title: Intraperitoneal injection improves the uptake of nanoparticle-labeled high-density lipoprotein to atherosclerotic plaques compared with intravenous injection: a multimodal imaging study in ApoE knockout mice.
abstract: BACKGROUND
  The aim of this study was to assess whether high-density lipoprotein (HDL) labeled with superparamagnetic iron oxide nanoparticles (SPIOs) and quantum dots was able to detect atherosclerotic lesions in mice after intravenous and intraperitoneal injection by multimodal imaging.
  
  
  RESULTS
  Nanoparticle-labeled HDLs (NP-HDLs) were characterized in vitro by dynamic light scattering and size exclusion chromatography with subsequent cholesterol and fluorescence measurements. For biodistribution and blood clearance studies, NP-HDL(SPIOs) radiolabeled with (59)Fe (NP-HDL(59Fe-SPIOs)) were injected intravenously or intraperitoneally into ApoE knockout mice (n=6), and radioactivity was measured using a gamma counter. NP-HDL accumulation within atherosclerotic plaques in vivo and ex vivo was estimated by MRI at 7 Tesla, ex vivo confocal fluorescence microscopy, x-ray fluorescence microscopy, and histological analysis (n=3). Statistical analyses were performed using a 2-tailed Student t-test. In vitro characterization of NP-HDL confirmed properties similar to endogenous HDL. Blood concentration time curves showed a biexponential decrease for the intravenous injection, whereas a slow increase followed by a steady state was noted for intraperitoneal injection. Radioactivity measurements showed predominant accumulation in the liver and spleen after both application approaches. NP-HDL(59Fe-SPIOs) uptake into atherosclerotic plaques increased significantly after intraperitoneal compared with intravenous injection (P<0.01). In vivo MRI showed an increased uptake of NP-HDL into atherosclerotic lesions after intraperitoneal injection, which was confirmed by ex vivo MRI, x-ray fluorescence microscopy, confocal fluorescence microscopy, and histological analysis.
  
  
  CONCLUSIONS
  In vivo MRI and ex vivo multimodal imaging of atherosclerotic plaque using NP-HDL is feasible, and intraperitoneal application improves the uptake within vessel wall lesions compared with intravenous injection.
authors.affiliation: Departments of Diagnostic and Interventional Radiology.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jung
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaul
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Bruns
authors.forename: Tanja
authors.initials: T
authors.lastname: Dučić
authors.forename: Barbara
authors.initials: B
authors.lastname: Freund
authors.forename: Markus
authors.initials: M
authors.lastname: Heine
authors.forename: Rudolph
authors.initials: R
authors.lastname: Reimer
authors.forename: Alke
authors.initials: A
authors.lastname: Meents
authors.forename: Sunhild C
authors.initials: SC
authors.lastname: Salmen
authors.forename: Horst
authors.initials: H
authors.lastname: Weller
authors.forename: Peter
authors.initials: P
authors.lastname: Nielsen
authors.forename: Gerhard
authors.initials: G
authors.lastname: Adam
authors.forename: Jörg
authors.initials: J
authors.lastname: Heeren
authors.forename: Harald
authors.initials: H
authors.lastname: Ittrich
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005240:Feasibility Studies; D052203:Ferrosoferric Oxide / Q000008:administration & dosage*; D006801:Humans; D007274:Injections, Intraperitoneal; D008075:Lipoproteins, HDL / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D053768:Metal Nanoparticles / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; C025121:apolipoprotein E-rich HDL; C427127:superparamagnetic blood pool agent; D052203:Ferrosoferric Oxide
keywords: atherosclerosis; magnetic resonance imaging; quantum dots