Leedale Joseph A, Kyffin Jonathan A, Harding Amy L, Colley Helen E, Murdoch Craig, Sharma Parveen, Williams Dominic P, Webb Steven D, Bearon Rachel N
EPSRC Liverpool Centre for Mathematics in Healthcare, Department of Mathematical Sciences, University of Liverpool, Liverpool L69 7ZL, UK.
Department of Applied Mathematics, Liverpool John Moores University, Liverpool L3 3AF, UK.
Interface Focus. 2020 Apr 6;10(2):20190041. doi: 10.1098/rsfs.2019.0041. Epub 2020 Feb 14.
In early preclinical drug development, potential candidates are tested in the laboratory using isolated cells. These 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 . 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.
在临床前药物研发早期，潜在候选药物会在实验室中使用分离细胞进行测试。这些实验传统上涉及在二维单层环境中培养的细胞。然而，已证明在三维球体系统中培养的细胞与细胞的功能和形态更相似。虽然肝球体培养物的使用日益增加，使得在更现实的生物环境中能够进行更相关的实验，但药物在这些球体中的运输、摄取和代谢等潜在物理过程对药物空间分布的影响仍知之甚少。开发一个描述多细胞环境中药物时空动态的多尺度数学建模框架，能够深入了解这些系统的行为机制。在这里，我们对整个球体的细胞膜渗透和孔隙率进行分析，揭示了这些特性对药物渗透的影响，对于中等亲脂性药物，区域代谢率之间的差异最大。我们的研究展示了如何使用数学模型来模拟药物在肝球体以及原则上任何类器官中的活性和运输，最终目的是更好地告知实验人员如何调节给药和培养条件，以更有效地优化药物递送。
