Prediction of Antiangiogenic Treatment Efficacy by Iron Oxide Enhanced Parametric Magnetic Resonance Imaging

Abstract

Tools for monitoring modern target-specific antiangiogenic and antivascular therapies are highly desirable because treatment strategies are time consuming, expensive, and yet sometimes ineffective. Therefore, the aim of this experimental study was to evaluate the predictive value of steady-state ultrasmall particles of iron oxide (USPIO; SH U 555 C)-enhanced magnetic resonance imaging (MRI) for early assessment of antivascular tumor-treatment effectiveness. Mice were inoculated with an HT-1080 fibrosarcoma xenograft and subjected to target-specific antivascular therapy using a selective thrombogenic vascular-targeting agent (truncated tissue factor fused to RGD peptide) or saline as control. Four to 8 hours after treatment, the USPIO-induced change in the transverse relaxation rate DeltaR2* was measured by MRI, and the vascular volume fraction (VVF) was calculated by calibrating DeltaR2* of the tumor by DeltaR2* of muscle tissue. Treatment response was defined by histologic grading of vascular thrombosis and tumor necrosis. After thrombogenic treatment, half of the HT-1080 xenograft-bearing animals showed only minor (=nonresponder) whereas the other half showed extensive tumor thrombosis (=responders). For responders, a significant decrease of DeltaR2* and VVF was observed compared with the control group (DeltaR2*: controls: 16 +/- 1 s-1 vs. responder: 4 +/- 2 s-1; P < 0.001) whereas DeltaR2* and VVF remained nearly unchanged for nonresponders (DeltaR2*: nonresponder 14 +/- 2 s-1). VVF and DeltaR2* values correlated inversely with the histologic grading of vascular thrombosis and tumor necrosis (VVF: r = -0.8; DeltaR2*: r = -0.71; P < 0.01). USPIO-enhanced MRI allows a noninvasive, early assessment of treatment efficacy of thrombogenic vascular-targeting agents.