Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques

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

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

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 (Zr-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 Zr-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 Zr-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.

Original languageEnglish
Pages (from-to)755-761
Number of pages7
JournalCirculation Research
Volume112
Issue number5
DOIs
StatePublished - 1 Mar 2013
Externally publishedYes

Keywords

  • PET/MRI
  • atherosclerosis
  • inflammation
  • macrophage
  • molecular imaging
  • nanoparticles

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