Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, United States; Engineering Research Center for Pharmaceuticals and Equipments of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China.
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, United States.
Nanomedicine. 2022 Aug;44:102571. doi: 10.1016/j.nano.2022.102571. Epub 2022 May 24.
Synthetic high-density lipoprotein (sHDL) and rapamycin (Rap) have both been shown to be potential treatments for age-related macular degeneration (AMD). The low aqueous solubility of Rap, however, limits its therapeutic utility. Here we used an Apolipoprotein A-I mimetic peptide and phospholipid-based sHDL for the intravitreal delivery of Rap. By incorporation of Rap in sHDL nanoparticles (sHDL-Rap), we achieve 125-fold increase in drug aqueous concentration. When applied in vitro to retinal pigment epithelium cells, sHDL-Rap exhibited the abilities to efflux cholesterol, neutralize endotoxin, and suppress NF-κB activation. As an mTOR inhibitor, Rap induced autophagy and inhibited NF-κB-mediated pro-inflammatory signaling. Additionally, a greater reduction in lipofuscin accumulation and increased anti-inflammatory effects were achieved by sHDL-Rap relative to free drug or sHDL alone. In vivo studies demonstrated that sHDL reached the target retina pigment epithelium (RPE) layer following intravitreal administration in rats. These results suggest that sHDL-Rap holds potential as a treatment for AMD.
合成高密度脂蛋白 (sHDL) 和雷帕霉素 (Rap) 已被证明可用于治疗年龄相关性黄斑变性 (AMD)。然而，Rap 的水溶性低限制了其治疗用途。在这里，我们使用载脂蛋白 A-I 模拟肽和基于磷脂的 sHDL 进行雷帕霉素的玻璃体内递药。通过将 Rap 整合到 sHDL 纳米颗粒 (sHDL-Rap) 中，我们将药物在水中的浓度提高了 125 倍。当将 sHDL-Rap 体外应用于视网膜色素上皮细胞时，它表现出了排出胆固醇、中和内毒素和抑制 NF-κB 激活的能力。作为 mTOR 抑制剂，Rap 诱导自噬并抑制 NF-κB 介导的促炎信号。此外，与游离药物或 sHDL 相比，sHDL-Rap 可实现脂褐质积累的更大减少和抗炎作用的增强。体内研究表明，sHDL 在大鼠玻璃体内给药后可到达靶视网膜色素上皮 (RPE) 层。这些结果表明，sHDL-Rap 有潜力成为 AMD 的治疗方法。
