Chemotherapeutic response assessment in cancer cells using a microcavity array-based bioreactor system and sodium triple-quantum MR signal

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A low intracellular sodium concentration is of vital importance for cell viability. Chemotherapeutic response manifests itself in the induction of apoptosis and, thus, in the ionic reversal of intracellular sodium and potassium concentrations followed by apoptotic body formation. Sodium magnetic resonance (MR) as a non-invasive technique can be a potential biomarker for early treatment response assessment. Interactions of sodium ions with proteins create a unique intracellular sensitive triple-quantum (TQ) signal. This TQ signal correlated linearly with the intracellular sodium concentration in perfused hearts and, hence, represents an attractive feature to quantify cellular responses. The combination of TQ signal and bioreactor system featuring an organotypic 3D cell culture in a finely controllable environment allowed us to monitor changes in the intracellular sodium concentration of cancer cells during two Na/K-ATPase inhibitions. Therefore, we propose the sodium TQ signal as a biomarker for early treatment response assessment due to its unique intracellular sensitivity and the importance of intracellular sodium changes during apoptosis. To establish this, we will monitor the chemotherapeutic treatment of organotypic 3D cell cultures using an improved setup of sodium TQ signal and bioreactor system. Further improvements of our proposed fixed TQ time proportional phase incrementation (TQTPPI) pulse sequence will enable us quantitative and fast TQ measurements with the highest possible TQ signal-to-noise ratio. Therefore, we will evaluate a novel reconstruction technique of TQTPPI data combined with incoherent undersampling techniques. Extension of the established bioreactor system by a method for the determination of the intracellular sodium concentration per cell will deepen our understanding of TQ signal changes on a cellular level during chemotherapeutic treatment. In addition, we will verify the linear correlation of TQ signal with intracellular sodium concentration during various Na/K-ATPase inhibitions to quantify cellular responses during chemotherapeutic treatment using the TQ signal. Finally, we will monitor the chemotherapeutic response of the well-characterized rat 9L gliosarcoma cell line to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment using the improved setup of the TQ signal and bioreactor system. The effects of BCNU treatment of rat 9L cells on intracellular sodium concentration and single-quantum MR signal are well known. Hence, the TQ signal can be established as a biomarker for early treatment response assessment. Furthermore, the rat 9L cell line and BCNU treatment will allow us in future studies to investigate the vital importance of a low intracellular sodium concentration on chemotherapeutic resistance using TQ signal. The long-term goal of our work is to establish the combination of TQ signal and bioreactor system as a novel tool for anticancer drug development in a translational approach.