Effect of Spheroidal Age on Sorafenib Diffusivity and Toxicity in a 3D HepG2 Spheroid Model
Effect of Spheroidal Age on Sorafenib Diffusivity and Toxicity in a 3D HepG2 Spheroid Model
复制标题
DOI：
10.1038/s41598-019-41273-3
复制
发表时间：
2019-03-19
影响因子：
4.6
通讯作者：
Kuepcue, Seta
中科院分区：
文献类型：
--
作者：
Eilenberger, Christoph;Rothbauer, Mario;Kuepcue, Seta
与传统的单层培养相比，三维多细胞球体的预测能力增强，使其成为一种有前途的药物筛选工具。然而，药理学和毒理学的临床翻译技术发展滞后。尽管球体显示出类似于天然组织的生物复杂性，但球体形成过程中不断变化的生理参数影响了药物筛选方案的标准化和有效性。这种细胞异质性阻碍了药物疗效研究和毒理学筛选的可比性。在本文中，我们证明了除了已经建立的生理参数外，球体年龄是影响3D细胞培养模型中药物扩散和毒性的另一个关键参数。在自组装的超低附着纳米生物界面上生成并维持HepG2球体，并表征其形态、功能和抗癌耐药的随时间变化。我们证明，由于球体微观结构和器官型功能的演变，球体老化直接影响药物反应，从而改变向内扩散，从而改变药物摄取。
The enhanced predictive power of 3D multi-cellular spheroids in comparison to conventional monolayer cultures makes them a promising drug screening tool. However, clinical translation for pharmacology and toxicology is lagging its technological progression. Even though spheroids show a biological complexity resembling native tissue, standardization and validation of drug screening protocols are influenced by continuously changing physiological parameters during spheroid formation. Such cellular heterogeneities impede the comparability of drug efficacy studies and toxicological screenings. In this paper, we demonstrated that aside from already well-established physiological parameters, spheroidal age is an additional critical parameter that impacts drug diffusivity and toxicity in 3D cell culture models. HepG2 spheroids were generated and maintained on a self-assembled ultra-low attachment nanobiointerface and characterized regarding time-dependent changes in morphology, functionality as well as anti-cancer drug resistance. We demonstrated that spheroidal aging directly influences drug response due to the evolution of spheroid micro-structure and organo-typic functions, that alter inward diffusion, thus drug uptake.