Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI

Abstract

We investigated the ability of targeted immunomicelles to detect and assess macrophages in atherosclerotic plaque using MRI in vivo. There is a large clinical need for a noninvasive tool to assess atherosclerosis from a molecular and cellular standpoint. Macrophages play a central role in atherosclerosis and are associated with plaques vulnerable to rupture. Therefore, macrophage scavenger receptor (MSR) was chosen as a target for molecular MRI. MSR-targeted immunomicelles, micelles, and gadolinium-diethyltriaminepentaacetic acid (DTPA) were tested in ApoE؊/؊ and WT mice by using in vivo MRI. Confocal laser-scanning microscopy colocalization, macrophage immunostaining and MRI correlation, competitive inhibition, and various other analyses were performed. In vivo MRI revealed that at 24 h postinjection, immunomicelles provided a 79% increase in signal intensity of atherosclerotic aortas in ApoE؊/؊ mice compared with only 34% using untargeted micelles and no enhancement using gadolinium-DTPA. Confocal laser-scanning microscopy revealed colocalization between fluorescent immunomicelles and macrophages in plaques. There was a strong correlation between macrophage content in atherosclerotic plaques and the matched in vivo MRI results as measured by the percent normalized enhancement ratio. Monoclonal antibodies to MSR were able to significantly hinder immunomicelles from providing contrast enhancement of atherosclerotic vessels in vivo. Immunomicelles provided excellent validated in vivo enhancement of atherosclerotic plaques. The enhancement seen is related to the macrophage content of the atherosclerotic vessel areas imaged. Immunomicelles may aid in the detection of high macrophage content associated with plaques vulnerable to rupture. macrophage scavenger receptor ͉ molecular imaging ͉ vulnerable plaque ͉ immunomicelles ͉ gadolinium

Preparation and initial characterization of biodegradable particles containing gadolinium-DTPA contrast agent for enhanced MRI

“…The particles are spherically shaped, stable, and not agglomerated. The encapsulation of Gd-DTPA with this W/O/O protocol is similar to or higher than that shown with other encapsulation methods (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Most importantly, the Gd-DTPA-loaded microparticles were shown to augment contrast in in vitro studies similarly to Gd-DTPA alone.…”

“…Faranesh and colleagues (18) demonstrated the utility of the inclusion of small amounts of Gd-DTPA in PLGA microparticles for tracking a drug delivery vehicle. Additionally, several groups have created gadolinium-containing micelles, microspheres, nanoparticles, and liposomes for the purposes of targeting delivery or modifying the biodistribution to increase the site-specific concentration of gadolinium over that of aqueous gadolinium or gadolinium directly conjugated to the targeting molecule (19)(20)(21)(22)(23)(24)(25)(26). Toward the same goals, this article details a method for the entrapment of hydrophilic agents, specifically Gd-DTPA, with very high loading in a polymeric particulate system as well as work toward achieving a targetable imaging agent particle formulation for the detection of staged atherosclerosis.…”

Imaging of Inflamed and Vulnerable Plaque in Coronary Arteries with 18F-FDG PET/CT in Patients with Suppression of Myocardial Uptake Using a Low-Carbohydrate, High-Fat Preparation

“…These features include a thin fibrous cap greater than 65 mm and large lipid core (.40% of the plaque), are macrophage-rich, and have endothelial denudation. There are no accepted gold standard techniques to identify such plaques by noninvasive means (7,(20)(21)(22)(23)(24)(25)(26). Invasive means such as intravascular ultrasound, optical coherence tomography (27), thermography (28)(29)(30), or angioscopy (31) and invasive cardiac catheterization all have their limitations, from resolution to depth of penetration (optical coherence tomography).…”

The macrophage: Past, present and future

“…Remarkable progress on imaging within the living host [71] has already been made by multi-photon, fluorescent and NMR studies, e.g. in studying the recruitment of monocytes/macrophages to atherosclerotic plaques in mouse and in man.…”