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

每年约有180万人死于结核病，它是全世界导致大多数人死亡的传染病。导致这种疾病的病原体（结核分枝杆菌）存在于肺的免疫细胞（主要是肺泡巨噬细胞）中，因此溶性抗结核药物很难接近。因此，治疗结核病的主要挑战之一是在其细胞内定位获得高浓度的抗结核药物。表面修饰纳米颗粒是一种有前途的方法，可以选择性地向肺泡巨噬细胞递送高剂量的抗感染药物。然而，为了在细菌的居住地达到有效剂量，这种纳米颗粒给药系统需要与分枝杆菌共定位。众所周知，在肺部，结核分枝杆菌利用表面活性剂蛋白a （SP-A）受体进入肺泡巨噬细胞。此外，最近可以证明SP-A在与纳米颗粒结合时选择性地增加了它们的摄取。在本研究项目中，将设计一种基于纳米颗粒的系统，能够选择性地吸附SP-A，而吸附的蛋白质随后介导肺泡巨噬细胞的纳米颗粒内化并与分枝杆菌共定位。这种纳米颗粒与具有效应功能的生物分子之间的原位相互作用导致一定的生物效应可以被认为是生物源靶向。设计和研究经历这种受控生物纳米相互作用的纳米颗粒，可能是开发结核病治疗新治疗策略的起点，但也将为这种系统与人类肺部结构的一般相互作用提供新的见解。

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.