MRI with magnetic nanoparticles monitors downstream anti-angiogenic effects of mTOR inhibition

Purpose: To study the effect of mammalian target of rapamycin (mTOR) inhibition on angiogenesis with magnetic resonance imaging (MRI) using magnetic iron oxide nanoparticles (MNP). Procedures: 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 fromcontrol (p<0.05) and declined weekly with treatment. VVF changes with rapamycin were similar to high-dose sorafenib. Conclusion: This study demonstrates noninvasive, in vivo anti-angiogenic monitoring using MRI of mTOR inhibition.