Superoxide dismutase in nanoarchaeosomes for targeted delivery to inflammatory macrophages

Abstract

Oxidative stress plays an essential role in the pathogenesis and progression of inflammatory bowel disease. Co-administration of antioxidants and anti-inflammatory drugs has shown clinical benefits. Due to its significant reactive oxygen species (ROS) scavenging ability, great interest has been focused on superoxide dismutase (SOD) for therapeutic use. However, oral SOD is exposed to biochemical degradation along gastrointestinal transit. Furthermore, the antioxidant activity of SOD must be achieved intracellularly, therefore its cell entry requires endocytic mediating mechanisms. In this work, SOD was loaded into nanoarchaeosomes (ARC-SOD), nanovesicles fully made of sn 2,3 ether linked phytanyl saturated archaeolipids to protect and target SOD to inflammatory macrophages upon oral administration. Antioxidant and antiinflammatory activities of ARC-SOD, non-digested and digested in simulated gastrointestinal fluids, on macrophages stimulated with H2O2 and lipopolysaccharide were determined and compared with those of free SOD and SOD encapsulated into highly stable liposomes (LIPOSOD). Compared to SOD and LIPO-SOD, ARC-SOD (170 ± 14 nm, -30 ± 4 mV zeta potential, 122 mg protein/g phospholipids) showed the highest antioxidant and anti-inflammatory activity: it reversed the cytotoxic effect of H2O2, decreased intracellular ROS and completely suppressed the production of IL-6 and TNF- on stimulated J774A.1 cells. Moreover, while the activity of LIPO-SOD was lost upon preparation, gastrointestinal digestion and storage, ARC-SOD was easy to prepare and retained its antioxidant capacity upon digestion in simulated gastrointestinal fluids and after 5 months of storage. Because of their structural and pharmacodynamic features, ARC-SOD may be suitable for oral targeted delivery of SOD to inflamed mucosa.