한빛사논문
Maulik D. Majmudar, Jeongsoo Yoo, Edmund J. Keliher, Jessica J. Truelove, Yoshiko Iwamoto, Brena Sena, Partha Dutta, Anna Borodovsky, Kevin Fitzgerald, Marcelo F. Di Carli, Peter Libby, Daniel G. Anderson, Filip K. Swirski, Ralph Weissleder*, Matthias Nahrendorf*
From the Center for Systems Biology, Massachusetts General Hospital, Boston, MA (M.D.M., J.Y., E.J.K., J.J.T., Y.I., B.S., P.D., F.K.S., R.W., M.N.); Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA (M.D.M., P.L.); Department of Molecular Medicine, Kyungpook National University School of Medicine, Daegu, South Korea (J.Y.); Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women’s Hospital, Boston, MA (M.F.D.C.); David H. Koch Institute for Integrative Cancer Research (D.G.A.), Department of Chemical Engineering (D.G.A.), Division of Health Science Technology (D.G.A.), Massachusetts Institute of Technology, Cambridge, MA; and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
*Correspondence to Ralph Weissleder, Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114. or Matthias Nahrendorf, Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114.
Drs Majmudar and Yoo contributed equally to this study
Abstract
Rationale: Myeloid cell content in atherosclerotic plaques associates with rupture and thrombosis. Thus, imaging of lesional monocytes and macrophages could serve as a biomarker of disease progression and therapeutic intervention.
Objective: To noninvasively assess plaque inflammation with dextran nanoparticle (DNP)-facilitated hybrid positron emission tomography/magnetic resonance imaging (PET/MRI).
Methods and Results: Using clinically approved building blocks, we systematically developed 13-nm polymeric nanoparticles consisting of cross-linked short chain dextrans, which were modified with desferoxamine for zirconium-89 radiolabeling (89Zr-DNP) and a near-infrared fluorochrome (VT680) for microscopic and cellular validation. Flow cytometry of cells isolated from excised aortas showed DNP uptake predominantly in monocytes and macrophages (76.7%) and lower signal originating from other leukocytes, such as neutrophils and lymphocytes (11.8% and 0.7%, P< 0.05 versus monocytes and macrophages). DNP colocalized with the myeloid cell marker CD11b on immunohistochemistry. PET/MRI revealed high uptake of 89Zr-DNP in the aortic root of apolipoprotein E knock out (ApoE-/-) mice (standard uptake value, ApoE-/- mice versus wild-type controls, 1.9±0.28 versus 1.3±0.03; P< 0.05), corroborated by ex vivo scintillation counting and autoradiography. Therapeutic silencing of the monocyte-recruiting receptor C-C chemokine receptor type 2 with short-interfering RNA decreased 89Zr-DNP plaque signal (P< 0.05) and inflammatory gene expression (P<0.05).
Conclusions: Hybrid PET/MRI with a 13-nm DNP enables noninvasive assessment of inflammation in experimental atherosclerotic plaques and reports on therapeutic efficacy of anti-inflammatory therapy.
Key Words: atherosclerosis, inflammation, macrophage, molecular imaging, nanoparticles, PET/MRI
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