J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive Biomedical Sciences Building JG-56, P.O. Box 116131, Gainesville, FL 32611-6131, USA.
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive Biomedical Sciences Building JG-56, P.O. Box 116131, Gainesville, FL 32611-6131, USA.
Biomaterials. 2019 Dec;224:119467. doi: 10.1016/j.biomaterials.2019.119467. Epub 2019 Sep 11.
Oxidative stress has been implicated in the pathogenesis of osteoarthritis and has become an important therapeutic target. Investigations of various antioxidant supplements, reactive oxidative species (ROS) pathway mediators, and free radical scavengers for treating osteoarthritis have demonstrated common disadvantages including poor bioavailability and stability, as well as rapid joint clearance or release profiles from delivery vehicles. Moreover, these therapies do not target cartilage, which irreversibly degenerates in the presence of oxidative stress. The goal of this study was to engineer a nanoparticle system capable of sustained retention in the joint space, localization to cartilage, and mitigation of oxidative stress. Towards this goal, ROS scavenging manganese dioxide nanoparticles with physicochemical properties (less than 20 nm and cationic) that facilitate their uptake into cartilage were developed and characterized. These particles penetrated through the depth of cartilage explants and were found both in the extracellular matrix as well as intracellularly within the resident chondrocytes. Furthermore, the particles demonstrated chondroprotection of cytokine-challenged cartilage explants by reducing the loss of glycosaminoglycans and release of nitric oxide. Quantitative PCR analysis revealed that the particles mitigated impacts of oxidative stress related genes in cytokine-challenged chondrocytes. When injected intra-articularly into rats, the particles persisted in the joint space over one week, with 75% of the initial signal remaining in the joint. Biodistribution and histological analysis revealed accumulation of particles at the chondral surfaces and colocalization of the particles with the lacunae of chondrocytes. The results suggest that the manganese dioxide nanoparticles could be a promising approach for the chondroprotection of osteoarthritic cartilage.
氧化应激与骨关节炎的发病机制有关，已成为重要的治疗靶点。研究各种抗氧化补充剂、活性氧（ROS）途径调节剂和自由基清除剂治疗骨关节炎，发现其共同的缺点包括生物利用度和稳定性差，以及从给药载体中快速清除或释放。此外，这些疗法不能针对软骨，软骨在氧化应激存在下会不可逆转地退化。本研究的目的是设计一种能够在关节腔内持续保留、定位于软骨并减轻氧化应激的纳米颗粒系统。为此，开发并表征了具有物理化学性质（小于 20nm 和阳离子）的 ROS 清除二氧化锰纳米颗粒，这些性质有助于其被软骨吸收。这些颗粒穿透软骨外植体的深度，不仅存在于细胞外基质中，也存在于驻留软骨细胞内。此外，这些颗粒通过减少糖胺聚糖的丢失和一氧化氮的释放，对细胞因子刺激的软骨外植体表现出软骨保护作用。定量 PCR 分析显示，这些颗粒减轻了细胞因子刺激的软骨细胞中与氧化应激相关基因的影响。当将这些颗粒关节内注射到大鼠体内时，它们在关节腔内持续存在一周以上，初始信号的 75%仍保留在关节内。生物分布和组织学分析显示，颗粒在软骨表面聚集，并且与软骨细胞的陷窝共定位。结果表明，二氧化锰纳米颗粒可能是治疗骨关节炎软骨的一种有前途的方法。
