MRI with magnetic nanoparticles monitors downstream anti-angiogenic effects of mTOR inhibition.
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.
Guimaraes
Alexander R
AR
Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA. aguimaraes1@partners.org
Ross
Robert
R
Figuereido
Jose L
JL
Waterman
Peter
P
Weissleder
Ralph
R
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
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