Asthma is the most common chronic illness in childhood and affects 5 to 10% of the population. The disease is characterized by acute bronchoconstriction, chronic inflammation, and airway remodeling which may lead to progressive, irreversible lung damage. Current asthma therapy is directed at reducing the lung inflammation with the use of anti-inflammatory drugs, such as inhaled corticosteroids. If administered early in the course of the disease, they may prevent progression of the disease. However, current treatment regimens are limited by toxicity and non-compliance by the patients. Compliance is critical in interrupting the chronic inflammation and subsequent progression of asthma. Problems with compliance lead to increased hospitalizations and risk of sudden death. We propose to investigate the hypothesis that when budesonide, a frequently prescribed inhaled steroid, is encapsulated into sterically-stabilized """"""""stealth"""""""" liposomes, it prevents inflammation of asthma in lower doses given at less frequent intervals compared to conventional daily steroid therapy. The hypothesis will be tested in a mouse model of asthma. Initial studies will define the optimal doses and frequency of dosing intervals to decrease lung inflammation, airway responsiveness to methacholine challenge, as well as toxicity of frequent dosing of the drug-liposome complex. Studies will also be performed to evaluate the stability of the drug-liposome complex. Liposomes, which are lipid bi-layer vesicles will be sterically stabilized with polyethylene glycol to encapsulate the steroid. Then the drug-encapsulated liposome will be tested in the asthma model. Asthma model will be produced in C57BI/6 mice using ovalbumin (OVA) sensitization. Experiments will be conducted on day 25, after sensitization is completed (baseline). The sensitized animals will receive aerosolized: 1) budesonide encapsulated in stealth liposomes weekly; 2) budesonide (without liposomes) either daily or weekly; 3) empty stealth liposomes (without drug) weekly. All treatment groups will be compared to 1) untreated sensitized 2) unsensitized normal mice. Histopathological examination of the lung tissues and serial measurements of eosinophil-peroxidase activity, peripheral blood eosinophil counts, and total serum IgE levels will be obtained weekly. Airway responsiveness to methacholine challenge on spontaneously breathing, intubated conscious mice will be obtained every two weeks, for sixteen weeks. Levels of budesonide will also be evaluated in bronchioalveolar lavage fluid, blood, and urine from treated animals using high performance liquid chromatography. This will be the first study, aimed at developing a slow release drug delivery system for inhaled steroids using stealth liposomes, with a potential to reduce toxicity and improve compliance. ? ?
