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- Title
Preparation and Preclinical Evaluation of Inhalable Particles Containing Rapamycin and Anti-Tuberculosis Agents for Induction of Autophagy.
- Authors
Gupta, Anuradha; Sharma, Deepak; Meena, Jairam; Pandya, Sanketkumar; Sachan, Madhur; Kumar, Sadan; Singh, Kavita; Mitra, Kalyan; Sharma, Sharad; Panda, Amulya; Gupta, Pushpa; Gupta, Umesh; Misra, Amit
- Abstract
Purpose: 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. Methods: 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. Results: Aerodynamic diameters of formulations were 0.7-4.7 μm. Inhaled particles reached deep lungs and were phagocytosed by alveolar macrophages, yielding AUC0-48 of 102 compared to 0.1 μg/ml × 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. Conclusions: 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.
- Subjects
RAPAMYCIN; MYCOBACTERIUM tuberculosis; INHALATION administration; ANTITUBERCULAR agents; AUTOPHAGY; THERAPEUTICS
- Publication
Pharmaceutical Research, 2016, Vol 33, Issue 8, p1899
- ISSN
0724-8741
- Publication type
Article
- DOI
10.1007/s11095-016-1926-0