Laboratory of Ethnopharmacology, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
Department of Ophthalmology, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
ACS Appl Mater Interfaces. 2020 Dec 30;12(52):57710-57720. doi: 10.1021/acsami.0c17296. Epub 2020 Dec 15.
There is a continuing, urgent need for an ophthalmic (eye) drop for the clinical therapy of age-related macular degeneration (AMD), a leading cause of blindness. Here, we report the first formulation of an eye drop that is effective via autophagy for AMD treatment. This eye drop is based on a single natural product derivative (ACD), which is an amphiphilic molecule containing a 6-aminohexanoate group (HN(CH)COO-). We demonstrate that this eye drop reverses the abnormal angiogenesis induced in a primate model of AMD that has the pathological characteristics close to that of human AMD. The ACD molecule was self-assembled in an aqueous environment leading to nanoparticles (NPs) about 9.0 nm in diameter. These NPs were encapsulated in calcium alginate hydrogel. The resulting eye drop effectively slowed the release of ACD and displayed extended release periods in both simulated blood (pH 7.4) and inflammatory (pH 5.2) environments. We show that the eye drop penetrated both the corneal and blood-eye barriers and reached the fundus. With low cellular toxicity, the drop targeted S1,25D-membrane-associated rapid response steroid-binding protein (1,25D-MARRS) promoting autophagy in a dose-dependent manner. In addition, the drop inhibited cell migration and tubular formation. On the other hand, when protein 1,25D-MARRS was knocked down, the eye drop did not exhibit such inhibition functionalities. Our study indicates that the 6-aminohexanoate group on self-assembled NPs encapsulated in hydrogel leads to the positive outcomes. The present formulation offers a promising approach for clinical treatment of human AMD.
对于年龄相关性黄斑变性（AMD）这种导致失明的主要原因，临床上仍急需一种眼科（眼）滴剂来进行治疗。在此，我们报告了第一个可通过自噬作用有效治疗 AMD 的滴眼剂配方。这种滴眼剂基于一种单一的天然产物衍生物（ACD），它是一种两亲分子，含有 6-氨基己酸基团（HN(CH)COO-）。我们证明，这种滴眼剂可逆转在具有与人 AMD 非常相似的病理特征的 AMD 灵长类动物模型中诱导的异常血管生成。在水性环境中，ACD 分子自组装形成直径约 9.0nm 的纳米颗粒（NPs）。这些 NPs 被包封在钙藻酸盐水凝胶中。由此产生的滴眼剂有效地减缓了 ACD 的释放，并在模拟血液（pH7.4）和炎症（pH5.2）环境中显示出延长的释放期。我们表明，滴眼剂可穿透角膜和血眼屏障并到达眼底。该滴眼剂具有低细胞毒性，以剂量依赖的方式靶向 S1,25D-膜相关快速反应类固醇结合蛋白（1,25D-MARRS），促进自噬。此外，该滴眼剂抑制细胞迁移和管状形成。另一方面，当蛋白 1,25D-MARRS 被敲低时，滴眼剂则没有表现出这种抑制功能。我们的研究表明，水凝胶中包封的自组装 NPs 上的 6-氨基己酸基团导致了积极的结果。该制剂为临床治疗人类 AMD 提供了一种有前途的方法。
