Journal
PHARMACEUTICAL RESEARCH
Volume 33, Issue 8, Pages 1899-1912Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-016-1926-0
Keywords
autophagy; biodistribution; dry powder inhalation; macrophage targeting; microparticles; microspheres; pharmacokinetics; pulmonary drug delivery; tuberculosis
Funding
- Council of Scientific and Industrial Research [BSC0112, ESC0103]
- CDRI [9212]
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Mycobacterium tuberculosis (Mtb) inhibits host defense mechanisms, including autophagy. We investigated particles containing rapamycin (RAP) alone or in combination with isoniazid (INH) and rifabutin (RFB) for: targeting lung macrophages on inhalation; inducing autophagy; and killing macrophage-resident Mtb and/or augmenting anti-tuberculosis (TB) drugs. PLGA and drugs were spray-dried. Pharmacokinetics, partial biodistribution (LC-MS/MS) and efficacy (colony forming units, qPCR, acid fast staining, histopathology) in mice following dry powder inhalation were evaluated. Aerodynamic diameters of formulations were 0.7-4.7 mu m. Inhaled particles reached deep lungs and were phagocytosed by alveolar macrophages, yielding AUC0-48 of 102 compared to 0.1 mu g/ml x h obtained with equivalent intravenous dose. RAP particles induced more autophagy in Mtb-infected macrophages than solutions. Inhaled particles containing RAP alone in daily, alternate-day and weekly dosing regimens reduced bacterial burden in lungs and spleens, inducing autophagy and phagosome-lysosome fusion. Inhalation of particles containing RAP with INH and RFB cleared the lungs and spleens of culturable bacteria. Targeting a potent autophagy-inducing agent to airway and lung macrophages alone is feasible, but not sufficient to eliminate Mtb. Combination of macrophage-targeted inhaled RAP with classical anti-TB drugs contributes to restoring tissue architecture and killing Mtb.
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