Computational Multi-Scale Modeling of Drug Delivery into an Anti-Angiogenic Therapy-Treated Tumor.

Simple Summary: The investigation of chemotherapy combined with anti-angiogenesis has garnered significant attention from researchers. The aim of this study is to provide a numerical model, the first of its kind, considering more realistic phenomena in simulating drug delivery into a solid tumor with a remodeled dynamic microvascular network affected by the anti-angiogenic agent, angiostatin. This research aims to open a new horizon in understanding the efficiency of combination therapy involving anti-angiogenesis and chemotherapy. Results show that, for improving drug delivery with the aid of anti-angiogenesis, the uniformity of micro-vessel distribution, accompanied by the modification in drug exposure schedule caused by the alterations in transport properties induced by vascular normalization, is more effective than the suppression of the microvasculature. Therefore, it can be concluded that the 39% enhancement in uniformity of drug delivery in R = 0.2 cm is a result of the well-proportioned distribution of the capillary network in the second approach of anti-angiogenic therapy. The present study develops a numerical model, which is the most complex one, in comparison to previous research to investigate drug delivery accompanied by the anti-angiogenesis effect. This paper simulates intravascular blood flow and interstitial fluid flow using a dynamic model. The model accounts for the non-Newtonian behavior of blood and incorporates the adaptation of the diameter of a heterogeneous microvascular network derived from modeling the evolution of endothelial cells toward a circular tumor sprouting from two-parent vessels, with and without imposing the inhibitory effect of angiostatin on a modified discrete angiogenesis model. The average solute exposure and its uniformity in solid tumors of different sizes are studied by numerically solving the convection-diffusion equation. Three different methodologies are considered for simulating anti-angiogenesis: modifying the capillary network, updating the transport properties, and considering both microvasculature and transport properties modifications. It is shown that anti-angiogenic therapy decreases drug wash-out in the periphery of the tumor. Results show the decisive role of microvascular structure, particularly its distribution, and interstitial transport properties modifications induced via vascular normalization on the quality of drug delivery, such that it is improved by 39% in uniformity by the second approach in R = 0.2 cm. [ABSTRACT FROM AUTHOR]