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

摘要

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 2.0T 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 24hours after a single dose of bevacizumab (1mg) or saline to quantitatively assess the endothelial-surface permeability constant (KPS, μL{dot operator}min{dot operator}100cm3) and the fractional plasma volume (fPV,%), using a two-compartment kinetic model. Results: Mean KPS values, assessed with PEG12,000-Gen4-(Gd-DOTA)16, declined significantly (P.05) from 29.5±10μL{dot operator}min{dot operator}100cm3 to 10.4±7.8μL{dot operator}min{dot operator}100cm3 by 24hours after a single dose of bevacizumab. In parallel, KPS 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 24hours. 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 24hours 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.