title: Increased biological half-life of aerosolized liposomal recombinant human Cu/Zn superoxide dismutase in pigs.
abstract: Reactive oxygen species (ROS) are dangerous intermediates of cellular oxygen metabolisms, and are involved in pathogenesis of a wide range of diseases. Superoxide Dismutases (SODs) are an important part of antioxidant defense systems in mammalian cells capable of reducing the harmful effect of ROS on human tissues. Unfortunately, intravenously administered SOD shows a biological half-life of a few minutes, and enteral administration fails due to biodegradation of the enzyme in the gastrointestinal system. The aim of our study was to improve biological half-life of recombinant human Cu/Zn SOD (rhSOD) within systemic circulation by liposomal encapsulation and aerosolization into the lungs. We studied the feasibility of a "needle-free" route of drug administration via the lungs combined with the sustained release effect of liposomes in an experimental pig model. We studied 14 anesthetized pigs separated into three groups. The first group (n = 5) received 15 mg aerosolized liposomal rhSOD. The second group (n = 4) received 15 mg intravenously injected liposomal rhSOD. The third group (n = 5) served as an untreated control. We determined rhSOD concentration as well as activity within the lungs by the use of bronchoalveolar lavages (BALs). RhSOD plasma concentrations were determined by blood sampling. In animals treated with aerosolized liposomal rhSOD plasma concentration of the enzyme increased and formed a plateau ranging from 19 to 21 ng/mL over the whole observational period (5 h). At the end of the experiment 5 h after completion of aerosol administration 95.2% of peak plasma concentration was found in this group. Three and 5 h after completion of aerosolization leucocytes (p = 0.54, 0.40) in BALs as well as PaO2 (p = 0.44, 0.35), PaCO(2) (p = 0.83, 0.75), and pH (p = 0.07, 0.07) in arterial blood remained unchanged compared to baseline. In animals treated with intravenously injected liposomal rhSOD, plasma concentration of the enzyme substantially increased to 3987 ng/mL but rapidly decreased over the observational period (5 h). At the end of the experiment 14.1% of peak plasma concentration was found in this group. Aerosolization of liposomal rhSOD leads to long-term and uniform uptake into systemic circulation without acute deleterious effects on respiratory tract. Compared to intravenously administered liposomal rhSOD, biologic half-life within systemic circulation was substantially prolonged in aerosol-treated animals. It could be a feasible strategy for administration of radical scavenging enzymes for treatment of systemic diseases.
authors.affiliation: Orthopaedic Department, University Hospital Basel, Basel, Switzerland. KaipelM@uhbs.ch
authors.forename: Martin
authors.initials: M
authors.lastname: Kaipel
authors.forename: Andreas
authors.initials: A
authors.lastname: Wagner
authors.forename: Esther
authors.initials: E
authors.lastname: Wassermann
authors.forename: Karola
authors.initials: K
authors.lastname: Vorauer-Uhl
authors.forename: Richard
authors.initials: R
authors.lastname: Kellner
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.forename: Hermann
authors.initials: H
authors.lastname: Katinger
authors.forename: Roman
authors.initials: R
authors.lastname: Ullrich
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000831:Animals, Newborn; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003692:Delayed-Action Preparations; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013552:Swine
chemical_list: D000336:Aerosols; D003692:Delayed-Action Preparations; D016166:Free Radical Scavengers; D008081:Liposomes; D011994:Recombinant Proteins; D013482:Superoxide Dismutase