Impact of Blood–Brain Barrier to Delivering a Vascular-Disrupting Agent: Predictive Role of Multiparametric MRI in Rodent Craniofacial Metastasis Models

Abstract

Vascular-disrupting agents (VDAs) have shown a preliminary anti-cancer effect in extracranial tumors; however, the therapeutic potential of VDAs in intracranial metastatic lesions remains unclear. Simultaneous intracranial and extracranial tumors were induced by the implantation of rhabdomyosarcoma in 15 WAG/Rij rats. Pre-treatment characterizations were performed at a 3.0 T clinical magnet including a T2 relaxation map, T1 relaxation map, diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI). Shortly afterward, a VDA was intravenously given and MRI scans at 1 h, 8 h, and 24 h after treatment were performed. In vivo findings were further confirmed by postmortem angiography and histopathology staining with H&E, Ki67, and CD31. Before VDA treatment, better perfusion (AUC30: 0.067 vs. 0.058, p < 0.05) and AUC300 value (0.193 vs. 0.063, p < 0.001) were observed in extracranial lesions, compared with intracranial lesions. After VDA treatment, more significant and persistent perfusion deficiency measured by PWI (AUC30: 0.067 vs. 0.008, p < 0.0001) and a T1 map (T1 ratio: 0.429 vs. 0.587, p < 0.05) were observed in extracranial tumors, in contrast to the intracranial tumor (AUC30: 0.058 vs. 0.049, p > 0.05, T1 ratio: 0.497 vs. 0.625, p < 0.05). Additionally, significant changes in the T2 value and apparent diffusion coefficient (ADC) value were observed in extracranial lesions, instead of intracranial lesions. Postmortem angiography and pathology showed a significantly larger H&E-stained area of necrosis (86.2% vs. 18.3%, p < 0.0001), lower CD31 level (42.7% vs. 54.3%, p < 0.05), and lower Ki67 level (12.2% vs. 32.3%, p < 0.01) in extracranial tumors, compared with intracranial lesions. The BBB functioned as a barrier against the delivery of VDA into intracranial tumors and multiparametric MRI may predict the efficacy of VDAs on craniofacial tumors.