Quantifying Drug-Induced Nanomechanics and Mechanical Effects to Single Cardiomyocytes for Optimal Drug Administration To Minimize Cardiotoxicity

摘要

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.