Evaluation of a Novel Macromolecular Cascade-Polymer Contrast Medium for Dynamic Contrast-Enhanced MRI Monitoring of Antiangiogenic Bevacizumab Therapy in a Human Melanoma Model.

Rationale and Objectives: To assess the applicability of a novel macromolecular polyethylene glycol (PEG)-core gadolinium contrast agent for monitoring early antiangiogenic effects of bevacizumab using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Materials and Methods: Athymic rats (n = 26) implanted with subcutaneous human melanoma xenografts underwent DCE-MRI at 2.0 T using two different macromolecular contrast agents. The PEG core cascade polymer PEG12,000-Gen4-(Gd-DOTA)₁₆, designed for clinical development, was compared to the prototype, animal-only, macromolecular contrast medium (MMCM) albumin-(Gd-DTPA)₃₅. The treatment (n = 13) and control (n = 13) group was imaged at baseline and 24 hours after a single dose of bevacizumab (1 mg) or saline to quantitatively assess the endothelial-surface permeability constant (K^PS, μL⋅min⋅100 cm³) and the fractional plasma volume (fPV,%), using a two-compartment kinetic model. Results: Mean K^PS values, assessed with PEG12,000-Gen4-(Gd-DOTA)₁₆, declined significantly (P < .05) from 29.5 ± 10 μL⋅min⋅100 cm³ to 10.4 ± 7.8 μL⋅min⋅100 cm³ by 24 hours after a single dose of bevacizumab. In parallel, K^PS values quantified using the prototype MMCM albumin-(Gd-DTPA)₃₅ showed an analogous, significant decline (P < .05) in the therapy group. No significant effects were detected on tumor vascularity or on microcirculatory parameters in the control group between the baseline and the follow-up scan at 24 hours. Conclusion: DCE-MRI enhanced with the novel MMCM PEG12,000-Gen4-(Gd-DOTA)₁₆ was able to monitor the effects of bevacizumab on melanoma xenografts within 24 hours of a single application, validated by the prototype, animal-only albumin-(Gd-DTPA)₃₅. PEG12,000-Gen4-(Gd-DOTA)₁₆ may be a promising candidate for further clinical development as a macromolecular blood pool contrast MRI agent. [Copyright &y& Elsevier]