Calcium-chelated nanosystem reversing cancer chemoresistance via replenishing intracellular calcium ions

Chemoresistance is the major reason for the failure of chemotherapy, which is a major cause of death in patients with advanced cancer. However, the current approach to reversing cancer chemoresistance is limited. Calcium ions are indispensable for all physiological activities of the body. Because a calcium concentration was reduced in chemoresistant cancer cells, we fabricated calcium-chelated nanoparticles upon self-assembly to replenish intracellular calcium ions in the cells. Through employing an amphipathic polyethylene glycosylated (PEGy-lated) lipids covalent bonding chelator molecule to bind calcium ions, the chelate calcium ions are used for the first time to reverse the chemoresistance of cancer cells. This nanoparticle released calcium ions more rapidly in a weakly acidic environment than in neutral and weak base conditions, which ensures the effective release of calcium ions in the acidic microenvironment of tumors. As assessed by in vitro and in vivo experiments, this calcium-chelated nanoparticle indeed restored calcium homeostasis and reversed chemoresistance in a variety of chemoresistant cancer cells, whereas calcium chloride solution did not increase the concentration of calcium ions in chemoresistant cancer cells. Furthermore, the mechanism study showed that calcium-chelated nanoparticles affected the expression of chemoresistant genes and promoted cancer cell apoptosis by inhibiting the NF-kappa B signaling pathway. In conclusion, our data provide direct insight into an effective approach for the reversal of chemoresistance and calcium-chelated nanoparticles may have potential applications for treating chemoresistant patients.