Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Republic of Korea.
Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Republic of Korea; Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, Republic of Korea.
Biomaterials. 2019 Mar;197:1-11. doi: 10.1016/j.biomaterials.2019.01.008. Epub 2019 Jan 7.
Obesity and overweight, the most serious health problems, are associated with chronic metabolic complications such as type 2 diabetes, insulin resistance, and nonalcoholic fatty liver disease (NAFLD). However, current pharmacological therapies for obesity are challenged by potential side effects, low effectiveness, and low aqueous solubility, which limit their clinical application. Here, we develop nifedipine-loaded nanoparticles (NFD-NPs) that alleviate obesity-related metabolic dysfunction to be used as instruments for translational medicine. Nanoparticles (NPs) composed of poly (lactic-co-glycolic acid) (PLGA) not only enhance water solubility of hydrophobic nifedipine (NFD), a calcium channel blocker, without modifying the chemical structure of NFD for intravenous administration, but also allow prolonged release of NFD in vivo. NFD-NPs do not show cytotoxicity and reduce palmitate-induced protein inclusions and endoplasmic reticulum stress in human hepatoma HepG2 cells. Importantly, tail-vein injection of NFD-NPs into diet-induced obese mice results in sustained retention of NFD-NPs in the liver and suppression of metabolic derangements associated with NAFLD by enhancing autophagic clearance through Ca2+/calmodulin-dependent kinase II (CaMKII) phosphorylation, consequently decreasing diet-induced insulin resistance and improving glucose tolerance. Our findings offer new clinical tools for NP-mediated pharmaceutical strategies to treat NAFLD and its related metabolic dysfunction.
肥胖和超重是最严重的健康问题，与 2 型糖尿病、胰岛素抵抗和非酒精性脂肪性肝病 (NAFLD) 等慢性代谢并发症有关。然而，肥胖的当前药物治疗受到潜在副作用、低效率和低水溶性的限制，限制了它们的临床应用。在这里，我们开发了载有硝苯地平的纳米颗粒（NFD-NPs），以缓解与肥胖相关的代谢功能障碍，用作转化医学的工具。由聚（乳酸-共-乙醇酸）（PLGA）组成的纳米颗粒（NPs）不仅增强了疏水性硝苯地平（NFD）的水溶性，NFD 是一种钙通道阻滞剂，而不改变 NFD 的化学结构用于静脉注射，而且还允许 NFD 在体内的持续释放。NFD-NPs 没有显示出细胞毒性，并减少了棕榈酸诱导的人肝癌 HepG2 细胞中的蛋白包涵体和内质网应激。重要的是，尾静脉注射 NFD-NPs 到饮食诱导的肥胖小鼠中导致 NFD-NPs 在肝脏中的持续保留，并通过增强自噬清除来抑制与 NAFLD 相关的代谢紊乱，通过 Ca2+/钙调蛋白依赖性激酶 II（CaMKII）磷酸化，从而降低饮食诱导的胰岛素抵抗并改善葡萄糖耐量。我们的发现为 NP 介导的药物策略提供了新的临床工具，以治疗 NAFLD 及其相关的代谢功能障碍。
