According to the World Health Organization, one third of the world`s population is infected with tuberculosis (TB). Current treatment regimens are based on multiple drugs and dosages, via oral or injectable routes, and require prolonged periods to be effective. Recent strategies for anti-TB drug delivery systems consider inhalable dry powders a promising alternative to target delivery of reduced dosages directly to infected macrophages, with potential to significantly improve the therapeutics efficiency.

Thus, the aim of this work was to develop inhalable microparticulate systems (MPs) with magnetic responsiveness for pulmonary delivery of a new anti-TB drug, a purine derivative (P3). The MPs were produced using gelatine microgels casted over calcium carbonate cores as sacrificial templates. The cores also incorporated bovine serum albumin to increase the MPs surface area and respective drug loading capacity, and superparamagnetic iron oxide nanoparticles (SPIONs) for targeting and release the drug upon actuation of an alternate magnetic field (AMF). The size and morphology of the MPs were assessed by confocal microscopy, TEM and SEM. The incorporation of SPIONs within the MPs was confirmed by magnetic sorting, EDXS and TGA and their superparamagnetic behaviour assessed by SQUID. MPs have a diameter of 4.0±0.1 µm when swelled in water and 2.7±0.1 µm in dry powder form, both within the phagocytable range by macrophages. With an estimated aerodynamic diameter of 3.3±0.1 mm, the developed MPs present aerodynamic features enabling the efficient delivery of the drug to the lower airways. Moreover, P3 was successfully loaded into the MPs with an efficiency of 82.7±0.9 %. Considering the dissimilar pH values of the lung microenvironment and in the phagocytic vesicles within the macrophages, the P3 release profile was evaluated at pH 7.4 and 5.4 and in culture medium, at 37ºC. The drug release from the MPs showed an initial burst, which is higher at pH 5.4, followed by a sustained release stage. Moreover, a peak of P3 release can be triggered at pre-determined time points applying an external AMF. As a preliminary assessment, MPs carrying P3 loads up to 5IC90 were cultured in the presence of L929 cells for up to 7 days in basal medium in static and under the influence of a magnetic field. Nor the magnetic stimulation, nor the P3 loaded MPs concentration evidenced detrimental cytotoxicity to L929 cells.

Overall, the developed MPs present unique and promising features as drug carriers aiming at the treatment of tuberculosis.

 Acknowledgments: M.S. Miranda thanks Fundação para a Ciência e a Tecnologia (FCT) the postdoctoral scholarship (SFRH/BPD/110868/2015) and Recognize project (UTAP-ICDT/CTM-BIO/0023/2014).