Tuberculosis (TB) is a communicable infectious disease caused by inhalation of tubercle bacilli, Mycobacterium tuberculosis, in airborne droplets (< 10 um in size) emitted by the coughing pulmonary patient. Upon deposition in the alveolus, the tubercle bacilli can be phagocytosed and grow within the alveolar macrophages (AMs), and be eventually released causing widespread infections in the lungs and other body sites. Despite the fact that therapies are available for controlling the vast majority of existing cases, the incidence of TB is increasing. This is because many TB patients (AIDS patients, elderly, drug abusers and the urban poor) have significant social problems, and compliance with multi-month drug therapy is frequently difficult. Further, current therapies, which require patients to take large oral doses of drugs, such as isoniazid, can often produce significant side effects. This further compounds the compliance problem. Therefore, the major objectives of this research proposal are to improve the overall treatment rate of TB by developing specific pulmonary sustained drug delivery systems that would (1) improve patient's compliance with drug therapy, (2) reduce the manifestation of associated side effects, and (3) target the therapy to AM which plays an important role in the pathogenesis of TB. These objectives will be accomplished by pursuing the following specific aims: (1) developing drug-impregnated biodegradable nanoparticles of different size, shape, loading factor, and crystallinity and to determine the effects of these parameters on the release kinetics of the model antitubercular drug, isoniazid, (2) characterizing nanoparticle interaction with alveolar macrophages, (3) determining the pulmonary disposition of inhaled nanoparticles and nanoparticle-associated drugs in vivo, (4) identifying acute and chronic effects of inhaled nanoparticles on lung function and morphology, and (5) evaluating the ability of inhaled isoniazid-impregnated nanoparticles to arrest or reverse the progression of TB in an experimental animal model. It is expected this multidisciplinary approach will provide significant advances in the treatment of TB and other airway diseases in which sustained drug release or targeting AMs would be advantageous.
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