UCLouvain, Louvain Drug Research Institute (LDRI), Biomedical Magnetic Resonance Research Group, 1200 Brussels, Belgium; UCLouvain, Louvain Drug Research Institute (LDRI), Advanced Drug Delivery and Biomaterials Research Group, 1200 Brussels, Belgium.
Louvain Nuclear and Electron Spin Technologies (NEST) Platform, Drug Research Institute (LDRI), UCLouvain, Brussels, Belgium.
Acta Oncol. 2024 Aug 14;63:689-700. doi: 10.2340/1651-226X.2024.40116.
The poor delivery of drugs to infiltrating tumor cells contributes to therapeutic failure in glioblastoma. During the early phase of an anti-angiogenic treatment, a remodeling of the tumor vasculature could occur, leading to a more functional vessel network that could enhance drug delivery. However, the restructuration of blood vessels could increase the proportion of normal endothelial cells that could be a barrier for the free diffusion of drugs. The net balance, in favor or not, of a better delivery of compounds during the course of an antiangiogenic treatment remains to be established. This study explored whether cediranib and thalidomide could modulate perfusion and vessel permeability in the brain U87 tumor mouse model.
The dynamic evolution of the diffusion of agents outside the tumor core using the fluorescent dye Evans Blue in histology and Gd-DOTA using dynamic contrast-enhanced (DCE)-MRI. CD31 labelling of endothelial cells was used to measure the vascular density.
Cediranib and thalidomide effectively reduced tumor size over time. The accessibility of Evans Blue outside the tumor core continuously decreased over time. The vascular density was significantly decreased after treatment while the proportion of normal vessels remained unchanged over time. In contrast to histological studies, DCE-MRI did not tackle any significant change in hemodynamic parameters, in the core or margins of the tumor, whatever the parameter used or the pharmacokinetic model used. While cediranib and thalidomide were effective in decreasing the tumor size, they were ineffective in transiently increasing the delivery of agents in the core and the margins of the tumor.
药物向浸润性肿瘤细胞的递释不佳导致胶质母细胞瘤的治疗失败。在抗血管生成治疗的早期阶段，肿瘤血管可能发生重塑，导致更具功能性的血管网络，从而增强药物递释。然而，血管的重构可能会增加正常内皮细胞的比例，这可能成为药物自由扩散的障碍。在抗血管生成治疗过程中，化合物递释是否得到改善的净平衡（有利或不利）仍有待确定。本研究探讨了西地尼布和沙利度胺是否可以调节脑 U87 肿瘤小鼠模型中的灌注和血管通透性。
使用组织学中的荧光染料 Evans Blue 和动态对比增强（DCE）-MRI 测量药物在肿瘤核心外的扩散的动态演变。CD31 标记内皮细胞以测量血管密度。
西地尼布和沙利度胺可有效缩小肿瘤体积。肿瘤核心外 Evans Blue 的可及性随时间不断降低。治疗后血管密度显著降低，而正常血管的比例随时间保持不变。与组织学研究相反，无论使用何种参数或药代动力学模型，DCE-MRI 均未检测到肿瘤核心和边缘的任何血流动力学参数发生显著变化。尽管西地尼布和沙利度胺可有效缩小肿瘤体积，但它们无法在肿瘤核心和边缘暂时增加药物递释。
