Delivery of antioxidant enzyme proteins to the lung.
Protection of alveolar epithelial cells (alveolocytes) and vascular endothelial cells against pulmonary oxidative stress is an important problem. An inadequate delivery to the target cells limits the protective utility of the antioxidant enzymes, superoxide dismutase (SOD) and catalase. SOD and catalase modifications, such as coupling with polyethylene glycol and encapsulation in liposomes, prolong the life span of the active enzymes in vivo. The airway administration of SOD and catalase protects alveolocytes against hyperoxic oxidative stress. Although pulmonary endothelium is poorly accessible from the airways, it is accessible from circulation. However, antioxidant enzymes and their derivatives display poor targeting to pulmonary endothelium. To improve the targeting and provide intracellular delivery to endothelium, the enzymes can be conjugated with antibodies against endothelial antigens, such as angiotensin-converting enzyme and adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) or platelet-endothelial cell adhesion molecule-1 (PECAM-1)]. These immunoconjugates accumulate in the pulmonary vasculature in intact animals, enter endothelium, and augment the antioxidant defenses. The immunoconjugates directed against ICAM-1 and PECAM-1 may also provide a secondary therapeutic benefit by blocking of sequestration and infiltration of leukocytes in the lungs. Further investigations are necessary to evaluate the therapeutic effectiveness of the vascular immunotargeting of antioxidant enzymes and solve technical problems associated with production of safe, clinically useful conjugates.
Muzykantov
V R
VR
Institute for Environmental Medicine and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. muzykant@mail.med.upenn.edu
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000378:metabolism; D002374:Catalase / Q000008:administration & dosage* / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D008168:Lung / Q000187:drug effects*; D008171:Lung Diseases / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000378:metabolism
D000975:Antioxidants; D002374:Catalase; D013482:Superoxide Dismutase