Shin Kyeonggon, Klosterhoff Brett S, Han Bumsoo
School of Mechanical Engineering, Purdue University , West Lafayette, Indiana 47907, United States.
Weldon School of Biomedical Engineering, Birck Nanotechnology Center, and Purdue Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
Mol Pharm. 2016 Jul 5;13(7):2214-23. doi: 10.1021/acs.molpharmaceut.6b00131. Epub 2016 Jun 10.
Heterogeneous response and resistance of cancer cells to chemotherapeutic drugs pose a significant challenge for successful cancer treatments. In this study, an integrated experimental and theoretical analysis of cellular drug transport was developed. The experimental platform, called tumor-microenvironment-on-chip (T-MOC), is a microfluidic platform where cancer cells were cultured within a three-dimensional extracellular matrix perfused with interstitial fluid. Three types of human breast cancer cell lines (MCF-7, MDA-MB-231, and SUM-159PT) were cultured on this T-MOC platform, and their drug response and resistance to doxorubicin were characterized by time-lapse quantitative fluorescence microscopy. To study the effects of nanoparticle-mediated drug delivery, the transport and action of doxorubicin encapsulated nanoparticles were also examined. Based on the experimental data obtained, a theoretical model was developed to quantify and ultimately predict the cellular transport processes of drugs cell-type specifically. The results demonstrate that the cellular drug transport can be cell-type-specifically quantified by rate constants representing the uptake and efflux of doxorubicin across the cellular membrane.
癌细胞对化疗药物的异质性反应和耐药性给癌症治疗的成功带来了重大挑战。在本研究中，开展了细胞药物转运的综合实验和理论分析。实验平台称为芯片上的肿瘤微环境（T-MOC），是一个微流控平台，癌细胞在灌注间质液的三维细胞外基质中培养。三种人类乳腺癌细胞系（MCF-7、MDA-MB-231和SUM-159PT）在该T-MOC平台上培养，并通过延时定量荧光显微镜对它们对阿霉素的药物反应和耐药性进行了表征。为了研究纳米颗粒介导的药物递送的效果，还检测了阿霉素包封纳米颗粒的转运和作用。基于获得的实验数据，建立了一个理论模型，以细胞类型特异性地量化并最终预测药物的细胞转运过程。结果表明，细胞药物转运可以通过代表阿霉素跨细胞膜摄取和流出的速率常数进行细胞类型特异性量化。
