迁移和管腔形成，这是CNV最重要的三个与血管生成相关的细胞变化。接下来，使用碱性烧伤小鼠CNV模型评估了Dasa-NLC的体内抗CNV效果，结果显示其显著抑制了CNV的发展和角膜的病理变化。免疫组织化学分析表明，Dasa-NLC能够抑制Src家族激酶的表达和激活，而Src家族激酶是血管生成级联反应中的关键成分。因此，Dasa-NLC在治疗CNV方面显示出巨大的前景。
