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

Simple Summary The role of the blood-brain barrier in intracranial cancer treatment by vascular-disrupting agents remains unclear. Intraindividual comparison of vascular shutdown by a craniofacial metastasis model was performed, on the basis of in vivo MRI imaging, postmortem NanoCT and pathology analyses. The differential VDA therapeutic effects between intracranial and extracranial tumors were observed, with stronger vascular shutdown in the extracranial tumor. In vivo multiparametric MRI may serve as a predictor for the efficacy of VDAs on craniofacial tumors. 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.

Automated summary

The role of the blood-brain barrier in intracranial cancer treatment with vascular-disrupting agents is not clear. This study used a craniofacial metastasis model to compare the vascular shutdown between intracranial and extracranial tumors using in vivo MRI imaging, postmortem NanoCT, and pathology analyses. The results showed that intracranial tumors had weaker vascular shutdown compared to extracranial tumors. In vivo multiparametric MRI may predict the efficacy of vascular-disrupting agents on craniofacial tumors.