Surfactant protein A - mediated biogenic targeting of alveolar macrophages using surface-modified nanoparticles for treatment of pulmonary tuberculosis

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With about 1.8 millions deaths per year, tuberculosis is the infectious disease that kills most people worldwide. The pathogen being responsible for this disease (Mycobacterium tuberculosis) resides inside immune cells of the lungs (mainly alveolar macrophages), and is therefore hardly accessible for solubilized anti-tuberculosis drugs. Therefore, one of the main challenges in the treatment of tuberculosis is to achieve high concentrations of anti-tuberculosis drugs at its intracellular localization. A promising approach to selectively deliver high doses of anti-infective drugs to alveolar macrophages are surface-modified nanoparticles. However, to reach effective doses at the bacterial site of residence, such nanoparticulate drug delivery systems would need to co-localize with the mycobacteria. It is known that in the lungs, Mycobacterium tuberculosis exploits a Surfactant protein A (SP-A) receptor to enter the alveolar macrophages. Further, it could recently be demonstrated that SP-A selectively increases the uptake of nanoparticles when binding to them. In this research project, a nanoparticle-based systems will be designed that is capable to selectively adsorb SP-A, whereas the adsorbed protein subsequently mediates the nanoparticle internalization by alveolar macrophages and co-localization with mycobacteria. Such an in situ interaction between nanoparticles and biomolecules bearing an effector function that leads to a certain biological effect could be considered as biogenic targeting. The design and investigation of nanoparticles undergoing such controlled bio-nano interactions, could be a starting basis for the development of new therapeutic strategies in tuberculosis treatment, but would also give new insights in general interactions of such systems with the structures of the human lungs.