天然产品衍生的纳米颗粒滴眼液，用于治疗与年龄有关的黄斑变性,ACS Applied Materials & Interfaces

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天然产品衍生的纳米颗粒滴眼液，用于治疗与年龄有关的黄斑变性
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2020-12-15 , DOI: 10.1021/acsami.0c17296
Guang Xin ₁ , Ming Zhang ₂ , Zhihui Zhong ₁ , Li Tang ₂ , Yuliang Feng ₂ , Zeliang Wei ₁ , Shiyi Li ₁ , Youping Li ₁ , Junhua Zhang ₃ , Boli Zhang ₃ , Meng Zhang ₄ , Nelson Rowell ₅ , Zhen Chen ₁ , Hai Niu ₆ , Kui Yu ₇ , Wen Huang ₁

Affiliation

迫切需要眼药水（眼药水）用于年龄相关性黄斑变性（AMD）的临床治疗，这是失明的主要原因。在这里，我们报告了通过自噬有效治疗AMD的眼药水的第一种配方。该眼药水基于单一的天然产物衍生物（ACD），它是一种含有6个氨基己酸酯基团（H ₂ N（CH ₂）₅COO-）。我们证明，这种眼药水可以逆转在灵长类动物的灵长类动物模型中诱导的异常血管生成，该模型具有与人类AMD相似的病理特征。ACD分子在水性环境中自组装，形成直径约9.0 nm的纳米颗粒（NPs）。这些NP被封装在藻酸钙水凝胶中。在模拟血液（pH 7.4）和炎性（pH 5.2）环境中，所得的眼药水有效地减慢了ACD的释放并显示了更长的释放时间。我们表明，眼药水穿透了角膜和血眼屏障，并到达了眼底。具有低细胞毒性，该液滴靶向S1,25D _3-膜相关的快速反应类固醇结合蛋白（1,25D ₃-MARRS）以剂量依赖性方式促进自噬。另外，该液滴抑制细胞迁移和肾小管形成。另一方面，当蛋白1，25D ₃ -MARRS被击倒时，该眼药水没有表现出这种抑制功能。我们的研究表明，封装在水凝胶中的自组装NP上的6-氨基己酸酯基团导致体内阳性结果。本制剂为人AMD的临床治疗提供了有希望的方法。

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Ophthalmic Drops with Nanoparticles Derived from a Natural Product for Treating Age-Related Macular Degeneration

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 (H₂N(CH₂)₅COO−). 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 S1,25D₃-membrane-associated rapid response steroid-binding protein (1,25D₃-MARRS) promoting autophagy in a dose-dependent manner. In addition, the drop inhibited cell migration and tubular formation. On the other hand, when protein 1,25D₃-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 in vivo outcomes. The present formulation offers a promising approach for clinical treatment of human AMD.

更新日期：2020-12-30

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