Targeted elimination of intracellular reactive oxygen species using nanoparticle-like chitosan- superoxide dismutase conjugate for treatment of monoiodoacetate-induced osteoarthritis

Abstract

In our previous work, cationic functionalized chitosan was chemically conjugated with superoxide dismutase (SOD) to yield a unique nanoparticle-like conjugate O-HTCC-SOD that has demonstrated superior potential in treating reactive oxygen species (ROS)-related disorders to SOD. Considering contribution of ROS to pathogenesis of osteoarthritis, O-HTCC-SOD was firstly measured for effect on rat chondrocytes exposure to monoiodoacetate (MIA). O-HTCC-SOD was nontoxic to chondrocytes and had more long-acting and intracellular protection effects on chondrocytes against MIA-induced oxidative damage due to its superior elimination of intracellular ROS to SOD. Pharmacokinetic analysis demonstrated that O-HTCC-conjugated SOD significantly prolonged half-life and residence in rat joint cavity, and improved bioavailability compared with unmodified SOD. Intra-articular injection of O-HTCC-SOD significantly attenuated mechanical allodynia in MIA-induced osteoarthritis rats, dramatically suppressed gross morphological and histological lesions of articular cartilage, and greatly enhanced in vivo antioxidant capacity and anti-inflammatory effect. But native SOD had no obvious therapeutic effects. Consequently, the nanoparticle-like conjugate O-HTCC-SOD of the excellent efficacy resulted from its targeted intracellular ROS clearance capability and improved pharmacokinetic profiles, opening up a novel avenue for disease-modifying osteoarthritis drugs.

Keywords: Chitosan; Monoiodoacetate; Nanoparticle-like conjugate; Osteoarthritis; Reactive oxygen species; Superoxide dismutase.