Rastegari Banafsheh, Ghamar Talepoor Atefe, Khosropanah Shahdad, Doroudchi Mehrnoosh
Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz 71439-14693, Iran.
Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran.
ACS Omega. 2023 Dec 18;9(1):658-674. doi: 10.1021/acsomega.3c06389. eCollection 2024 Jan 9.
Atherosclerosis, a leading cause of mortality worldwide, involves various subsets of macrophages that contribute to its initiation and progression. Current treatment approaches focus on systemic, long-term administration of cholesterol-lowering antioxidants such as statins and certain vitamins, which unfortunately come with prolonged side effects. To overcome these drawbacks, a mannose-containing magnetic nanoparticle (NP) is introduced as a drug delivery system to specifically target macrophages in vitro using simvastatin or niacin and a combinational therapy approach that reduces local inflammation while avoiding unwanted side effects. The synthesized NPs exhibited superparamagnetic behavior, neutrally charged thin coating with a hydrodynamic size of 77.23 ± 13.90 nm, and a metallic core ranging from 15 to 25 nm. Efficient loading of niacin (87.21%) and simvastatin (75.36%) on the NPs was achieved at respective weights of 20.13 and 5.03 (w/w). In the presence of a mannan hydrolyzing enzyme, 79.51% of simvastatin and 67.23% of niacin were released from the NPs within 90 min, with a leakage rate below 19.22%. Additionally, the coated NPs showed no destructive effect on J774A macrophages up to a concentration of 200 μg/mL. Simvastatin-loaded NPs exhibited a minimal increase in expression. The low dosage of simvastatin decreased both and expressions, while niacin and combined simvastatin/niacin increased the level of expression significantly. Toxicity evaluations on human umbilical vein endothelial cells and murine liver cells revealed that free simvastatin administration caused significant toxicity, whereas the encapsulated forms of simvastatin, niacin, and a combination of simvastatin/niacin at equivalent concentrations exhibited no significant toxicity. Hence, the controlled release of the encapsulated form of simvastatin and niacin resulted in the effective modulation of macrophage polarization. The delivery system showed suitability for targeting macrophages to atherosclerotic plaque.
动脉粥样硬化是全球主要的死亡原因之一，涉及多种巨噬细胞亚群，这些亚群在其发生和发展过程中发挥作用。目前的治疗方法侧重于全身性、长期给予降胆固醇抗氧化剂，如他汀类药物和某些维生素，但不幸的是，这些药物会带来长期的副作用。为了克服这些缺点，引入了一种含甘露糖的磁性纳米颗粒（NP）作为药物递送系统，使用辛伐他汀或烟酸在体外特异性靶向巨噬细胞，并采用联合治疗方法，减少局部炎症，同时避免不必要的副作用。合成的纳米颗粒表现出超顺磁性行为，具有中性电荷的薄涂层，流体动力学尺寸为77.23±13.90nm，金属核心尺寸在15至25nm之间。在各自重量为20.13和5.03（w/w）时，纳米颗粒上烟酸（87.21%）和辛伐他汀（75.36%）实现了高效负载。在甘露聚糖水解酶存在的情况下，90分钟内79.51%的辛伐他汀和67.23%的烟酸从纳米颗粒中释放出来，泄漏率低于19.22%。此外，包被的纳米颗粒在浓度高达200μg/mL时对J774A巨噬细胞没有破坏作用。负载辛伐他汀的纳米颗粒表现出表达的最小增加。低剂量的辛伐他汀降低了和的表达，而烟酸以及辛伐他汀/烟酸联合使用显著增加了表达水平。对人脐静脉内皮细胞和小鼠肝细胞的毒性评估表明，游离辛伐他汀给药会引起显著毒性，而同等浓度的辛伐他汀、烟酸以及辛伐他汀/烟酸的包封形式则没有显著毒性。因此，包封形式的辛伐他汀和烟酸的控释导致了巨噬细胞极化的有效调节。该递送系统显示出适用于将巨噬细胞靶向动脉粥样硬化斑块。
