RESUMO
Cancer remains a leading health threat in the United States, and cardiovascular drug toxicity is a primary cause to eliminate a drug from FDA approval. As a result, the demand to develop new anticancer drugs without cardiovascular toxicity is high. Human induced pluripotent stem (iPS) cell-derived tissue chips provide potentially a cost-effective preclinical drug testing platform, including potential avenues for personalized medicine. We have developed a three-dimensional microfluidic device that simultaneously cultures tumor cell spheroids with iPS-derived cardiomyocytes (iPS-CMs) and iPS-derived endothelial cells (iPS-EC). The iPS-derived cells include a GCaMP6 fluorescence reporter to allow real-time imaging to monitor intracellular calcium transients. The multiple-chambered tissue chip features electrodes for pacing of the cardiac tissue to assess cardiomyocyte function such as the maximum capture rate and conduction velocity. We measured the inhibition concentration (IC50) of the anticancer drugs, Doxorubicin (0.1 µM) and Oxaliplatin (4.2 µM), on the tissue chip loaded with colon cancer cells (SW620). We simultaneously evaluated the cardiotoxicity of these anticancer drugs by assessing the drug effect on the spontaneous beat frequency and conduction velocity of iPS-derived cardiac tissue. Consistent with in vivo observations, Doxorubicin reduced the spontaneous beating rate and maximum capture rate at or near the IC50 (0.04 and 0.22 µM, respectively), whereas the toxicity of Oxaliplatin was only observed at concentrations beyond the IC50 (33 and 9.9 µM, respectively). Our platform demonstrates the feasibility to simultaneously assess cardiac toxicity and antitumor effects of drugs and could be used to enhance personalized drug testing safety and efficacy. Impact statement Drug development using murine models for preclinical testing is no longer adequate nor acceptable both financially for the pharmaceutical industry as well as for generalized or personalized assessment of safety and efficacy. Innovative solutions using human cells and tissues provide exciting new opportunities. In this study, we report on the creation of a 3D microfluidic device that simultaneously cultures human tumor cell spheroids with cardiomyocytes and endothelial cells derived from the same induced pluripotent stem cell line. The platform provides the opportunity to assess efficacy of anticancer agents while simultaneously screening for potential cardiovascular toxicity in a format conducive for personalized medicine.
