title: MRI with magnetic nanoparticles monitors downstream anti-angiogenic effects of mTOR inhibition.
abstract: OBJECTIVE
  To study the effect of mammalian target of rapamycin (mTOR) inhibition on angiogenesis with magnetic resonance imaging (MRI) using magnetic iron oxide nanoparticles (MNP).
  
  
  METHODS
  One million CAK-1 renal cell carcinoma cells were subcutaneously implanted into each of 20 nude mice. When tumors reached ∼750 μl, four daily treatment arms began and continued for 4 weeks: rapamycin (mTOR inhibitor) 10 mg/kg/day; sorafenib (VEGF inhibitor) high dose (80 mg/kg/day) and low dose (30 mg/kg/day); and saline control. Weekly MRI (4.7 T Bruker Pharmascan) was performed before and after IV MION-48, a prototype MNP similar to MNP in clinical trials. Vascular volume fraction (VVF) was quantified as ΔR2 (from multi-contrast T2 sequences) and normalized to assumed muscle VVF of 3%. Linear regression compared VVF to microvascular density (MVD) as determined by histology.
  
  
  RESULTS
  VVF correlated with MVD (R(2) = 0.95). VVF in all treatment arms differed from control (p < 0.05) and declined weekly with treatment. VVF changes with rapamycin were similar to high-dose sorafenib.
  
  
  CONCLUSIONS
  This study demonstrates noninvasive, in vivo anti-angiogenic monitoring using MRI of mTOR inhibition.
authors.affiliation: Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA. aguimaraes1@partners.org
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Guimaraes
authors.forename: Robert
authors.initials: R
authors.lastname: Ross
authors.forename: Jose L
authors.initials: JL
authors.lastname: Figuereido
authors.forename: Peter
authors.initials: P
authors.lastname: Waterman
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D052203:Ferrosoferric Oxide; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D053758:Nanoparticles; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
chemical_list: D020533:Angiogenesis Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D047428:Protein Kinase Inhibitors; C499827:monocrystalline iron oxide nanoparticle; D058570:TOR Serine-Threonine Kinases; D052203:Ferrosoferric Oxide