Abstract
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.