Multi-slice computed tomography with N1177 identifies ruptured atherosclerotic plaques in rabbits

Abstract

Rupture-prone and ruptured plaques are characterized by the presence of large numbers of macrophages. N1177 is a contrast agent consisting of iodinated nanoparticles that are selectively phagocytosed by macrophages. The aim of this study was to investigate the effect of N1177 on the CT attenuation of rupture-prone and ruptured plaques in rabbits. In addition, we examined in vitro whether uptake of N1177 occurred without cytotoxic or pro-inflammatory effects on macrophages. In vitro, the viability of J774 macrophages was not affected by treatment with N1177. Moreover, N1177 had no effect on the phagocytic capacity or cytokine production of macrophages. For the in vivo experiments, 6 New Zealand White rabbits were fed a cholesterol-supplemented diet for 12-15 months, resulting in the development of large atherosclerotic plaques that resembled rupture-prone plaques in humans. In three rabbits, mechanical plaque rupture was induced by retrograde pullback of an embolic protection device. N1177 had no effect on the median density of rupture-prone plaques [35 HU (range 3-85) before injection vs. 32 HU (range 1-93) 2 h after injection of N1177; P > 0.05]. However, after induction of mechanical plaque rupture, the median density of the atherosclerotic plaques increased from 40 HU (range 6-86) before injection to 74 HU (range 14-111) 2 h after injection of N1177 (P < 0.001). Using time-of-flight static secondary ion mass spectrometry, the presence of N1177 nanoparticles was demonstrated in macrophage-rich areas of ruptured plaques, but not of non-ruptured plaques. In conclusion, our results show that N1177 is a contrast agent that can identify ruptured atherosclerotic plaques.

Toll-like receptor 7 stimulation by imiquimod induces macrophage autophagy and inflammation in atherosclerotic plaques

“…Numerous macrophages are present in the shoulder regions of rupture-prone life-threatening atherosclerotic plaques [20,22,36,38,39]. These cells produce matrix metalloproteinases that degrade the extracellular matrix [4,31] and induce smooth muscle cell (SMC) apoptosis, which leads to a decrease in collagen-producing cells [6], indicating that they play a major role in plaque destabilization and rupture.…”

Arterial double-contrast dual-energy MDCT: in-vivo rabbit atherosclerosis with iodinated nanoparticles and gadolinium agents

“…After six months, the rabbits developed complex atherosclerotic plaques in the aorta and iliac vessels. Recently it was shown that macrophages in atherosclerotic plaques of rabbits can be detected with CT after an intravenous injection of iodinated nanoparticles N1177 designed for the assessment of density of macrophages which are abundant in vulnerable plaques 3,4,5 . This material, which is based on iodine nanoparticles typically 100 nm in diameter, has a long circulation time in the body and it usually shows an optimal uptake by plaque between two hours to four hours after administration.…”

Nanotechnology and Diagnostic Imaging: New Advances in Contrast Agent Technology

“…In order to overcome these limitations, iodine is being incorporated into various engineered nanostructures. Some of the various strategies that have been employed include using nanoscale coordination polymers capable of carrying a large iodine payload [78], encapsulating the iodine in liposomes (Figure 3) [79,[84][85][86], using iodinated polymeric nanoparticles [80][81][82], and incorporating iodine into various other nanostructure [87][88][89]. These strategies lead to longer circulation times compared to conventional CT imaging agents, which can allow for the development of targeted imaging agents as well as CT contrast agents capable of molecular imaging [90].…”