Polyphenol-Based Nanoscale Iron Exchangers for Regulating Anticancer Chemotherapy by Modulating the Activity of Intracellular Glutathione

The elevated glutathione (GSH) level in cancer cells contributes to the poor response to chemotherapy and necessitates the use of maximum tolerated drug doses, leading to myriad side effects. We have developed a biocompatible and fluorescently trackable nanosystem, iron(III)-bound nanocarbonaceous polyphenol (FeNCP), to modulate the available GSH pool in cancer cells for synergistic effects in treatments with a cytotoxic anticancer drug, doxorubicin (Dox). This nanosystem was designed using a nanoscale carbon system as a platform to generate a GSH-responsive gallic acid-iron complex. The effective interaction between FeNCP and GSH was probed in PBS (pH 7.4) and cell lysates using UV-Vis, fluorescence spectrophotometry, 1H NMR, flow cytometry, and confocal and transmission electron microscopic studies. The concurrent treatment of cancer cells with subcytotoxic FeNCP and Dox leads to dose reduction indices of Dox of similar to 6.1 for HepG2 (hepatocellular carcinoma) and 6.7 for B16F0 (melanoma) to kill similar to 50% of the cell population, which is suggestive of the requirement of a multifold lower dose of Dox. Notably, this combination was relatively more cytotoxic toward cancer cell lines than the model normal cell line, Vero. The increased reactive oxygen species levels in combinatorial treatment reveal that FeNCP serves as a potential candidate for modulating glutathione activity and potentiating cytotoxic effects of Dox. The intelligent multifold design of this nanosystem might enable the applicability in optical detection of GSH and imaging-assisted surgery in the future, in addition to the potential to advance treatment regimens in anticancer chemotherapy.