Influence of physicochemical properties of Nanoparticles on mucociliary and macrophage cleareance
Final Report Abstract
The results of the presented project period could clarify several points as addressed in the original proposal: considering particle-mucus interactions, we could show by the applied ex vivo model that individual particle properties seem less important in the context of mucociliary clearance. This was a surprising result, as previous findings implied significant differences in particle clearance depending on surface chemistry. However, in the course of the reported period we were able to improve the experimental setup significantly, elucidating that these previous results may partly have resulted from artifacts during the measurements. Using additional in silico modeling, the described results could be confirmed to be mainly due to fluid dynamics of the mucus layer. Molecular interactions between mucus and particles as measured by AFM, as well as mobility of particles in artificial or native mucus are planned for the near future with promising preliminary work already accomplished. With respect to nanoparticle inhalation and deposition into the alveolar region, there is a general need in fundamentally understanding bio-nano interactions that occur in the physiological environment of the deep lungs. This can be considered as a major challenge in pulmonary Nanomedicine, and is actually an indispensable prerequisite to be investigated in terms of Nano-safety. In this context, protein adsorption to nanoparticles in the peripheral lungs is a crucial intermediate effect between nanoparticle deposition on the one hand, and particle clearance, translocation or also toxic effects on the other hand. We could successfully demonstrate that the lung specific protein Surfactant Protein A can enhance the association and uptake by alveolar macrophages, whereas albumin as the most abundant protein in the blood stream did not. We hereby provided evidence that after inhalation of nanoparticles, where the first encountered body liquid is the alveolar lining fluid a different corona and thus different biological behavior may result than after direct administration to the blood stream. These findings demonstrate that when new nanomaterials shall be evaluated concerning their potential biological effects after inhalation, it is important to take SP-A into account when investigating bio-nano interactions within the lungs. With respect to potential applications in pulmonary drug delivery, such SP-A triggered effects could eventually be exploited for new targeting strategies, e.g. to treat alveolar macrophage-related diseases like tuberculosis. Interestingly, preliminary results on SP-A-mediated effects on macrophage clearance of nanoparticles in presence of phospholipids, which are the main constituents of pulmonary surfactant, revealed an inhibitory effect compared to SP-A. These findings may indicate that the whole entity of pulmonary surfactant must be considered as a non-cellular biological barrier to nanoparticles. Especially the question in how far the very sensitively balanced situation in pulmonary surfactant concerning immunological effects does decide over the biological fate of inhaled nanoparticles is of tremendous importance and must be investigated.
Publications
- Interactions of particles with the alveolar lining fluid: Role of surfactant proteins; Annual meeting of the German Pharmaceutical Society (DPhG) 2009, Jena, Germany
Ruge CA, Bur M, Schaefer UF, Lehr CM
- Computational Fluid Dynamics of Nanoparticle Deposition in Mucus and Mucociliary Clearance, ISAM Conference 2011, Rotterdam, The Netherlands
Kirch J, Guenther M, Doshi N, Schaefer UF, Schneider M, Mitragotri S, Lehr CM
- Computational Fluid Dynamics of Nanoparticle Deposition in the Lung and Mucociliary Clearance; MBM 2011, Frankfurt, Germany
Kirch J, Guenther M, Schaefer UF, Schneider M, Lehr CM
- Interaction of metal oxide nanoparticles with lung surfactant protein A, European Journal of Biopharmaceutics, 2011; 77(3):1376-9
Schulze C, Schaefer UF, Ruge CA, Wohlleben W, Lehr CM
- Template-assisted polyelectrolyte encapsulation of nanoparticles into dispersible, hierarchically nanostructured microfibers (2011) Advanced Materials, 23 (11), pp. 1376-1379
Kohler D., Schneider M., Krüger M., Lehr C.-M., Möhwald H., Wang D.
- The Influence of the Lung Relevant Pulmonary Surfactant Protein A on Nanoparticle Clearance by Alveolar Macrophages, ISAM Conference 2011, Rotterdam, The Netherlands
Ruge CA
