Computational fluid dynamics with imaging of cleared tissue and of in vivo perfusion predicts drug uptake and treatment responses in tumours

Abstract

Understanding the uptake of a drug by diseased tissue, and the drug's subsequent spatiotemporal distribution, are central factors in the development of effective targeted therapies. However, the interaction between the pathophysiology of diseased tissue and individual therapeutic agents can be complex, and can vary across tissue types and across subjects. Here, we show that the combination of mathematical modelling, of high-resolution optical imaging of intact and optically cleared tumour tissue from animal models, and of in vivo imaging of vascular perfusion predicts the heterogeneous uptake, by large tissue samples, of specific therapeutic agents, as well as their spatiotemporal distribution. In particular, by using murine models of colorectal cancer and glioma, we report and validate predictions of steady-state blood flow and intravascular and interstitial fluid pressure in tumours, of the spatially heterogeneous uptake of chelated gadolinium by tumours, and of the effect of a vascular disrupting agent on tumour vasculature.

Multi-Fluorescence High-Resolution Episcopic Microscopy (MF-HREM) for Three-Dimensional Imaging of Adult Murine Organs

“…For vascular staining, use of i.v. injection of fluorescently-conjugated lectins is widely used to stain vasculature throughout the mouse body (8). This technique is transferrable to MF-HREM and in Figure 6, Figure 7 and Figure 8, we show the use of fluorescently conjugated lectin administered via tail vein i.v.…”

“…All 3D microscopy techniques must overcome the opacity of biological tissue caused by optical scatter of tissue structures. Approaches to this can be grouped into two categories: clearing-based, where the tissue is rendered optically transparent through de-lipidation and refractive index matching (6–8)(9); and serial sectioning, where the entire sample is physically cut.…”

A four‐compartment multiscale model of fluid and drug distribution in vascular tumours

“…Drug treatments (mainly antiangiogenics such as avastin and vascular disrupting and regularising agents such as combretastatins and nelfinavir, respectively) have been developed specifically to target the abnormal vasculature in tumours; however, their impact is hard to predict as the relationship between network structure and the functional parameters that determine mass transport is subtle. For example, increasing the number or diameter of vessels can impair the blood flow distribution, whilst inhibiting angiogenesis is hypothesised to improve circulation; in addition, tumours have been shown to display resistance to vascular disruption therapy via physical mechanisms, such network connectivity and redundancy …”

“…For example, increasing the number or diameter of vessels can impair the blood flow distribution, whilst inhibiting angiogenesis is hypothesised to improve circulation 2 ; in addition, tumours have been shown to display resistance to vascular disruption therapy via physical mechanisms, such network connectivity and redundancy. 3 The quality and volume of data characterising tissue vascular architecture is increasing, and it is now possible to describe vascular structure in a highly detailed way. As the resolution of these data continues to increase, it may become too computationally intensive to simulate flow and mass transport in the entire vascular tree using a discrete approach, where vessels are treated individually.…”

“…11 Instead, a complex tortuous network of angiogenic blood vessels exists, which are fed and drained by large, often tortuous blood vessels 12 that results in elevated interstitial fluid pressure 13 and poor drug penetration to the core of a tumour. 1,3,14 Here, we use mathematical methods to explore this abnormal tumour microenvironment.…”