Improved evaluation of antivascular cancer therapy using constrained tracer-kinetic modeling for multi-agent dynamic contrast-enhanced MRI

Dynamic contrast-enhanced MRI (DCE-MRI) is a promising technique for assessing the response of tumor vasculature to anti-vascular therapies. Multi-agent DCE-MRI employs a combination of low and high molecular weight contrast agents, which potentially improves the accuracy of estimation of tumor hemodynamic and vascular permeability parameters. In this study, we employed multi-agent DCE-MRI to assess changes in tumor hemodynamics and vascular permeability after vascular-disrupting therapy. Multi-agent DCE-MRI (sequential injection of G5 dendrimer, G2 dendrimer, and Gd-DOTA) was performed in tumor-bearing mice before, 2 h and 24 h after treatment with vascular disrupting agent DMXAA or placebo. Constrained DCE-MRI gamma capillary transit time modeling was employed to estimate flow F, blood volume fraction vb, mean capillary transit time tc, bolus arrival time td, extracellular extravascular fraction ve, vascular heterogeneity index α-1 (all identical between agents) and extraction fraction E (reflective of permeability) and transfer constant Ktrans (both agent-specific) in perfused pixels. F, vb, and α-1 decreased at both time points after DMXAA, while tc increased. E (G2 and G5) showed an initial increase after which both parameters restored. Ktrans (G2 and Gd-DOTA) decreased at both time points after treatment. In the control, placebo-treated animals, only F, tc, and Ktrans Gd-DOTA showed significant changes. Histological perfused tumor fraction was significantly lower in DMXAA-treated versus control animals. Our results show how multi-agent tracer-kinetic modeling can accurately determine the effects of vascular-disrupting therapy, by separating simultaneous changes in tumor hemodynamics and vascular permeability