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Nano Research

Article Title

Uptake of citrate-coated iron oxide nanoparticles into atherosclerotic lesions in mice occurs via accelerated transcytosis through plaque endothelial cells

Authors

Wolfram C. Poller, Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany DZHK (German Centre for Cardiovascular Research), partner site Berlin, 10115 Berlin, Germany Berlin Institute of Health (BIH), 10117 Berlin, Germany
Evelyn Ramberger, Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
Philipp Boehm-Sturm, Abteilung für Experimentelle Neurologie, Center for Stroke Research, Charité-Universittsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Charité Core Facility "7 T experimental MRIs", Charité-Universittsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
Susanne Mueller, Abteilung für Experimentelle Neurologie, Center for Stroke Research, Charité-Universittsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Charité Core Facility "7 T experimental MRIs", Charité-Universittsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
Konstantin Mller, Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
Norbert Lwa, Physikalisch-Technische Bundesanstalt, Abbestr. 2-12, 10587 Berlin, Germany
Frank Wiekhorst, Physikalisch-Technische Bundesanstalt, Abbestr. 2-12, 10587 Berlin, Germany
Susanne Wagner, Institut für Radiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
Matthias Taupitz, Institut für Radiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
Eyk Schellenberger, Institut für Radiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
Gert Baumann, Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany DZHK (German Centre for Cardiovascular Research), partner site Berlin, 10115 Berlin, Germany
Karl Stangl, Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany DZHK (German Centre for Cardiovascular Research), partner site Berlin, 10115 Berlin, Germany
Verena Stangl, Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany DZHK (German Centre for Cardiovascular Research), partner site Berlin, 10115 Berlin, Germany
Antje Ludwig, Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité-Universittsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany DZHK (German Centre for Cardiovascular Research), partner site Berlin, 10115 Berlin, Germany

Keywords

atherosclerosis, unstable plaques, magnetic resonance imaging, decreased endothelial barrier function, superparamagnetic iron oxide nanoparticles

Abstract

ABSTRACT Very small superparamagnetic iron oxide nanoparticles (VSOPs) rapidly accumulate in atherosclerotic lesions, thereby enabling plaque visualization by magnetic resonance imaging (MRI). This study was performed to identify the uptake mechanisms of VSOPs into atherosclerotic plaques. Low-density lipoprotein receptor-deficient (LDLR−/−) mice with advanced atherosclerosis were analyzed using MRI and transmission electron microscopy (TEM) at various time points after intravenous administration of VSOPs. Post-mortem MRI detected VSOP labeling of atherosclerotic plaques 10 min after injection, and the signal increased over the first 3 h. TEM revealed that the intensive plaque labeling was mediated by accelerated transcytosis of VSOPs through endothelial cells overlaying atherosclerotic lesions. Experiments with endocytosis inhibitors and small interfering RNA (siRNA) revealed a dynamin-dependent mechanism involving both clathrin- and caveolin-mediated processes. In cell culture experiments, endothelial VSOP uptake was enhanced under proatherogenic flow and TNFα stimulation, conditions that are both present in plaque areas. Our study demonstrates that VSOPs enable non-invasive MRI assessment of accelerated endothelial transcytosis, an important pathomechanism in atherosclerotic plaque formation.

Graphical Abstract

Publisher

Tsinghua University Press

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