MRI monitoring of Avastin™ antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer

Abstract

Purpose:To evaluate the diagnostic and prognostic potential of a new protein-binding contrast medium, B22956/1, for quantitatively characterizing tumor microvessels by MRI and monitoring response to antiangiogenic therapy. Materials and Methods:Dynamic contrast-enhanced MRI (DCE-MRI) was performed in an experimental cancer model with the use of the novel protein-binding agent B22956/1, a low molecular contrast agent (ProHance™), and a macromolecular contrast medium, albumin-(Gd-DTPA). MDA-MB-435, a human cancer cell line, was implanted in 22 athymic rats. Animals were assigned randomly to a control (saline) or drug-treated (Avastin™) group. MRI was performed at baseline and after nine days of treatment. The transendothelial permeability (K PS ) and the fractional blood volume (fBV) were estimated from the kinetic analysis of dynamic MR data using a two-compartment model. Tumor growth was also measured from volumetric MRI.Results: Tumors grew more slowly, although not significantly (P ϭ 0.07), in the drug-treated group. The K PS determined for B22956/1 decreased significantly in the drugtreated group compared to baseline (P Ͻ 0.05), and progressed significantly in the control group. However, no significant changes were resolved with the use of ProHance or albumin-(Gd-DTPA). Conclusion:With the use of appropriate contrast media, the therapeutic effects of an anti-VEGF antibody on tumor microvessels can be monitored by dynamic MRI. The dynamic range of permeability to B22956/1, and the sensitivity to change of this parameter suggest a potential application in the clinical setting.

Cluster analysis of quantitative parametric maps from DCE-MRI: application in evaluating heterogeneity of tumor response to antiangiogenic treatment

“…The effect of an enhanced microvasculature permeability following the antiangiogenic treatment has already been reported in several cases, a process known as vasculature normalization [49]. In fact, our findings are in agreement with recently published data reporting an increase of permeability transfer constant under antiangiogenic treatment by exploiting intermediate MW contrast agents [50,51].…”

Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

“…An optimal payload of 22 Gd-DOTA with mal-BSA (Gd-DOTA) 22 showed contrast effects comparable to albumin (Gd-DTPA) 30 , which is used as a standard to evaluate performances of novel intravascular agents. (79)(80)(81)(82) Though further studies are required to evaluate immunogenicity of the agent, the high specificity of mal-BSA (Gd-DOTA) n shows promise for reducing dosage of administration and toxicity compared to high dose nonspecific contrast agents currently employed in the clinic. Future work includes isolating the regional domains of maleylated BSA that afford targeting in order to circumvent immune responses that may be provoked by full length protein.…”

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

“…DCE-MRI measurements showed that after just 2 days patupilone significantly decreased the rBVol (P = 0.0005). Other vascular variables, such as vessel permeability and overall perfusion, were unaffected, a distinct difference in vascular response in comparison with therapies that target vascular endothelial growth factor (24,37) or the vascular endothelial growth factor receptor (33) or the endothelial cells directly (38,39) and not necessarily expected given that other antivascular/disruptive therapies can decrease permeability and/or perfusion (9,40). Vascular casts of tumors made 2 days after treatment showed a trend for patupilone to induce a decrease in blood vessel mass, and at this time point, the tumor IFP was also decreased (P = 0.02).…”