Department of Chemistry and Biochemistry, University of Notre Dame, 236 Nieuwland Science Hall, Notre Dame, IN, 46556, USA.
Department of Chemistry and Biochemistry and the Comprehensive Cancer Center, The Ohio State University, 100 West 18th Ave, Columbus, OH, 43210, USA.
Anal Bioanal Chem. 2019 Nov;411(27):7087-7094. doi: 10.1007/s00216-019-02084-7. Epub 2019 Aug 30.
Accurate measurement and understanding of therapeutic uptake and metabolism is key in the drug development process. This work examines the amount of doxorubicin that can penetrate into spheroids after being encapsulated in a liposomal configuration in comparison with free drug. Through a process known as serial trypsinization, three distinct cellular populations of a spheroid were successfully separated and a small molecule extraction was used to isolate the chemotherapeutic. Doxorubicin showed a time-dependent permeability into spheroids with the most drug accumulating in the core at 24 h of treatment. Entrapment of the chemotherapeutic delayed the permeability of the drug and resulted in reduced amounts quantified at the earlier time points. These findings validate the claim that liposomal therapeutics have the ability to alter the pharmacokinetics and pharmacodynamics profiles of a drug while also demonstrating the combined power of mass spectrometry and three-dimensional cell cultures to evaluate drug penetration and metabolism. Graphical abstract.
准确测量和了解治疗性摄取和代谢是药物开发过程中的关键。这项工作研究了在脂质体构型中包裹阿霉素后，与游离药物相比，其进入球体的量。通过一种称为连续胰蛋白酶消化的过程，成功地分离了球体的三个不同的细胞群体，并使用小分子提取来分离化疗药物。阿霉素显示出时间依赖性地渗透到球体中，在治疗 24 小时时，药物在核心中积累最多。化疗药物的包封延迟了药物的渗透性，导致在较早的时间点定量减少。这些发现验证了这样一种说法，即脂质体治疗剂具有改变药物药代动力学和药效学特征的能力，同时也展示了质谱和三维细胞培养相结合的力量，用于评估药物渗透和代谢。图表摘要。
