The effect of DMSA-functionalized magnetic nanoparticles on transendothelial migration of monocytes in the murine lung via a β2 integrin-dependent pathway

• Published in: Biomaterials Vol. 31; no. 2; pp. 366 - 374
• Main Authors: Valois, Caroline R.A, Braz, Juliana M, Nunes, Eloiza S, Vinolo, Marco A.R, Lima, Emilia C.D, Curi, Rui, Kuebler, Wolfgang M, Azevedo, Ricardo B
• Format: Journal Article
• Language: English
• Published: 01-01-2010
• Subjects: Advanced Basic Science; Dentistry; Selectin; Integrin; Leukocyte; Nanoparticle; Lung; Cell adhesion
• ISSN: 0142-9612
• DOI: 10.1016/j.biomaterials.2009.09.053

Abstract Magnetic nanoparticles surface-functionalized with meso-2,3-dimercaptosuccinic acid (MNPs-DMSA) constitute an innovative and promising approach for tissue- and cell-targeted delivery of therapeutic drugs in the lung. Transendothelial migration of leukocytes in the lung is a side effect of endovenous administration of MNPs-DMSA. Using cytologic and phenotypic analysis of murine bronchoalveolar lavage cells, we identified monocytes/macrophages as the main subpopulation of leukocytes involved in this process. Moreover, ultrastructural analysis revealed the presence of nanoparticles inside of numerous macrophages from bronchoalveolar lavage. MNPs-DMSA at concentrations as high as 1 × 1015 nanoparticles/mL had no toxic effects on macrophages, as evidenced by 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. Notably, MNPs-DMSA up-regulated the mRNA expression of E-, L- and P-selectin and macrophage-1 antigen in the murine lung. Upregulation of these cell adhesion molecules was associated with an increased concentration of tumor necrosis factor-α in lung. Finally, the critical relevance of the β2 integrin-dependent pathway in leukocyte transmigration elicited by MNPs-DMSA was demonstrated by use of knockout mice. Our results characterize mechanisms of the pro-inflammatory effects of MNPs-DMSA in the lung, and identify β2 integrin-targeted interventions as promising strategies to reduce pulmonary side effects of MNPs-DMSA during biomedical applications.