title: Quantitative Activity Measurements of Brown Adipose Tissue at 7 T Magnetic Resonance Imaging After Application of Triglyceride-Rich Lipoprotein 59Fe-Superparamagnetic Iron Oxide Nanoparticle: Intravenous Versus Intraperitoneal Approach.
abstract: OBJECTIVE
  The aim of this study was to determine metabolic activity of brown adipose tissue (BAT) with in vivo magnetic resonance imaging (MRI) after intravenous (IV) and intraperitoneal (IP) injection of radioactively labeled superparamagnetic iron oxide nanoparticles (SPIOs) embedded into a lipoprotein layer.
  
  
  METHODS
  Fe-labeled SPIOs were either polymer-coated or embedded into the lipid core of triglyceride-rich lipoproteins (TRL-Fe-SPIOs). First biodistribution and blood half time analysis in thermoneutral mice after IP injection of either TRL-Fe-SPIOs or polymer-coated Fe-SPIOs (n = 3) were performed. In the next step, cold-exposed (24 hours), BAT-activated mice (n = 10), and control thermoneutral mice (n = 10) were starved for 4 hours before IP (n = 10) or IV (n = 10) injection of TRL-Fe-SPIOs. In vivo MRI was performed before and 24 hours after the application of the particles at a 7 T small animal MRI scanner using a T2*-weighted multiecho gradient echo sequence. R2* and ΔR2* were estimated in the liver, BAT, and muscle. The biodistribution of polymer-coated Fe-SPIOs and TRL-Fe-SPIOs was analyzed ex vivo using a sensitive, large-volume Hamburg whole-body radioactive counter. The amount of Fe-SPIOs in the liver, BAT, and muscle was correlated with the MRI measurements using the Pearson correlation coefficient. Tissue uptake of Fe-SPIOs was confirmed by histological and transmission electron microscopy analyses.
  
  
  RESULTS
  Triglyceride-rich lipoprotein Fe-SPIOs exhibited a higher blood concentration after IP injection (10.1% ± 0.91% after 24 hours) and a greater [INCREMENT]R2* in the liver (103 ± 5.0 s), while polymer-coated SPIOs did not increase substantially in the blood stream (0.19% ± 0.01% after 24 hours; P < 0.001) and the liver (57 ± 4.08 s; P < 0.001). In BAT activity studies, significantly higher uptake of TRL-Fe-SPIOs was detected in the BAT of cold-exposed mice, with [INCREMENT]R2* of 107 ± 5.5 s after IV application (control mice: [INCREMENT]R2* of 22 ± 5.8 s; P < 0.001) and 45 ± 5.5 s after IP application (control mice: [INCREMENT]R2* of 11 ± 2.9 s; P < 0.01). Fe radioactivity measurements and [INCREMENT]R2* values correlated strongly in BAT (r > 0.85; P < 0.001) and liver tissue (r > 0.85; P < 0.001). Histological and transmission electron microscopy analyses confirmed the uptake of TRL-Fe-SPIOs within the liver and BAT for both application approaches.
  
  
  CONCLUSIONS
  Triglyceride-rich lipoprotein-embedded SPIOs were able to escape the abdominal cavity barrier, whereas polymer-coated SPIOs did not increase substantially in the blood stream. Brown adipose tissue activity can be determined via MRI using TRL-Fe-SPIOs. The quantification of [INCREMENT]R2* using TRL-Fe-SPIOs is feasible and may serve as a noninvasive tool for the quantitative estimation of BAT activity.
authors.affiliation: From the Departments of *Diagnostic and Interventional Radiology, and †Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf; ‡Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Hamburg; §Department of Nuclear Medicine, Virchow Campus Charite Berlin, Berlin; ∥Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf; and ¶Institute of Physical Chemistry, University of Hamburg, Hamburg, Germany.
authors.forename: Caroline Sophie Laura
authors.initials: CS
authors.lastname: Jung
authors.forename: Markus
authors.initials: M
authors.lastname: Heine
authors.forename: Barbara
authors.initials: B
authors.lastname: Freund
authors.forename: Rudolph
authors.initials: R
authors.lastname: Reimer
authors.forename: Eva Jolanthe
authors.initials: EJ
authors.lastname: Koziolek
authors.forename: Michael Gerhard
authors.initials: MG
authors.lastname: Kaul
authors.forename: Fabian
authors.initials: F
authors.lastname: Kording
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
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: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage; D005290:Ferric Compounds / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008074:Lipoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D053758:Nanoparticles; D014018:Tissue Distribution; D014280:Triglycerides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D003287:Contrast Media; D005290:Ferric Compounds; D008074:Lipoproteins; D014280:Triglycerides; C030087:lipoprotein triglyceride