Liposomal superoxide dismutases and their use in the treatment of experimental arthritis.

ABSTRACT

It has long been suggested that superoxide dismutase (SOD) be used for antioxidant therapy on the basis of its ability to catalyze the dismutation of superoxide radicals involved in the pathogenesis of several inflammatory disorders such as rheumatoid arthritis. However, the administration of SOD in free form has some disadvantages, most importantly, the low accumulation of SOD in inflamed areas due to its reduced half-life in the bloodstream and its rapid renal excretion. To overcome this, SOD can be incorporated either in highly loaded conventional liposomes (SA-liposomes) or long circulating liposomes (PEG-liposomes). After an appropriate formulation of SOD in SA-liposomes, the therapeutic effect is strongly increased, as indicated by a reduction of about 40% of inflammation edema compared with treatment with nonencapsulated enzyme. Compared with SA-liposomes, PEG-liposomes show superior therapeutic activity. A second approach consists of the construction of a hydrophobic SOD derivative (Ac-SOD) that can be partially inserted within the lipid matrix of liposomes and that expresses enzymatic activity to the external medium. This hydrophobic enzyme, Ac-SOD, associated with liposomes (so called Ac-SOD-enzymosomes), is able to exert its therapeutic activity while circulating in the organism, regardless of the integrity of the liposomes. Ac-SOD-enzymosomes have a more rapid antiinflammatory effect than SOD liposomes, confirming that the release of Ac-SOD from liposomes is no longer required to achieve dismutation. Different methodologies for the preparation of SOD and Ac-SOD liposomal formulations (conventional and long circulating) have been established and are described in detail here.