Yue Tao, Park Ki Ho, Reese Benjamin E, Zhu Hua, Lyon Seth, Ma Jianjie, Mohler Peter J, Zhang Mingjun
Department of Biomedical Engineering, The Ohio State University , Columbus, Ohio 43210, United States.
Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center , Columbus, Ohio 43210, United States.
Langmuir. 2016 Feb 23;32(7):1909-19. doi: 10.1021/acs.langmuir.5b04314. Epub 2016 Feb 5.
Contrary to the well-studied dynamics and mechanics at organ and tissue levels, there is still a lack of good understanding for single cell dynamics and mechanics. Single cell dynamics and mechanics may act as an interface to provide unique information reflecting activities at the organ and tissue levels. This research was aimed at quantifying doxorubicin- and dexrazoxane-induced nanomechanics and mechanical effects to single cardiomyocytes, to reveal the therapeutic effectiveness of drugs at the single cell level and to optimize drug administration for reducing cardiotoxicity. This work employed a nanoinstrumentation platform, including a digital holographic microscope combined with an atomic force microscope, which can characterize cell stiffness and beating dynamics in response to drug exposures in real time and obtain time-dose-dependent effects of cardiotoxicity and protection. Through this research, an acute increase and a delayed decrease of surface beating force induced by doxorubicin was characterized. Dexrazoxane treated cells maintained better beating force and mechanical functions than cells without any treatment, which demonstrated cardioprotective effects of dexrazoxane. In addition, combined drug effects were quantitatively evaluated following various drug administration protocols. Preadministration of dexrazoxane was demonstrated to have protective effects against doxorubicin, which could lead to better strategies for cardiotoxicity prevention and anticancer drug administration. This study concluded that quantification of nanomechanics and mechanical effects at the single cell level could offer unique insights of molecular mechanisms involved in cellular activities influencing organ and tissue level responses to drug exposure, providing a new opportunity for the development of effective and time-dose-dependent strategies of drug administration.
与在器官和组织水平上经过充分研究的动力学和力学不同，目前对单细胞动力学和力学仍缺乏深入了解。单细胞动力学和力学可能作为一个界面，提供反映器官和组织水平活动的独特信息。本研究旨在量化阿霉素和右丙亚胺对单个心肌细胞的纳米力学和力学效应，以揭示药物在单细胞水平的治疗效果，并优化药物给药以降低心脏毒性。这项工作采用了一个纳米仪器平台，包括一台数字全息显微镜与一台原子力显微镜相结合，它可以实时表征细胞刚度和对药物暴露的搏动动力学，并获得心脏毒性和保护作用的时间-剂量依赖性效应。通过这项研究，表征了阿霉素诱导的表面搏动力量的急性增加和延迟降低。与未处理的细胞相比，右丙亚胺处理的细胞保持了更好的搏动力量和力学功能，这证明了右丙亚胺的心脏保护作用。此外，还按照各种给药方案对联合药物效应进行了定量评估。已证明预先给予右丙亚胺对阿霉素有保护作用，这可能会带来更好的心脏毒性预防和抗癌药物给药策略。本研究得出结论，在单细胞水平上量化纳米力学和力学效应可以为参与细胞活动影响器官和组织水平对药物暴露反应的分子机制提供独特见解，为开发有效且时间-剂量依赖性的药物给药策略提供新机会。
