Nanoparticle PET-CT Imaging of Macrophages in Inflammatory Atherosclerosis

Abstract

Background-Macrophages participate centrally in atherosclerosis, and macrophage markers (eg, CD68, correlate well with lesion severity and therapeutic modulation. On the basis of the avidity of lesional macrophages for polysaccharide-containing supramolecular structures such as nanoparticles, we have developed a new positron emission tomography (PET) agent with optimized pharmacokinetics to allow in vivo imaging at tracer concentrations. Methods and Results-A dextranated and DTPA-modified magnetofluorescent 20-nm nanoparticle was labeled with the PET tracer 64 Cu (1 mCi/0.1 mg nanoparticles) to yield a PET, magnetic resonance, and optically detectable imaging agent. Peak PET activity 24 hours after intravenous injection into mice deficient in apolipoprotein E with experimental atherosclerosis mapped to areas of high plaque load identified by computed tomography such as the aortic root and arch and correlated with magnetic resonance and optical imaging. Accumulated dose in apolipoprotein E-deficient aortas determined by gamma counting was 260% and in carotids 392% of respective wild-type organs (PϽ0.05 both). Autoradiography of aortas demonstrated uptake of the agent into macrophage-rich atheromata identified by Oil Red O staining of lipid deposits. The novel nanoagent accumulated predominantly in macrophages as determined by fluorescence microscopy and flow cytometry of cells dissociated from aortas. Conclusions-This report establishes the capability of a novel trimodality nanoparticle to directly detect macrophages in atherosclerotic plaques. Advantages include improved sensitivity; direct correlation of PET signal with an established biomarker (CD68); ability to readily quantify the PET signal, perform whole-body vascular surveys, and spatially localize and follow the trireporter by microscopy; and clinical translatability of the agent given similarities to magnetic resonance imaging probes in clinical trials. (Circulation. 2008;117:379-387.)

MRI-determined carotid artery flow velocities and wall shear stress in a mouse model of vulnerable and stable atherosclerotic plaque

“…Various imaging modalities have been used to study plaque formation and characteristics in the apoE−/− mouse model [9][10][11]. MRI has been used to study plaque burden in the abdominal aorta of mice [12][13][14][15], and recently, several studies have focused on pre-clinical evaluation of novel targeted contrast agents to identify molecular fingerprints of plaque vulnerability [7,[16][17][18][19][20].…”

Quantification of Inflammation Within Rabbit Atherosclerotic Plaques Using the Macrophage-Specific CT Contrast Agent N1177: A Comparison with 18F-FDG PET/CT and Histology

“…Additional inaccuracies may arise when attempts are made to distinguish the negative contrast due to USPIO accumulation from that secondary to vessel calcification or inherent image artifacts, although positive contrast methods such as gradient echo acquisition for superparamagnetic particles/ susceptibility may help the image interpretation (26). In recent work (27), a radiotracer was bound to iron oxide nanoparticles to quantify the accumulation of these particles using PET. Indeed, Nahrendorf et al (27) demonstrated a strong correlation between the activity measured with PET and macrophage content in corresponding sections of atherosclerotic plaques.…”

Collagens in the progression and complications of atherosclerosis

“…Plaque macrophages are then imaged using a variety of techniques including micro-single-photon emission computed tomography (micro-SPECT), magnetic resonance imaging (MRI), and near infrared fluorescence (NIRF) microscopy. [82][83][84] NIRF microscopy has also been used to image proteolysis in the plaque by detecting the degradation of fluorescent substrates for the MMPs and cathepsins in atherosclerotic plaques in live mice. 85,86 Investigators have used these methods to study plaque growth in mice, and plaque regression after statin treatment.…”