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

作     者：Wolfram C. Poller Evelyn Ramberger Philipp Boehm-Sturm Susanne Mueller Konstantin Moller Norbert Lowa Frank Wiekhorst Susanne Wagner Matthias Taupitz Eyk Schellenberger Gert Baumann Karl Stangl Verena Stangl Antje Ludwig 

作者机构：Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie Charite-Universitatsmedizin Berlin Campus Mitte Chariteplatz 1 10117 Berlin Germany Abteilung fur Experimentelle Neurologie Center for Stroke Research Charite-Universitatsmedizin Berlin Chariteplatz 1 10117 Berlin Germany Charite Core Facility '7 T experimental MRIs'Charite-Universitatsmedizin Berlin Chariteplatz 1 10117 Berlin Germany Physikalisch-Technische Bundesanstalt Abbestr. 2-12 10587Berlin Germany Institut fur Radiologie Charite-Universitatsmedizin Berlin Campus Mitte Charit@platz 1 10117 Berlin Germany DZHK (German Centre for Cardiovascular Research) partner site Berlin 10115 Berlin Germany Berlin Institute of Health (BIH) 10117 Berlin Germany 

出 版 物：《Nano Research》 (纳米研究（英文版）)

年 卷 期：2016年第9卷第11期

页      面：3437-3452页

核心收录：

学科分类：0808[工学-电气工程] 0809[工学-电子科学与技术（可授工学、理学学位）] 07[理学] 0805[工学-材料科学与工程（可授工学、理学学位）] 0702[理学-物理学] 

基　　金：supported by the Deutsche Forschungsgemeinschaft (DFG) within the Clinical Research Unit KFO 213 the Bundesministerium fur Bildung und Forschung (BMBF) Additional funding was provided by the DFG (EXC Neurocure) and the BMBF (Center for Stroke Research Berlin) ERA-NET-NEURON scheme funded by the European Commission (PBS) 

主　　题：atherosclerosis,unstable plaques,magnetic resonanceimaging decreased endothelial barrier function,superparamagnetic ironoxide nanoparticles 

摘      要：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.