Extracellular diffusion quantified by magnetic resonance imaging during rat C6 glioma cell progression

Solution reflux and edema hamper the convection-enhanced delivery of the standard treatment for glioma. Therefore, a real-time magnetic resonance imaging (MRI) method was developed to monitor the dosing process, but a quantitative analysis of local diffusion and clearance parameters has not been assessed. The objective of this study was to compare diffusion into the extracellular space (ECS) at different stages of rat C6 gliomas, and analyze the effects of the extracellular matrix (ECM) on the diffusion process. At 10 and 20 days, after successful glioma modeling, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) was introduced into the ECS of rat C6 gliomas. Diffusion parameters and half-life of the reagent were then detected using MRI, and quantified according to the mathematical model of diffusion. The main ECM components [chondroitin sulfate proteoglycans (CSPGs), collagen IV, and tenascin C] were detected by immunohistochemical and immunoblot analyses. In 20-day gliomas, Gd-DTPA diffused more slowly and derived higher tortuosity, with lower clearance rate and longer half-life compared to 10-day gliomas. The increased glioma ECM was associated with different diffusion and clearance parameters in 20-day rat gliomas compared to 10-day gliomas. ECS parameters were altered with C6 glioma progression from increased ECM content. Our study might help better understand the glioma microenvironment and provide benefits for interstitial drug delivery to treat brain gliomas.

溶液反流与脑水肿会阻碍胶质瘤标准治疗的对流增强递送（convection-enhanced delivery）。为此，研究人员开发了实时磁共振成像（MRI）方法以监测给药过程，但目前尚未针对局部扩散与清除参数开展定量分析。本研究旨在比较大鼠C6胶质瘤模型不同阶段的细胞外间隙（ECS）内扩散情况，并分析细胞外基质（ECM）对扩散过程的影响。在造模成功后的第10天与第20天，研究人员向大鼠C6胶质瘤模型的细胞外间隙注入钆喷酸葡胺（Gd-DTPA）。随后通过磁共振成像检测该造影剂的扩散参数与半衰期，并依据扩散数学模型完成量化分析。同时采用免疫组化与免疫印迹分析，检测细胞外基质的主要组分：硫酸软骨素蛋白聚糖（CSPGs）、IV型胶原（collagen IV）以及腱生蛋白C（tenascin C）。与第10天的胶质瘤模型相比，第20天的胶质瘤模型中Gd-DTPA扩散更为缓慢，曲折度更高，清除率更低且半衰期更长。相较于第10天的大鼠胶质瘤模型，第20天模型中增多的胶质瘤细胞外基质与改变后的扩散及清除参数密切相关。随着C6胶质瘤进展，细胞外基质含量逐渐升高，细胞外间隙参数亦随之发生改变。本研究有助于进一步阐明胶质瘤微环境，并为脑胶质瘤的间质内给药治疗提供理论依据。