@article {19798, title = {Targeting macrophages with inhalable microparticulate system for the treatment of tuberculosis}, journal = {Chem2Nature - Second School}, year = {2017}, month = {2017-06-05 00:00:00}, address = {Porto, Portugal}, abstract = {

Tuberculosis (TB) is an airborne disease of enormous public health impact. TB is initiated by inhalation of Mycobacterium tuberculosis (Mtb) infected droplets that travel the upper respiratory tract and bronchi, being deposited in the lower airways. Here, Mtb is thought to be recognized and phagocytosed by macrophages which are resident cells of the alveolar lumen. In some cases, Mtb is able to survive within macrophages phagosomes by arresting phagolysosome biogenesis and avoid direct cidal mechanisms, leading to granuloma tissue formation that hampers an efficient treatment.

In recent years, inhalable dry powder microparticulate systems (MPs) have been explored to target delivery of drugs into lung alveoli and infected macrophages. To reach the lower airways and alveoli MPs should have an aerodynamic diameter of 1-5 μm and should be spherical with a 1-6 μm diameter to be phagocytized by macrophages. Phagocytosis of drug carrier systems by infected macrophages has the potential to influx drugs directly to the intracellular pathogen, improving treatment efficiency and reducing drugs side effects.

Thus, the aim of this work was to target macrophages with previously developed MPs composed of gelatin, BSA and a new purine derivative drug (P3) which has previously demonstrated high in vitro anti-TB activity. MPs were developed to meet the internalization range of macrophages and alveoli particle deposition. These systems incorporate superparamagnetic iron oxide nanoparticles (SPIONs) so that P3 can be released in a controlled manner upon actuation of an external magnetic field. P3 release was monitored with an alternate magnetic field (AMF) of different frequencies and intensities during 30min to assess the most effective parameter.

For cell viability studies two different macrophages were used: THP-1 cell line of human macrophages and murine bone marrow derived macrophages (mBMDM). The macrophage targeting was performed culturing different mBMDM/MPs ratio for up to 24h. The internalization process was evaluated through H\&E staining and confocal microscopy. The MPs were successfully internalized by mBMDM without showing detrimental effects in cell viability.

Overall, the obtained results indicate that developed inhalable MPs present unique and promising features for targeting anti-TB drugs to alveolar macrophages which may provide a more efficient TB treatment.

Acknowledgments: M.S. Miranda and M.E. Gomes thank Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia (FCT) respectively the postdoctoral scholarship (SFRH/BPD/110868/2015) and grant (IF/00593/2015). Authors also thank project NORTE-01-0145-FEDER-000021 supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).

}, keywords = {microparticles, tuberculosis}, author = {Miranda, M. S. and Rodrigues, M. T. and Domingues, R. M. A. and Gon{\c c}alves, C. and Torrado, E. and Reis, R. L. and Pedrosa, J. and Gomes, M. E.} }