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Calcium-chelated nanosystem reversing cancer chemoresistance via replenishing intracellular calcium ions
Chemical Engineering Journal ( IF 13.3 ) Pub Date : 2022-06-13 , DOI: 10.1016/j.cej.2022.137500
Chenglong Wang , Xiaolin Xu , Shuhan Xiong , Peipei Zhang , Jia Yuan , Xuzhu Gao , Wencai Guan , Fanchen Wang , Xin Li , Tao Leng , Hongjing Dou , Guoxiong Xu

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 (PEGylated) 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-κB 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.



中文翻译:

钙螯合纳米系统通过补充细胞内钙离子逆转癌症化疗耐药

化疗耐药是导致化疗失败的主要原因,而化疗失败是晚期癌症患者死亡的主要原因。然而,目前逆转癌症化学抗性的方法是有限的。钙离子对于身体的所有生理活动都是不可缺少的。由于化学抗性癌细胞中钙浓度降低,我们在自组装后制造了钙螯合纳米颗粒以补充细胞中的细胞内钙离子。通过采用两亲性聚乙二醇化(PEGylated)脂质共价键合螯合剂分子结合钙离子,首次利用螯合钙离子逆转癌细胞的耐药性。这种纳米颗粒在弱酸性环境中比在中性和弱碱条件下更快地释放钙离子,保证了肿瘤酸性微环境中钙离子的有效释放。经评估在体外体内实验中,这种钙螯合纳米颗粒确实恢复了多种化学抗性癌细胞中的钙稳态并逆转了化学抗性,而氯化钙溶液并未增加化学抗性癌细胞中钙离子的浓度。此外,机制研究表明,钙螯合纳米颗粒通过抑制NF-κB信号通路影响化疗耐药基因的表达,促进癌细胞凋亡。总之,我们的数据提供了对逆转化学抗性的有效方法的直接见解,钙螯合纳米粒子可能具有治疗化学抗性患者的潜在应用。

更新日期:2022-06-14
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