Multiscale modelling of drug transport and metabolism in liver spheroids

Abstract

In early preclinical drug development, potential candidates are tested in the laboratory using isolated cells. These in vitro experiments traditionally involve cells cultured in a two-dimensional monolayer environment. However, cells cultured in three-dimensional spheroid systems have been shown to more closely resemble the functionality and morphology of cells in vivo . While the increasing usage of hepatic spheroid cultures allows for more relevant experimentation in a more realistic biological environment, the underlying physical processes of drug transport, uptake and metabolism contributing to the spatial distribution of drugs in these spheroids remain poorly understood. The development of a multiscale mathematical modelling framework describing the spatio-temporal dynamics of drugs in multicellular environments enables mechanistic insight into the behaviour of these systems. Here, our analysis of cell membrane permeation and porosity throughout the spheroid reveals the impact of these properties on drug penetration, with maximal disparity between zonal metabolism rates occurring for drugs of intermediate lipophilicity. Our research shows how mathematical models can be used to simulate the activity and transport of drugs in hepatic spheroids and in principle any organoid, with the ultimate aim of better informing experimentalists on how to regulate dosing and culture conditions to more effectively optimize drug delivery.

Mechanistic Computational Models of Epithelial Cell Transporters-the Adorned Heroes of Pharmacokinetics

“…Another model that displays excellent specificity in describing transport function is the research conducted by Leedale et al (2020) . In 2D and 3D spheroids, the liver transporters are modeled as microscale kinetic reactions between generic liver transporters and a generic drug.…”

“…There are limitations when explicitly modeling transporter density along the cell membrane. For example, in Leedale et al (2020) the hepatic uptake was modeled as being dependent on trans ( Layton and Layton, 2019 ) porter expression and binding kinetics on a transporter scale. They modeled the membrane transporter in general [T 0 , see Eq.…”

Development of Advanced Cell-Based Therapy by Regulating Cell–Cell Interactions

“…Multicellular spheroids of cancer cells or hepatocytes have been reported to show cellular characteristics closer to living organisms than monolayer culture cells, and are useful for the screening of anticancer drugs and evaluation of liver function. 34,35) Since cellular function can be significantly enhanced by assembling cells into a spherical form or constructing a tissue-like structure, the use of multicellular spheroids is expected to be applicable in cell-based therapy. However, there are very few reports regarding the application of multicellular spheroids in disease treatment.…”

Three-dimensional biological cultures and organoids

“…In the longer term, the image analysis workflow developed in [6] might be used to generate data to validate the mathematical and computational approaches proposed by Leedale et al [3]. Leedale et al recognize that 3D cell culture systems, such as multicellular spheroids, are increasingly being used in drug development and hepatic safety assessment because they are more physiologically relevant and predictive of outcomes in vivo.…”

“…At the same time, the 3D systems are more complex and mechanistic understanding of many of the interactions remains to be fully elucidated. In [3], the authors show how mathematical and computational approaches can help to fill this knowledge gap. They use a combination of multiscale and continuum mathematical models to study the transport and metabolism of drugs in hepatic spheroids.…”