Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia 22908, United States.
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
ACS Appl Bio Mater. 2022 Jun 20;5(6):2943-2955. doi: 10.1021/acsabm.2c00269. Epub 2022 May 16.
Low back pain is the most common health problem with a prevalence of over 80% worldwide and an estimated annual cost of $100 billion in the United States. Intervertebral disc degeneration accounts for a major cause of low back pain. However, there is still a lack of safe and effective treatment to tackle this devastating condition. In this study, we synthesized four functionalized trimetallic nitride endohedral metallofullerenes (carboxyl-f-ScN@C, carboxyl-f-GdN@C, amino-f-ScN@C, and amino-f-GdN@C) and characterized them with X-ray photoelectron spectroscopy, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, and UV-vis. Via electron paramagnetic resonance, all four metallofullerene derivatives possessed dose-dependent radical scavenging capabilities (hydroxyl radicals and superoxide anions), with the most promising radical scavenging properties shown in the amine functionalized C metallofullerenes. Both amino-f-ScN@C and amino-f-GdN@C at 1 μM significantly reduced lipopolysaccharide induced reactive oxygen species production and mRNA expressions of pro-inflammatory mediators (, , , and ) in macrophages without apparent cytotoxicity through regulating activity of p38 MAPK, p65, and nuclear translocation of NF-κB. Furthermore, in an established mouse model of lumbar radiculopathy, amino-f-ScN@C and amino-f-GdN@C effectively alleviated ipsilateral mechanical hyperalgesia for up to 2 weeks. In dorsal root ganglia explant culture, we also showed that amino-f-ScN@C and amino-f-GdN@C ameliorated TNF-α elicited neuroinflammation. In summary, we presented results for a potent radical scavenging, anti-inflammatory and analgesic nanoparticle, amino-functionalized eighty-carbon metallofullerenes and . Our study provides important assets for developing pleiotropic treatment strategies to tackle the inflammation, a significant pathological hallmark in the intervertebral disc degeneration and associated pain.
下腰痛是最常见的健康问题，全球患病率超过 80%，据估计，美国每年为此花费 1000 亿美元。椎间盘退变是导致下腰痛的主要原因。然而，目前仍然缺乏安全有效的治疗方法来应对这种破坏性疾病。在这项研究中，我们合成了四种功能化的三金属氮化物笼内金属富勒烯（羧基 f-ScN@C、羧基 f-GdN@C、氨基 f-ScN@C 和氨基 f-GdN@C），并用 X 射线光电子能谱、基质辅助激光解吸/电离飞行时间质谱和紫外可见光谱对其进行了表征。通过电子顺磁共振，所有四种金属富勒烯衍生物都具有剂量依赖性的自由基清除能力（羟基自由基和超氧阴离子），其中在胺功能化 C 金属富勒烯中表现出最有前途的自由基清除特性。在 1 μM 时，氨基 f-ScN@C 和氨基 f-GdN@C 均能显著降低脂多糖诱导的巨噬细胞中活性氧的产生和促炎介质（、、和）的 mRNA 表达，且无明显细胞毒性，这是通过调节 p38MAPK、p65 和 NF-κB 的核转位来实现的。此外，在建立的腰椎神经根病小鼠模型中，氨基 f-ScN@C 和氨基 f-GdN@C 可有效缓解同侧机械性痛觉过敏，持续时间长达 2 周。在背根神经节外植体培养中，我们还表明氨基 f-ScN@C 和氨基 f-GdN@C 可改善 TNF-α引起的神经炎症。总之，我们提出了一种具有强大自由基清除、抗炎和镇痛作用的纳米粒子——氨基功能化 80 碳富勒烯的研究结果。我们的研究为开发针对椎间盘退变和相关疼痛的炎症这一重要病理标志的多效治疗策略提供了重要资源。
