Effect of tissue permeability on drug transport in brain tumour after pressure-driven infusion

Glioblastoma is the most common primary malignant brain tumour classified as WHO Grade IV. The typical survival length is limited to 15 months even when the patients receive maximum treatment. Such disappointing efficacy can largely be attributed to the blood-brain barrier, which can successfully block more than 98% of anticancer drugs in the bloodstream after intravenous administration. As an alternative, convection-enhanced delivery is developed to directly infuse drugs into the tumour tissue through a catheter. Convection-enhanced delivery improves drug transport and accumulation by promoting the bulk movement of interstitial fluid flow. However, this flow is subject to the complex intratumoural environment, particularly the tissue permeability. Moreover, the fluid gain from blood vessels and brain ventricles will also contribute to the interstitial fluid. How these factors determine the outcome of convection-enhanced delivery remains unclear. In this study, a transport-based model is applied to examine the role of tissue permeability and the cross-influences with the fluid gain from the blood and brain ventricles. This modelling is based on a 3-D realistic brain tumour that is reconstructed from patient medical images. The model catches the key drug delivery process, including drug convective and diffusive transport with interstitial fluid flow, binding with proteins, cell uptake, elimination and release from nanoparticles. Modelling results show that drugs accumulate in limited regions in the poorly permeable tumour. Although the spatial-average concentration can be high, this heterogeneous distribution pattern leads to poor treatment outcomes, as there are insufficient drugs for effective cell killing in most tumour regions. Cross-comparisons show that tissue permeability and fluid gain from blood will play a more important role than fluid from brain ventricles. Results obtained from this study can advance the understanding of drug delivery in brain tumours.