Development of mucoadhesive cationic polypeptide micelles for sustained cabozantinib release and inhibition of corneal neovascularization
Development of mucoadhesive cationic polypeptide micelles for sustained cabozantinib release and inhibition of corneal neovascularization
复制标题
开发用于持续释放卡博替尼并抑制角膜新生血管的粘膜粘附阳离子多肽胶束
DOI：
10.1039/d0tb00874e
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发表时间：
2020-06-21
影响因子：
7
通讯作者：
Shentu, Xingchao
中科院分区：
文献类型：
--
作者：
Han, Haijie;Yin, Qichuan;Shentu, Xingchao
角膜新生血管（CNV）是视力丧失的主要危险因素之一。抗血管生成药物理论上可以扩展到CNV的治疗。然而，这些药物的应用经常受到传统给药方法的阻碍，例如，眼药水，这是归因于角膜和泪膜的独特结构。在这项研究中，开发了具有粘膜粘附能力的携带亲脂性卡博替尼（一种酪氨酸激酶抑制剂）的阳离子多肽纳米颗粒（称为Cabo-NP），用于持续释放卡博替尼和抑制CNV。通过N-羧酸酐开环聚合合成了多肽，并且可以在水溶液中与卡博替尼自组装成胶束。Cabo-NPs在角膜上皮细胞和小鼠角膜中均具有良好的生物相容性。更重要的是，在体外血管生成试验证明了Cabo-NP对细胞迁移和管形成的强烈抑制作用。此外，Cabo-NP发挥了上级抗血管生成作用，新生血管面积显著减少，其与临床地塞米松一样有效，但没有明显的副作用。Cabo-NPs的治疗机制与显著降低促血管生成因子和促炎因子、抑制新生血管形成和炎症密切相关。总的来说，阳离子Cabo-NPs通过提高亲脂性卡博替尼的生物利用度，为安全有效的CNV治疗提供了新的前景。
Corneal neovascularization (CNV) is one of the leading risk factors for vision loss. Anti-angiogenic drugs can theoretically be extended to the treatment of CNV. However, the application of these drugs is often hindered by traditional administration methods,e.g., eye drops, which is ascribed to the unique structure of the cornea and tear film. In this study, cationic polypeptide nanoparticles with mucoadhesive ability that carry lipophilic cabozantinib (a tyrosine kinase inhibitor), called Cabo-NPs, were developed for sustained cabozantinib release and inhibition of CNV. The polypeptides were synthesizedvia N-carboxyanhydride ring-opening polymerization and could self-assemble into micelles with cabozantinib in aqueous solution. The Cabo-NPs possessed good biocompatibility both in corneal epithelial cells and mouse corneas. More importantly,in vitroangiogenesis assays demonstrated the strong inhibitory effect of Cabo-NPs on cell migration and tube formation. Furthermore, the Cabo-NPs exerted superior anti-angiogenic effects with remarkable reductions in the neovascular area, which were as effective as the clinical dexamethasone but without apparent side effects. The therapeutic mechanism of the Cabo-NPs is closely related to the significant decrease in proangiogenic and proinflammatory factors, suppressing neovascularization and inflammation. Overall, cationic Cabo-NPs offer a new prospect for safe and effective CNV treatmentviaenhancing the bioavailability of lipophilic cabozantinib.