title: Lecithinized superoxide dismutase enhances its pharmacologic potency by increasing its cell membrane affinity.
abstract: We performed the present study to clarify whether lecithinized superoxide dismutase (PC-SOD) enhanced its pharmacologic potency by increasing its cell membrane affinity. PC-SOD, in which 4 molecules of a phosphatidylcholine (PC) derivative were covalently bound to each dimer of recombinant human CuZn-SOD (rhCuZn-SOD), was shown to have a high membrane affinity using a laser confocal imaging technique. PC-SOD efficiently scavenged superoxide anion (O2-) produced by phorbol myristate acetate (PMA)-stimulated human neutrophils (IC50 0.60 U/ml), and it exerted a dose-dependent scavenging effect (IC50 1.27 U/ml) even when the neutrophils were washed after incubation with PC-SOD. In contrast, neither unmodified SOD nor polyethylene glycol-bound SOD (PEG-SOD) showed a scavenging effect for washed neutrophils, even at a high concentration (100 U/ml). PC-SOD also showed a strong protective effect against human vascular endothelial cell damage caused by O2- generated by stimulated neutrophils, and PC-SOD was approximately 100-fold more potent than unmodified SOD (in vitro IC50 100 U/ml for PC-SOD and > 10,000 U/ml for unmodified SOD). Moreover, PC-SOD (50,000 U/kg) had an inhibitory effect on ischemia-reperfusion paw edema in mice, whereas neither unmodified SOD nor PEG-SOD had any effect. These results suggest that PC-SOD (designed to target for cell membranes) exerted a far higher pharmacologic activity by increasing cell membrane affinity than unmodified SOD and may be potentially useful for various clinical applications.
authors.affiliation: Division of Drug Delivery Systems, St. Marianna University, Kawasaki, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Igarashi
authors.forename: J
authors.initials: J
authors.lastname: Hoshino
authors.forename: A
authors.initials: A
authors.lastname: Ochiai
authors.forename: Y
authors.initials: Y
authors.lastname: Morizawa
authors.forename: Y
authors.initials: Y
authors.lastname: Mizushima
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004487:Edema / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010713:Phosphatidylcholines / Q000378:metabolism / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D010713:Phosphatidylcholines; D013482:Superoxide Dismutase