Treat Or Track: Nanoagents in the Service of Health

Abstract

Atherosclerosis is the most common cause of death worldwide. However, although considerable progress has been achieved in understanding, diagnosis and treatment of atherosclerosis, some important parts of the puzzle still remain unknown.In their paper, Stein-Merlob et al. aimed to test the hypothesis that atherosclerotic plaques predisposed to thrombosis display an abnormal permeability and, second, that these thrombosis-prone areas are characterized by a high cell density. To answer these questions, the authors induced atherosclerotic plaques in 31 rabbits by balloon injury and 8 weeks of western diet (i.e., chow with 1% cholesterol) followed by 4 weeks of normal chow. To assess the impaired barrier function of the plaque endothelium, ultrasmall superparamagnetic iron oxide nanoparticles (CLIO) were synthesized and coated with dextran, followed by crosslinking and functionalization with a near infrared probe CyAm7 (unfortunately, no size or reference is given). At the end of the nutrition scheme, 21 animals received 2.5 mg/kg CLIO-CyAm7 and 3 received saline. After further 24 h, 9 animals were sacrificed and 15 received pharmacological trigger consisting of Russell viper venom and histamine to induce plaque thrombosis. The remaining 7 animals were administered Evans Blue in addition to 5 mg/kg CLIO-CyAm7, to assess whether endothelial barrier function was impaired. The animals underwent in vivo intravascular near-infrared fluorescence imaging (NIRF) and/or intravascular ultrasound, followed by ex vivo NIRF and histological analyses of the representative artery sections.The results showed that the nanoparticles accumulated at the densely cellularized luminal surface of the plaques, but also appeared in deeper parts (33%), if neovascularization was observable. Co-staining with Evans Blue revealed a good correlation between the dye penetration and the fluorescence signal of the CLIOs, which led the authors to the conclusion that the particles mainly accumulated in the areas of higher endothelial permeability. Histological analysis showed that the nanoparticles were taken up not only by macrophages, but also by endothelial and smooth muscle cells, although no numeric distribution was given in the paper. In 10 out of 15 animals, plaque-adherent thrombi were detected after pharmacological triggering and a quantitative analysis showed that the areas with such thrombi showed higher nanoparticle signals than those, which were thrombus-negative. Finally, intravascular NIRF and ultrasound showed a good correlation between CLIO-signal and the occurrence of plaque-adherent thrombi after pharmacological triggering.The authors conclude that the used nanoparticles accumulate preferentially in plaque areas with impaired barrier function and increased surface cellularity, and that those areas are prone to plaque thrombosis. Since the accumulation of iron oxide-based nanoparticles in these areas can also be visualized by magnetic resonance imaging,