Abstract
ObjectivesTo obtain compensatory ultra-short echo time (UTE) imaging and T2-weighted (T2W) imaging of Watanabe heritable hyperlipidemic (WHHL) rabbits following dextran-coated magnetic nanocluster (DMNC) injection for the effective in vivo detection of inflammatory vascular wall.MethodsMagnetic nanoparticle was synthesized by thermal decomposition and encapsulated with dextran to prepare DMNC. The contrast enhancement efficiency of DMNC was investigated using UTE (repetition time [TR] = 5.58 and TE = 0.07 ms) and T2W (TR = 4000 and TE = 60 ms) imaging sequences. To confirm the internalization of DMNC into macrophages, DMNC-treated macrophages were visualized by cellular transmission electron microscope (TEM) and magnetic resonance (MR) imaging. WHHL rabbits expressing macrophage-rich plaques were subjected to UTE and T2W imaging before and after intravenous DMNC (120 μmol Fe/kg) treatment. Ex vivo MR imaging of plaques and immunostaining studies were also performed.ResultsPositive and negative contrast enhancement of DMNC solutions with increasing Fe concentrations were observed in UTE and T2W imaging, respectively. The relative signal intensities of the DMNC solution containing 2.9 mM Fe were calculated as 3.53 and 0.99 in UTE and T2W imaging, respectively. DMNC uptake into the macrophage cytoplasm was visualized by electron microscopy. Cellular MR imaging of DMNC-treated macrophages revealed relative signals of 3.00 in UTE imaging and 0.98 in T2W imaging. In vivo MR images revealed significant brightening and darkening of plaque areas in the WHHL rabbit 24 h after DMNC injection in UTE and T2W imaging, respectively. Ex vivo MR imaging results agreed with these in vivo MR imaging results. Histological analysis showed that DMNCs were localized to areas of inflammatory vascular wall.ConclusionsUsing compensatory UTE and T2W imaging in conjunction with DMNC is an effective approach for the noninvasive in vivo imaging of atherosclerotic plaque.
Highlights
Positive and negative contrast enhancement of dextran-coated magnetic nanocluster (DMNC) solutions with increasing Fe concentrations were observed in ultra-short echo time (UTE) and T2W imaging, respectively
Using compensatory UTE and T2W imaging in conjunction with DMNC is an effective approach for the noninvasive in vivo imaging of atherosclerotic plaque
Superparamagnetic nanoparticles have been widely applied as magnetic resonance (MR) imaging contrast agents and molecular imaging probes combined with a targeting moiety in clinical studies, as in magnetic cell tracking with MR imaging, molecular imaging via MR imaging, and MR imaging-guided theragnosis.[1,2,3,4,5,6]
Summary
Superparamagnetic nanoparticles have been widely applied as MR imaging contrast agents and molecular imaging probes combined with a targeting moiety in clinical studies, as in magnetic cell tracking with MR imaging, molecular imaging via MR imaging, and MR imaging-guided theragnosis.[1,2,3,4,5,6] In most cases, magnetic nanoparticles have been used as T2 shortening negative contrast agents in T2W imaging, but have rarely been used for T1 contrast enhancement because of the predominant spin diphase effect of magnetic nanoparticles.[7,8,9] A fundamental drawback of T2W imaging with negative contrast, is that the agent cannot be distinguished from other sources of signal loss in the image due to intrinsic signal voids, such as motion artifacts, hemorrhage, and organs with originally low background signals, such as lung (air) and lumen (blood). UTE imaging, which involves positive contrast based on extremely short echo time, allowing for T1 signal acquisition with suppressed T2 decay from magnetic nanoparticles, can supplement the limitations of negative contrast imaging.[12, 13] In this study, we developed a dextran-coated magnetic nanocluster (DMNC) as a molecular imaging probe to enable the precise detection of macrophages expressing scavenger receptor A (SR-A) via compensatory UTE and T2W imaging. To assess the compensatory UTE and T2W imaging potential of DMNC, solution MR imaging and cellular MR imaging experiments were performed and in vivo MR imaging was conducted in WHHL rabbits as a chronic inflammation model with macrophage-initiated atherosclerotic plaques, following the intravenous injection of DMNC.[24,25,26] In atherosclerosis, macrophage accumulation leads to the formation of unstable plaques by inducing the production of various cytokines and chemokines, and may result in sudden death due to the rupture of the thrombus.[27,28,29] Compensatory UTE and T2W imaging of macrophages based on DMNC should overcome the limitations of a single negative contrast imaging sequence, provide accurate diagnoses, and facilitate the pathological investigation of atherosclerosis
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