Intravenous administration of superoxide dismutase entrapped in long circulating liposomes

Abstract

Rheumatoid arthritis (RA) is a prevalent and debilitating autoimmune disease that affects the joints. RA is characterized by an infiltration of the affected joint by blood-derived cells. In response to activation, these cells generate reactive oxygen species, resulting in an oxidative stress situation. One approach to counteract this oxidative stress situation is the use of antioxidants as therapeutic agents. The free radical scavenger enzyme superoxide dismutase (SOD) may be used as a therapeutic agent in rheumatoid arthritis, but its rapid elimination from the circulation is a major limitation. Targeted delivery of SOD may overcome this limitation. In this study, the utility of PEGylated liposomes (PEG-liposomes) for targeting SOD to arthritic sites was explored. The targeting of SOD to arthritic sites following intravenous administration of both PEG-liposomes and positively charged liposomes lacking PEG but containing stearylamine (SA-liposomes) in rats with adjuvant arthritis was studied. At 24 h post injection, the blood levels of long circulating liposomes with a mean size of 0.11 micrometer and 0.20 micrometer were 8- and 3-fold higher, respectively, as compared to the SA-liposomes. The majority of SOD administered in liposomal form remains within the liposomes when they circulate in the bloodstream. The highest target uptake was observed with PEG-liposomes with a mean size of 0.11 micrometer and the lowest uptake with the SA-liposomes. These results demonstrate that SOD can be targeted to inflamed sites most efficiently via small-sized PEG-liposomes. Small-sized PEG-coated liposomes are to be preferred if prolonged circulation and enhanced localization of SOD at arthritic sites are desired.

Platelet-Endothelial Cell Adhesion Molecule-1-Directed Endothelial Targeting of Superoxide Dismutase Alleviates Oxidative Stress Caused by Either Extracellular or Intracellular Superoxide

“…Diverse chemical modifications of SOD have been designed to prolong the circulation time and improve its delivery, including coupling with polyethylene glycol, mannose, succinylate, and putrescine encapsulation into liposomes (Freeman et al, 1983;Fujita et al, 1992;Corvo et al, 1999). Some of these derivatives (e.g., polyethylene glycol -SOD, and some SOD mimetics) showed enhanced potency in animal models of systemic (e.g., sepsis) and focal oxidative stress (Tamura et al, 1988;Day et al, 1995;Corvo et al, 1999;Duann et al, 2006). Considerable efforts have also been devoted to optimize SOD delivery to endothelial cells, arguably one of the most important therapeutic targets in vascular oxidative stress.…”

Therapeutic Efficacy of Liposome-Encapsulated Gentamicin in Rat Klebsiella pneumoniae Pneumonia in Relation to Impaired Host Defense and Low Bacterial Susceptibility to Gentamicin

“…Liposomes have attracted considerable interest as targeted drug carriers in infectious diseases. A number of studies have convincingly demonstrated that so-called long-circulating liposomes tend to localize preferentially at foci of infection or inflammation after intravenous administration (1,9,11,17,19). The preferential localization appears to be the result of the inflammatory response provoking a locally increased capillary permeability, allowing liposome extravasation.…”

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“…Preferential localization of SSL at sites of infection or inflammation that have developed outside the MPS has been reported by a number of investigators (7)(8)(9)(10)(11)(12)(13). Which host factors contribute to selective extravasation of SSL at infectious or inflammatory foci is not clear.…”

“…In experimental models representing a variety of inflammatory and infectious foci outside the MPS, substantial SSL localization at the site of infection has been demonstrated. The presence of an infectious process is essential as SSL localization in uninfected controls is limited (7)(8)(9)(10)(11)(12)(13). Previous reports have suggested that presence of the long circulation property is also essential to achieve significant localization at the target site (5)(6)14).…”