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.
Department of Physics and Astronomy, University of British Columbia, Vancouver, Canada.
Jennifer H E
JH
Baker
Department of Physics and Astronomy, University of British Columbia, Vancouver, Canada.
Kelly C
KC
McPhee
Department of Physics and Astronomy, University of British Columbia, Vancouver, Canada.
Firas
F
Moosvi
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Katayoun
K
Saatchi
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Urs O
UO
Häfeli
Radiation Biology Unit, British Columbia Cancer Research Centre, Vancouver, Canada.
Andrew I
AI
Minchinton
Department of Physics and Astronomy, University of British Columbia, Vancouver, Canada.
Stefan A
http://orcid.org/0000-0002-0975-3776
SA
Reinsberg
D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000008:administration & dosage* / Q000737:chemistry; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000737:chemistry; D005990:Glycerol / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D007089:Image Enhancement / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry; D011859:Radiography; D023041:Xenograft Model Antitumor Assays
D003287:Contrast Media; D009942:Organometallic Compounds; D011108:Polymers; C090600:gadobutrol; C043941:polyglycerol; D019786:Gadolinium DTPA; D005990:Glycerol
DCE-MRI; macromolecular; microenvironment; multi-modal imaging; tumor mapping; tumor vessels; vascular function