Cerebral Blood Volume Quantification in a C6 Tumor Model Using Gadolinium per (3,6-Anhydro) α-Cyclodextrin as a New Magnetic Resonance Imaging Preclinical Contrast Agent

Abstract

In magnetic resonance imaging (MRI), cerebral blood volume (CBV) quantification is dependent on the MRI sequence and on the properties of the contrast agents (CAs). By using the rapid steadystate T 1 method, we show the potential of gadolinium per (3,6-anhydro) a-cyclodextrin (Gd-ACX), a new MRI paramagnetic CA (inclusion complex of Gd 3 + with per (3,6-anhydro)-a-cyclodextrin), for the CBV quantification in the presence of blood-brain barrier lesions. After biocompatibility and relaxivity experiments, in vivo experiments on rats were performed on a C6 tumor model with 0.05 mmol Gd-ACX/kg ( < 1/10 of the median lethal dose) injected at a 25 mmol/L concentration, inducing neither nephrotoxicity nor hemolysis. On T 1 -weighted images, a signal enhancement of 170% appeared in vessels after injection, but not in the tumor (during the 1 h of observation), in contrast to the 90% signal enhancement obtained with Gd-DOTA (a clinical MRI CA) injected at a T 1 isoefficient dose. This result shows the absence of Gd-ACX extravasation into the tumor tissue and its confinement to the vascular space. Fractional CBV values were found similar to Gd-ACX and Gd-DOTA in healthy brain tissue and in the contralateral hemisphere of tumor-bearing rats, whereas only Gd-ACX was appropriate for CBV quantification in tumor regions.

How Stereological Analysis of Vascular Morphology Can Quantify the Blood Volume Fraction as a Marker for Tumor Vasculature: Comparison with Magnetic Resonance Imaging

“…Rats (weighing 310 to 400 g) were anesthetized with isoflurane, equipped with a venous and an arterial cannula, thermoregulated, and placed in the prone position for the imaging experiment (Lahrech et al, 2008).…”

“…A homogeneous radio frequency (RF) saddle coil was used for emission, and a surface coil for reception. BVf maps were obtained in a coronal plane through the largest extension of the tumor with a spatial resolution of 0.75 Â 0.75 Â 2 mm 3 (Lahrech et al, 2008) using the RSST 1 -MRI method (Perles-Barbacaru and Lahrech, 2007). During MRI examination, each rat underwent two CA injections: Gd-ACX (administered at a dose of 0.05 mmol/kg in terms of gadolinium) was the CA under investigation and has been found to remain confined to the blood pool even in the tumor tissue, allowing quantification of tumor BVf in this tumor model (Lahrech et al, 2008).…”

“…For tumor BVf measurement with the RSST 1 method, we investigated the blood-pool properties of an experimental CA Gd-ACX composed of gadolinium linked to a modified a-cyclodextrin (hexakis(2-O-carboxymethyl-3,6-anhydro)-a-cyclodextrin) in a C6 brain tumor model in rats (Lahrech et al, 2008). The cerebral BVf measured in brain tissue contralateral to the tumor could be validated by a second measurement in the same animals 1 hour later using Gd-DOTA.…”

“…The cerebral BVf measured in brain tissue contralateral to the tumor could be validated by a second measurement in the same animals 1 hour later using Gd-DOTA. Although from the MRI point of view, there is evidence that Gd-ACX remains confined to the vasculature in the C6 tumor model (Lahrech et al, 2008), we sought to confirm the obtained tumor BVf using an independent method.…”

“…The results were also compared with published values obtained by alternative techniques for this tumor model. In Vivo Blood Volume Fraction Measurement: Four Wistar rats were unilaterally implanted with C6 tumor cells as described in the study by Lahrech et al (2008).…”