Multi‐modal magnetic resonance imaging and histology of vascular function in xenografts using macromolecular contrast agent hyperbranched polyglycerol (HPG‐GdF)

Macromolecular gadolinium (Gd)‐based contrast agents are in development as blood pool markers for MRI. HPG‐GdF is a 583 kDa hyperbranched polyglycerol doubly tagged with Gd and Alexa 647 nm dye, making it both MR and histologically visible. In this study we examined the location of HPG‐GdF in whole‐tumor xenograft sections matched to in vivo DCE‐MR images of both HPG‐GdF and Gadovist. Despite its large size, we have shown that HPG‐GdF extravasates from some tumor vessels and accumulates over time, but does not distribute beyond a few cell diameters from vessels. Fractional plasma volume (fPV) and apparent permeability–surface area product (aPS) parameters were derived from the MR concentration–time curves of HPG‐GdF. Non‐viable necrotic tumor tissue was excluded from the analysis by applying a novel bolus arrival time (BAT) algorithm to all voxels. aPS derived from HPG‐GdF was the only MR parameter to identify a difference in vascular function between HCT116 and HT29 colorectal tumors. This study is the first to relate low and high molecular weight contrast agents with matched whole‐tumor histological sections. These detailed comparisons identified tumor regions that appear distinct from each other using the HPG‐GdF biomarkers related to perfusion and vessel leakiness, while Gadovist‐imaged parameter measures in the same regions were unable to detect variation in vascular function. We have established HPG‐GdF as a biocompatible multi‐modal high molecular weight contrast agent with application for examining vascular function in both MR and histological modalities. Copyright © 2015 John Wiley & Sons, Ltd. HPG‐GdF (583 kDa) is a largely intravascular macromolecular contrast agent that selectively extravasates from permeable vessels and is doubly labeled for MR (left) and histological (right) visibility. Comprehensive comparisons were performed for Gadovist and HPG‐GdF in the same tumors with matched histological sections. MR‐derived biomarkers for fractional plasma volume (fPV) and apparent permeability surface area product (aPS) (centre) were calculated in voxels with HPG‐GdF enhancement using a screen for bolus arrival time (BAT) that excludes necrotic tissues. HPG‐GdF (aPS) was the most sensitive MR measure for detecting histologically measured variability in vascular function between HCT116 and HT29 colorectal xenografts.