The effect of DMSA-functionalized magnetic nanoparticles on transendothelial migration of monocytes in the murine lung via a beta2 integrin-dependent pathway.
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 x 10(15) 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-alpha in lung. Finally, the critical relevance of the beta(2) 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 beta(2) integrin-targeted interventions as promising strategies to reduce pulmonary side effects of MNPs-DMSA during biomedical applications.
Valois
Caroline R A
CR
Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília, Brasília, DF 70910-900, Brazil.
Braz
Juliana M
JM
Nunes
Eloiza S
ES
Vinolo
Marco A R
MA
Lima
Emilia C D
EC
Curi
Rui
R
Kuebler
Wolfgang M
WM
Azevedo
Ricardo B
RB
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018821:CD18 Antigens / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects*; D004727:Endothelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D008280:Magnetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D004113:Succimer / Q000494:pharmacology*
D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D012333:RNA, Messenger; D004113:Succimer