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(Circulation. 2008;117:379-387.)
© 2008 American Heart Association, Inc.

Imaging

Nanoparticle PET-CT Imaging of Macrophages in Inflammatory Atherosclerosis

Matthias Nahrendorf, MD; Hanwen Zhang, PhD; Sheena Hembrador, BS; Peter Panizzi, PhD; David E. Sosnovik, MD; Elena Aikawa, MD, PhD; Peter Libby, MD; Filip K. Swirski, PhD; Ralph Weissleder, MD, PhD

From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (M.N., R.W.); Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Charlestown (M.N., H.Z., S.H., P.P., D.E.S., E.A., F.K.S., R.W.); Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis at Harvard Medical School, Boston, Mass (M.N., E.A., P.L., R.W.); Department of Cardiology, Massachusetts General Hospital, Boston (D.E.S.); and Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (P.L.).

Correspondence to Ralph Weissleder, MD, PhD, MGH-CSB, 185 Cambridge St, Boston, MA 02114. E-mail rweissleder{at}mgh.harvard.edu

Received August 3, 2007; accepted October 19, 2007.

Background— Macrophages participate centrally in atherosclerosis, and macrophage markers (eg, CD68, MAC-3) 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 ⁶⁴Cu (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 (P<0.05 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 117: 331-332. [Full Text]