Convection-Enhanced Delivery of Antiangiogenic Drugs and Liposomal Cytotoxic Drugs to Heterogeneous Brain Tumor for Combination Therapy

SIMPLE SUMMARY: Although developed anticancer drugs have shown desirable effects in preclinical trials, the clinical efficacy of chemotherapy against brain cancer remains disappointing. One of the important obstacles is the highly heterogeneous environment in tumors. This study aims to evaluate the performance of an emerging treatment using antiangiogenic and cytotoxic drugs. Our mathematical modelling confirms the advantage of this combination therapy in homogenizing the intratumoral environment for better drug delivery outcomes. In addition, the effects of local microvasculature and cell density on this therapy are also discussed. The results would contribute to the development of more effective treatments for brain cancer. ABSTRACT: Although convection-enhanced delivery can successfully bypass the blood-brain barrier, its clinical performance remains disappointing. This is primarily attributed to the heterogeneous intratumoral environment, particularly the tumor microvasculature. This study investigates the combined convection-enhanced delivery of antiangiogenic drugs and liposomal cytotoxic drugs in a heterogeneous brain tumor environment using a transport-based mathematical model. The patient-specific 3D brain tumor geometry and the tumor’s heterogeneous tissue properties, including microvascular density, porosity and cell density, are extracted from dynamic contrast-enhanced magnetic resonance imaging data. Results show that antiangiogenic drugs can effectively reduce the tumor microvascular density. This change in tissue structure would inhibit the fluid loss from the blood to prevent drug concentration from dilution, and also reduce the drug loss by blood drainage. The comparisons between different dosing regimens demonstrate that the co-infusion of liposomal cytotoxic drugs and antiangiogenic drugs has the advantages of homogenizing drug distribution, increasing drug accumulation, and enlarging the volume where tumor cells can be effectively killed. The delivery outcomes are susceptible to the location of the infusion site. This combination treatment can be improved by infusing drugs at higher microvascular density sites. In contrast, infusion at a site with high cell density would lower the treatment effectiveness of the whole brain tumor. Results obtained from this study can deepen the understanding of this combination therapy and provide a reference for treatment design and optimization that can further improve survival and patient quality of life.