Role of tumor microvessel architecture and function in chemotherapeutic drug delivery: A three-dimensional numerical study

To investigate the dynamic changes of solid tumor and neo-vasculature in response to chemotherapeutic agent, we proposed a multi-discipline three-dimensional mathematical model by coupling tumor growth, angiogenesis, vessel remodelling, microcirculation and drug delivery. The tumor growth is described by the cell automaton model, in which three cell phenotypes (proliferating cell, quiescent cell and necrotic cell) are assumed to reflect the dynamics of tumor progress. A 3D tree-like architecture network with different orders for vessel diameter is generated as pre-existing vasculature in host tissue. The chemical substances including oxygen, vascular endothelial growth factor, extra-cellular matrix and matrix degradation enzymes are calculated based on the reaction-diffusion equations associated with haemodynamic environment, which is obtained by coupled modelling of intravascular blood flow with interstitial fluid flow. The haemodynamic changes, including vessel diameter and permeability, are introduced to reflect a series of pathological characteristics of abnormal tumor vessels involving vessel dilation, leakage, angiogenesis, regression and collapse. The chemotherapeutic drug is transported across the vessel wall and through diffusion and convection mechanisms in the interstitial media, which is governed by the second Fick’s law. Finally, we coupled the tumor growth model and the vessel remodelling model according to the changes in the chemical and hemodynamical microenvironment, to investigate the tumor inhibition with different drug strategies. The results showed the growth histories of tumor cell population in response to chemotherapeutic agent. The efficacies of tumor inhibition by different drug strategies had been compared. In addition, we studied the influences of the pathological abnormalities of tumor microvessels, such as high density, heterogeneous capillary diameter and high permeability of vessel wall, on the drug transport and chemotherapeutic efficacy