Antiangiogenic tumor treatment: early noninvasive monitoring with USPIO-enhanced MR imaging in mice.

Abstract

To prospectively investigate steady-state blood volume measurements for early quantitative monitoring of antiangiogenic treatment with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging. The institutional animal care committee approved all experiments. HT-1080 fibrosarcoma-bearing nude mice were injected with a thrombogenic vascular targeting agent (VTA) (11 nude mice, 20 tumors) or saline (12 nude mice, 20 tumors). USPIO-enhanced (SH U 555C) MR imaging was performed after the VTA was administered. USPIO-induced changes in tissue R2* (DeltaR2*) were measured with a T2-weighted dual-echo echo-planar imaging sequence, and the vascular volume fraction (VVF) was calculated. Parametric DeltaR2* maps were analyzed with respect to tumor perfusion patterns. Correlative histologic analysis was performed for grading of tissue thrombosis, and tissue perfusion was quantified with fluorescent microbeads. Unpaired Student t test and Spearman nonparametric correlation coefficient were used for statistical analysis. The DeltaR2* values were significantly (P < .001) reduced shortly after treatment initiation (mean DeltaR2*, 0.017 msec(-1) +/- 0.0014 [standard error] in control animals vs 0.005 msec(-1) +/- 0.0007 in animals that received VTA), which was also reflected by a decrease in the VVF (2.47% +/- 0.18 vs 0.41% +/- 0.48, P < .001). Histologic analysis revealed various degrees of tumor thrombosis after VTA treatment that correlated inversely with the DeltaR2* values (r = -0.83). Moreover, tumor perfusion measurements corroborated the MR results, indicating a significant reduction in tissue perfusion after VTA treatment (mean tissue fluorescence, 570.4 arbitrary units [au] per gram +/- 27 vs 161.7 au/g +/- 17; P < .05). USPIO-enhanced MR imaging enables early monitoring of antiangiogenic treatment of tumors.