Multiscale modelling of drug transport and metabolism in liver spheroids
Multiscale modelling of drug transport and metabolism in liver spheroids
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DOI：
10.1098/rsfs.2019.0041
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发表时间：
2020-04-06
期刊：
影响因子：
4.4
通讯作者：
Bearon, Rachel N.
中科院分区：
文献类型：
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作者：
Leedale, Joseph A.;Kyffin, Jonathan A.;Bearon, Rachel N.
在早期的临床前药物开发中，在实验室中使用分离的细胞测试潜在的候选药物。这些体外实验传统上涉及在二维单层环境中培养的细胞。然而，在三维球体系统中培养的细胞已显示出更接近于体内细胞的功能和形态。虽然越来越多地使用肝球体文化允许在更现实的生物环境中进行更相关的实验，但对这些球体中药物空间分布的药物转运，摄取和代谢的潜在物理过程仍然知之甚少。描述药物在多细胞环境中的时空动力学的多尺度数学建模框架的发展，使这些系统的行为机制的洞察力。在这里，我们的细胞膜渗透性和孔隙率的分析揭示了这些属性对药物渗透的影响，中间亲脂性药物的区域代谢率之间的最大差异。我们的研究显示了数学模型如何用于模拟药物在肝球状体和原则上任何类器官中的活性和转运，最终目的是更好地告知实验人员如何调节剂量和培养条件，以更有效地优化药物递送。
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.