LaBonia Gabriel J, Lockwood Sarah Y, Heller Andrew A, Spence Dana M, Hummon Amanda B
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA.
Proteomics. 2016 Jun;16(11-12):1814-21. doi: 10.1002/pmic.201500524.
Realistic in vitro models are critical in the drug development process. In this study, a novel in vitro platform is employed to assess drug penetration and metabolism. This platform, which utilizes a 3D printed fluidic device, allows for dynamic dosing of three dimensional cell cultures, also known as spheroids. The penetration of the chemotherapeutic irinotecan into HCT 116 colon cancer spheroids was examined with MALDI imaging mass spectrometry (IMS). The active metabolite of irinotecan, SN-38, was also detected. After twenty-four hours of treatment, SN-38 was concentrated to the outside of the spheroid, a region of actively dividing cells. The irinotecan prodrug localization contrasted with SN-38 and was concentrated to the necrotic core of the spheroids, a region containing mostly dead and dying cells. These results demonstrate that this unique in vitro platform is an effective means to assess drug penetration and metabolism in 3D cell cultures. This innovative system can have a transformative impact on the preclinical evaluation of drug candidates due to its cost effectiveness and high throughput.
逼真的体外模型在药物研发过程中至关重要。在本研究中，采用了一种新型体外平台来评估药物渗透和代谢。该平台利用3D打印流体装置，可对三维细胞培养物（即球体）进行动态给药。用基质辅助激光解吸电离成像质谱（IMS）检测了化疗药物伊立替康进入HCT 116结肠癌细胞球体的渗透情况。还检测到了伊立替康的活性代谢物SN-38。处理24小时后，SN-38集中在球体外部，即活跃分裂细胞区域。伊立替康前药的定位与SN-38不同，集中在球体的坏死核心，该区域主要包含死亡和即将死亡的细胞。这些结果表明，这种独特的体外平台是评估三维细胞培养中药物渗透和代谢的有效手段。由于其成本效益和高通量，这种创新系统可能会对候选药物的临床前评估产生变革性影响。
