Phenotypic drug profiling in droplet microfluidics for better targeting of drug-resistant tumors.
Phenotypic drug profiling in droplet microfluidics for better targeting of drug-resistant tumors.
复制标题
液滴微流体中的表型药物分析，以更好地靶向抗药性肿瘤。
DOI：
10.1039/c5lc00923e
复制
发表时间：
2015-12-07
期刊：
影响因子：
6.1
通讯作者：
Konry T
中科院分区：
文献类型：
--
作者：
Sarkar S;Cohen N;Sabhachandani P;Konry T
获得性耐药是导致化疗失败的关键因素。由于肿瘤内的异质性，癌细胞在单个细胞水平上表现出细胞内药物摄取和外排的差异，这在整体分析中可能无法检测到。在这项研究中，我们提出了一种基于液滴微流体的方法来评估药物在药物敏感和耐药的乳腺癌细胞中的摄取、外排和细胞毒性的动力学。利用集成的液滴生成和对接微阵列来包裹单个细胞以及同型细胞聚集体。与耐药细胞相比，药物敏感细胞在存在或不存在阿霉素(Dox)的情况下表现出更大的死亡。我们观察到个体药物敏感细胞对Dox的异质性摄取，而耐药细胞表现出一致的低摄取和滞留。DOX抗性细胞根据其外排特性被分成不同的亚群。显示细胞外试剂滞留时间较长的细胞也表现出最大的死亡。我们进一步观察到两种细胞类型在液滴中的同型融合，这导致了在高剂量Dox存在下细胞存活率增加。我们的结果建立了该微流控平台在单细胞和多细胞相互作用中定量药物筛选的适用性。
Acquired drug resistance is a key factor in the failure of chemotherapy. Due to intratumoral heterogeneity, cancer cells depict variations in intracellular drug uptake and efflux at the single cell level, which may not be detectable in bulk assays. In this study we present a droplet microfluidics-based approach to assess the dynamics of drug uptake, efflux and cytotoxicity in drug-sensitive and drug-resistant breast cancer cells. An integrated droplet generation and docking microarray was utilized to encapsulate single cells as well as homotypic cell aggregates. Drug-sensitive cells showed greater death in the presence or absence of Doxorubicin (Dox) compared to the drug-resistant cells. We observed heterogeneous Dox uptake in individual drug-sensitive cells while the drug-resistant cells showed uniformly low uptake and retention. Dox-resistant cells were classified into distinct subsets based on their efflux properties. Cells that showed longer retention of extracellular reagents also demonstrated maximal death. We further observed homotypic fusion of both cell types in droplets, which resulted in increased cell survival in the presence of high doses of Dox. Our results establish the applicability of this microfluidic platform for quantitative drug screening in single cells and multicellular interactions.