Age-related macular degeneration (AMD), a multifactorial age-related retinal hypoxic disorder resulting in irreversible loss of vision, is the foremost cause of blindness in the United States. Current treatment strategies involve multiple intraocular injections of antivascular endothelial growth factor (VEGF) agents into the vitreous of eye. In addition to the challenges of drug localization and targeted delivery, the need of frequent injections into the eye raises patient compliance issues, and thus call for development of sustained drug delivery systems. In this study, a sustained drug delivery system was prepared by loading an antihypoxia-induced factor (HIF) agent, honokiol (HON), into methoxy poly (ethylene glycol) polycaprolactone (MPEG-PCL) polymer. These HON-MPEG-PCL micelles were characterized by evaluating size, ζ potential, in vitro drug release profile, and morphology by transmission electron microscopy. The cytotoxic nature of developed micelles was assessed on human retinal pigment epithelial cell line (ARPE-19) cells by cytotoxicity assay. The cellular uptake and HIF and VEGF expression levels were determined in in vitro settings. Micelles formed had a particle size of 30.8 ± 0.8 nm with the poly dispersity index of 0.19 ± 0.0004 and ζ potential was found to be −5.46 ± 0.49 mv. Entrapment efficiency was calculated to be 64 ± 0.135%. In vitro drug release showed sustained release of drug from the formulation. Result from in vitro cytotoxicity study confirmed noncytotoxic nature of HON-MPEG-PCL micelles compared to HON drug solution. Furthermore, enzyme-linked immunosorbent assay studies performed showed the periodic downregulation of HIF and VEGF, which are major growth factors involved in underlying mechanism of AMD. The results showed successful development of HON-MPEG-PCL micelles, which may be useful for the effective treatment of AMD.

中文翻译：

---

载和厚朴酚甲氧基聚（乙二醇）聚己内酯胶束治疗年龄相关性黄斑变性

年龄相关性黄斑变性 (AMD) 是一种与年龄相关的多因素视网膜缺氧性疾病，导致不可逆转的视力丧失，是美国失明的首要原因。目前的治疗策略包括将抗血管内皮生长因子 (VEGF) 药剂多次眼内注射到眼睛的玻璃体中。除了药物定位和靶向给药的挑战外，对眼部频繁注射的需求也引发了患者的依从性问题，因此需要开发持续的给药系统。在这项研究中，通过将抗缺氧诱导因子 (HIF) 剂和厚朴酚 (HON) 加载到甲氧基聚（乙二醇）聚己内酯 (MPEG-PCL) 聚合物中，制备了一种持续的药物递送系统。这些 HON-MPEG-PCL 胶束通过评估尺寸、ζ 电位、通过透射电子显微镜观察体外药物释放曲线和形态。通过细胞毒性测定对人视网膜色素上皮细胞系 (ARPE-19) 细胞评估开发的胶束的细胞毒性。在体外环境中测定细胞摄取和 HIF 和 VEGF 表达水平。形成的胶束粒径为 30.8 ± 0.8 nm，多分散指数为 0.19 ± 0.0004，ζ 电位为 -5.46 ± 0.49 mv。包埋效率计算为 64 ± 0.135%。体外药物释放显示药物从制剂中持续释放。体外结果细胞毒性研究证实了与 HON 药物溶液相比，HON-MPEG-PCL 胶束的非细胞毒性性质。此外，进行的酶联免疫吸附试验研究显示 HIF 和 VEGF 的周期性下调，它们是参与 AMD 潜在机制的主要生长因子。结果表明成功开发了HON-MPEG-PCL胶束，可用于有效治疗AMD。